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University Medical Center Groningen

PhD Ceremonies and Inaugural Lectures

Ms. M.F. Luxwolda: Omega-3 fatty acids and vitamin D in traditionally living east-African populations. Lessons from evolution for a healthy lifestyle

When:We 02-01-2013 at 16:15

PhD ceremony: Ms. M.F. Luxwolda, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Omega-3 fatty acids and vitamin D in traditionally living east-African populations. Lessons from evolution for a healthy lifestyle

Promotor(s): prof. F.A.J. Muskiet

Faculty: Medical Sciences

Current dietary recommendations are “Evidence Based.” They derive from research conducted in Western populations. This thesis highlights the subjectivity of these recommendations for two nutrients: the fish oil fatty acid DHA and vitamin D. We investigated African tribes in Tanzania, with lifestyles similar to those of our Paleolithic ancestors (2.5 million to 10.000 years ago). The mostly traditionally living populations that we investigated do not suffer from the typical Western diseases of affluence. It appears that their DHA and vitamin D levels were much higher than currently recommended in Western countries.

A high DHA level is associated with a low risk of psychiatric and cardiovascular diseases. A high milk-DHA might have beneficial effects on the neurological development of the newborn. The current recommendation for DHA intake in Western adults is 250-450 mg/day. Infant formula should contain 0.2-0.4 g% DHA. Tanzanian lactating women with daily fish intakes have a DHA of 8 g% and a milk-DHA of 1.0 g%. A low vitamin D [25(OH)D] is associated with many diseases of affluence. The current recommendation for 25(OH)D by the Dutch Health Council is ³ 30 nmol/L (<70 years) and ³ 50 nmol/L ( ³ 70 years). The mean 25(OH)D in healthy Dutch adults is 60 nmol/L. However, in the Tanzanian tribes we found 115 nmol/L, which increased with 25-60% during pregnancy. Due to the currently reigning, reductionist paradigm of “Evidence Based Nutrition” with single nutrients, we seriously question the way in which current dietary recommendations are developed.

Ms. R. Sinha: Adjustments to amputation and artificial limb, and quality of life in lower limb amputees

When:Mo 07-01-2013 at 14:30

PhD ceremony: Ms. R. Sinha, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Adjustments to amputation and artificial limb, and quality of life in lower limb amputees

Promotor(s): prof. W.J.A. van den Heuvel, prof. P. Arokiasamy

Faculty: Medical Sciences

Limb amputation has a major impact, not only in a distorted body image, but it also affects the individual’s social and psychological functioning. Prosthesis is the only means by which these people can be independent, participate in society, and resume their work. Various factors influence the use of prosthesis by amputees and also in turn affect their quality of life (QoL). In this research we found that studies pertaining to QoL in amputees are limited in methodological study design and in presentation of descriptive characteristics of the study population. Being younger and employed, daily use of prosthesis and non-use of an assistive device have a positive influence on the adjustments to amputation and prosthesis. Furthermore, the presence of comorbidity, and residual stump and phantom limb pain, negatively affect QoL. Appropriate vocational rehabilitation can help in improving the employment opportunities among young amputees. Lastly, probable causes of rejection and non-use of prosthesis, as well as the choice of assistive devices over prosthesis should be studied.

Mr. D. Halenahally Veeregowda: Lubrication by salivary conditioning films

When:Mo 07-01-2013 at 16:15

PhD ceremony: Mr. D. Halenahally Veeregowda, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Lubrication by salivary conditioning films

Promotor(s): prof. H.J. Busscher, prof. H.C. van der Mei, prof. A. Vissink

Faculty: Medical Sciences

This thesis emphasizes the advantages of using the oral cavity as a model system for biolubrication studies. Also, we highlight the role of biolubrication in tactile perception which can be of benefit for consumer based design of oral health care products. In the end, we provide details regarding naturally occurring SCFs lubricous architectures which can be important for biomimetic lubrication research to develop artificial lubricants that can provide better wetting of oral surfaces, reducing the sensation of pain due to oral dryness and improving the oral function like chewing, swallowing and speech.

Ms. E.G. Gerrits: Cardiovascular risk and its determinants in high risk patients

When:We 09-01-2013 at 11:00

PhD ceremony: Ms. E.G. Gerrits, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Cardiovascular risk and its determinants in high risk patients

Promotor(s): prof. H.J.G. Bilo, prof. R.O.B. Gans

Faculty: Medical Sciences

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Ms. K. Boyen: Tinnitus. An MRI study on brain mechanisms

When:We 09-01-2013 at 12:45
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PhD ceremony: Ms. K. Boyen, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Tinnitus. An MRI study on brain mechanisms

Promotor(s): prof. P. van Dijk

Faculty: Medical Sciences

Tinnitus. An MRI study on brain mechanisms

Tinnitus, or ‘ringing in the ears’, is the percept of a sound that is only heard by the patient. It is often associated with hearing loss. In this thesis, a number of studies investigated the human brain in tinnitus patients by means of structural and functional Magnetic Resonance Imaging (MRI).

A voxel-based morphometry approach was used to compare gray matter in a hearing-impaired group of subjects suffering from tinnitus to a hearing-impaired control group. Tinnitus was associated with gray matter increases in the left primary auditory cortex and several areas belonging to the limbic lobe. Comparing the same groups revealed that tinnitus is accompanied by a significantly decreased functional correlation between the auditory cortex and inferior colliculus as compared to the hearing-impaired controls. Many patients are able to modulate their tinnitus by both movements and pressure applied to the head, neck and face. The results of previous brain imaging studies show that modulated tinnitus corresponds to an increased level of activity throughout the central auditory system. We explored the relation between the loudness of modulated tinnitus due to eye movements and brain activity. An increase in loudness corresponded to an increase of activity in the auditory cortex, inferior colliculus and cochlear nucleus, but not in the medial geniculate body. Both the latter result as the weaker functional connection may be interpreted as an abnormal functioning of the thalamus in tinnitus patients.

Mr. J.A.J. Moonen: Endothelial plasticity: shaping health and disease

When:We 09-01-2013 at 16:15

PhD ceremony: Mr. J.A.J. Moonen, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Endothelial plasticity: shaping health and disease

Promotor(s): prof. M.J.A. van Luyn

Faculty: Medical Sciences

It is well established that endothelial cells (EC) play a crucial role in vascular physiology. Originally regarded as a passive barrier, the endothelium has become appreciated as a complex tissue with multiple functions and critical for shaping health. This requires a high degree of adaptation and plasticity. Adverse stimuli such as pro-fibrotic and pro-inflammatory cytokines or reactive oxygen species, induce endothelial injury and dysfunction. When persistent, this dysfunction can result in endothelial-to-mesenchymal transition (EndMT) which contributes to fibro-proliferative disease. Hence, EC plasticity can also shape disease.

In this thesis we investigated how local environmental cues dictate endothelial plasticity. We have shown that chronic inflammatory disease impacts endothelial progenitor cell (EPC) biology, through reducing their circulating numbers and by impairing their function. Both mature EC and EPC were shown to be highly plastic in vitro, as evidenced by their capacities to undergo TGF-beta-driven EndMT. Also we have shown how biochemical stimuli, i.e., pro-fibrotic and pro-inflammatory cytokines, can act in synergy in induction of EndMT. And finally, how hemodynamic forces modulate EndMT both through inhibition, and stimulation of this process. Our findings provide insights in the regulation of EndMT in vivo, and its potential involvement in disease. Most importantly, our studies have shown that EC retain a remarkable plasticity during adult life. These insights open new horizons for vascular regenerative medicine and challenge current dogmas on the pathophysiology of fibro-proliferative vascular disease.

Inaugural lecture Mr. prof. M.F. Reneman: Pijnrevalidatie werkt

When:Tu 15-01-2013 at 16:15

Inaugural lecture: Mr. prof. M.F. Reneman, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Pijnrevalidatie werkt

Chair: Revalidatiegeneeskunde, i.h.b. pijnrevalidatie en arbeidsparticipatie

Faculty: Medical Sciences

Ms. P.P. Landburg: ADMA, angiogenesis and clinical complications in sickle cell disease

When:We 16-01-2013 at 11:00

PhD ceremony: Ms. P.P. Landburg, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: ADMA, angiogenesis and clinical complications in sickle cell disease

Promotor(s): prof. A.J. Duits

Faculty: Medical Sciences

Sickle cell disease (SCD) is worldwide one of the most common inheritable diseases. Originally the disease was seen in Africa, Saudi-Arabia, India and Mediterranean countries. Due to immigration from Surinam, the Caribbean and Africa the prevalence of SCD is increasing in the Netherlands. Sickle hemoglobin is caused by a single point mutation in the β-globin gene which forms polymers when in deoxygenated state. SCD is characterized by chronic hemolysis, increased susceptibility for infections (due to functional asplenia) and complications such as vaso-occlusive pain crises, pulmonary hypertension and stroke. Organ damage in SCD has a multifactorial origin, in which hemolysis, hypoxia and angiogenesis play an important role. Angiogenesis and the process of vacular remodelling contribute to the morbidity in SCD. Hemolysis and hypoxia result in a characteristic decreased nitric oxide (NO) bioavailability.

In this thesis the roles of angiogenesis and specific factors influencing the bioavailability of NO in SCD and related complications are described. We did not find a relation between the altered angiogenic factor concentrations and the formation of SCD-related complications which does not exclude a role for angiogenic factors in the development of SCD-related complications. Our findings merely point out the complexity of the angiogenic response and pathophysiology of SCD. NO plays a central role in the vascular homeostasis and we showed that asymmetric dimethylarginine (ADMA) contributes to a reduction of NO bioavailability during the clinical asymptomatic state en possibly plays an important role in the development of SCD-related pulmonary hypertension.

Ms. N.D. Moes: Autoimmune enteropathy. Clinical and molecular aspects

When:We 16-01-2013 at 14:30

PhD ceremony: Ms. N.D. Moes, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Autoimmune enteropathy. Clinical and molecular aspects

Promotor(s): prof. E.H.H.M. Rings, prof. F.M. Ruemmele

Faculty: Medical Sciences

Autoimmune enteropathy (AIE) is a rare cause of immunologically mediated chronic diarrhea in childhood. Characteristic of the disorder are circulating autoantibodies and destruction of the intestinal wall. Besides affecting the bowel, the disease comprises other manifestations of autoimmunity, such as diabetes mellitus, autoimmune thyreoïdia and autoimmune anemia or thrombocytopenia. AIE is a severe disease, often leading to mortality at a young age. More clarity about the pathophysiology of AIE is important for a better diagnosis and defining targeted therapeutic options. Also, more knowledge of the pathophysiology of AIE and intestinal regulatory T-cell (Treg)-function provides important information on normal immune function of the intestine.

This thesis focuses on the understanding of the disease by investigating its molecular background. The studies show that Treg-dysfunction is very important in the pathophysiology of AIE, but the results also suggest that it is not the only disease causing mechanism. In some patients a mutation in the FOXP3-gene is present, in others the cause is unclear. Our findings support the hypothesis that environmental factors can affect Treg-function. This has important implications for the ways in which these cells work and creates new opportunities for therapeutic interventions. We describe a large variety in the clinical presentation of AIE, which implies that the disease should be considered in a much larger number of patients. Finally, we examined the current immunosuppressive treatment in this disease, presenting molecular evidence for the efficacy of sirolimus.

PhD ceremony Mr. M.J.H. Aries: Cerebral hemodynamics in stroke and traumatic brain injury. The interplay between blood pressure, cerebral perfusion, body position and autoregulation

When:Mo 21-01-2013 at 16:15

PhD ceremony: Mr. M.J.H. Aries, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Cerebral hemodynamics in stroke and traumatic brain injury. The interplay between blood pressure, cerebral perfusion, body position and autoregulation

Promotor(s): prof. H.P.H. Kremer, prof. J.H.A. de Keyser

Faculty: Medical Sciences

Following an acute ischemic stroke, patients are admitted to a special hospital ward to monitor and treat circulatory and respiratory disturbances. Quick upright care or out of bed mobilisation might be beneficial to recover from stroke, but there are indications that this position compromises cerebral blood flow in vulnerable brain tissue. In this study we found that during upright positioning the blood pressure increased in these patients. This phenomenon was mainly observed on day 1 after acute stroke. Noteworthy, patients who had a significant rise in blood pressure upon standing (> 20%) appeared to have a better recovery after three months. In a group of 50 stroke patients ‘upright sitting’ was studied in detail. First, disability did not increase with postural changes. Second, continuous blood pressure and ultrasound measurements in the large cerebral vessels together with near-infrared measurements of the anterior brain regions showed no differences between acute stroke patients and healthy subjects. We found no evidence that the sitting position in mildly to moderately affected stroke patients is unsafe during the first three days in the ward. In a large study using a new mathematical method to estimate cerebral blood flow regulation based on continuous ‘pressure inside the skull’ (intracranial pressure) and blood pressure measurements, we demonstrated that intensive monitoring is also important for patients with significantly swollen or bruised brains after a serious accident (severe traumatic brain injury).

PhD-ceremony Ms. S.D. Soechitram: Polychlorinated and hydroxypolychlorinated biphenyls. Influence on child neurological and endocrine development

When:We 23-01-2013 at 12:45

PhD-ceremony: Ms. S.D. Soechitram, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Polychlorinated and hydroxypolychlorinated biphenyls. Influence on child neurological and endocrine development

Promotor(s): prof. P.J.J. Sauer

Faculty: Medical Sciences

PCBs and dioxins are persistent to environmental (chemical or biological) degradation and accumulate in the food chain because of their lipophylic nature and stability. Developmental effects on neurobehavioral, reproductive and endocrine parameters were observed in experiments in animals, in background and accidentally exposed human infants after in utero and lactational exposure to PCBs and dioxins. More recently, concerns raised about the degradation products of PCBs, the hydroxylated PCBs. In this Renco study we measured the levels and effects of PCBs and OH-PCBs on neurological and endocrine development in newborns till the age of 18 months. OH-PCBs cross the placenta more easily than PCBs because of their water solubility and binding to TTR. PCBs however influence T3/rT3 ratio negatively which resemble inhibition of type III deiodinase activity (D3). D3 is predominantly found in placenta en fetal brain. This might suggest that PCBs and OH-PCBs can also have a negative effect on neurological outcome (negative effects on motor optimality scores were measured). Brain development depends on appropriate levels of thyroid hormones during critical developmental periods. With the present background levels of PCBs and OH-PCBs no negative correlations was found in testicular volume at 3 and 18 months. Although these endocrine disruptors are banned for several years and decreased over a ten years period in one geographical area in the Netherlands, we can still detect these pollutants in pregnant mothers and their infants. Efforts to decrease the contamination of this planet by manmade compounds, which might have negative effects on humans, therefore remains of great importance.

PhD ceremony Mr. J.H. Kedde: Sexual health of people with disability and chronic illness

When:We 23-01-2013 at 14:30

PhD ceremony: Mr. J.H. Kedde, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Sexual health of people with disability and chronic illness

Promotor(s): prof. H.B.M. van de Wiel, prof. W.C.M. Weijmar Schultz

Faculty: Medical Sciences

Previous studies have shown that sexual health problems are more prevalent among people with physical disabilities and chronic diseases than among able-bodied people. However, several important knowledge gaps remain. In general these questions concern the factors that are associated with the sexual well-being of people with physical disabilities and chronic diseases, as well as the factors that are associated with help-seeking behaviour, and the efficacy of psychosexual therapy. Young women with breast cancer are a case in point. In this dissertation, two studies provide insight into their sexual health problems, especially with regard to the rehabilitation period, as well as associated treatment methods, and treatment-related disturbances and side effects.

The results show that health care professionals are not adequately dealing with sexual problems so that people with a disease or disability experience their needs are appropriately met. Only a third of the contacts are evaluated positively. We found that a short-term psychosexual intervention by sexologists can be of great value; it has a positive effect on clients’ overall sexual health. In the wake of breast cancer, women seem to resume their sexual lives but have trouble enjoying sex. Sexual dysfunctions also remain highly prevalent among young women with breast cancer after treatment. Therefore, resuming one’s sexual life after breast cancer is a difficult and time-consuming process.

PhD ceremony Ms. E.M. Kingma: Intelligence and functional somatic symptoms and syndromes

When:We 23-01-2013 at 16:15

PhD ceremony: Ms. E.M. Kingma, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Intelligence and functional somatic symptoms and syndromes

Promotor(s): prof. J.G.M. Rosmalen, prof. J. Ormel, prof. P. de Jonge

Faculty: Medical Sciences

Functional somatic symptoms (FSS) cannot be conclusively explained in terms of conventionally defined organic pathology. The still poorly understood etiology urges the need for research on factors that are associated with the development of FSS. We hypothesized that one of the factors contributing to the etiology of FSS might be low intelligence. Lower intelligence predicted FSS over the life course and in different types of populations, indicating a robust relationship between lower intelligence and FSS. Thus, people with lower intelligence have on average higher numbers of FSS than people with higher intelligence.

Different pathways for the link between intelligence and FSS were studied. Plausible pathways indicate a role for low socioeconomic status and psychosocial stress, but the nature of these pathways seems to differ over the life course. In early life, adolescents with lower intelligence are especially at risk for FSS when perceived academic expectations are high. However, this effect from high academic expectations does not seem to extend into adulthood. In adulthood, an unfavorable work situation might be a possible mediator in the association between intelligence and FSS. Adults with lower intelligence are more often unwillingly unemployed, which could predispose them to develop FSS. The role of intelligence in health deserves further study, especially with regard to the mechanisms responsible for the association between intelligence and FSS.

PhD ceremony Mr. H.R. Bouma: Immunological aspects of hibernation as leads in the prevention of acute organ injury

When:Mo 28-01-2013 at 16:15

PhD ceremony: Mr. H.R. Bouma, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Immunological aspects of hibernation as leads in the prevention of acute organ injury

Promotor(s): prof. R.H. Henning, prof. F.G.M. Kroese

Faculty: Medical Sciences

Mammalian hibernation consists of periods of low body temperature (~4°C; “torpor”), interspersed by euthermic periods, without signs of organ injury. We explored the modulation of the immune system during natural and pharmacological induced torpor, with the ultimate aim to exploit such mechanisms to limit organ injury in the clinical setting. In a retrospective study of patients that underwent cardiac surgery employing cardiopulmonary bypass (CPB), and an animal model of CPB, we revealed hypothermia and inflammation as important players in the etiology of renal injury following CPB. Therefore, we studied which mechanisms might underlie the protection of organ injury during hibernation. One such a mechanism might be the reversible clearance of circulating leukocytes during torpor. Neutropenia during torpor is probably due to margination of neutrophils induced by low temperature, while lymphopenia is secondary to reduced egress of lymphocytes from secondary lymphoid organs due to a decreased plasma level of Sphingosine-1-phosphate. Although the number of lymphocytes restores upon arousal, the function of the immune system remains suppressed, leading to a reduced capacity to induce a humoral immune response during hibernation. To assess whether similar changes could be induced pharmacologically, we tested such a strategy using 5’-AMP in mice and demonstrated that 5’-AMP administration in mice leads to a reversible reduction in the body temperature and temperature-independent retention of lymphocytes. Pharmacologic induction of a torpor-like state with increased resistance to hypothermia and a reduced immune function may be of therapeutic use to improve outcome following CPB.

PhD ceremony Ms I. Tsiligianni: Measurement of health status in COPD in daily clinical practice

When:We 30-01-2013 at 12:45

PhD ceremony: Ms I. Tsiligianni, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Measurement of health status in COPD in daily clinical practice

Promotor(s): prof. T. van der Molen

Faculty: Medical Sciences

COPD patients often experience impairments in their quality of life (QoL) and/or other health status aspects. A major goal in COPD management is to ensure that patients reach the best possible quality of life and health status. This thesis emphasizes health status measurement in COPD patients in daily clinical practice and evaluates available health status tools to support clinicians in choosing the optimal tool. Lung function has been traditionally considered as crucial in disease classification and decision making in COPD management. This thesis revealed dyspnea, depression, anxiety and exercise tolerance, and not lung function, as the most important factors that influence QoL in COPD, indicating the need for their evaluation in daily clinical practice. Moreover, results from a combined database (from three European countries) confirmed that lung function does not reflect health status. A systematic review of the available tools for assessing health status in primary care showed that the Clinical COPD Questionnaire (CCQ) was the best tool, followed by the COPD Assessment Tool (CAT). Subsequently, a study comparing CCQ and CAT showed similar psychometric properties with a slight advantage for CCQ mainly in terms of patient preferences. In summary, the CCQ is a valuable tool in assessing COPD health status and should be included in daily clinical practice. Finally, a first attempt was made to incorporate a telehealth integrated COPD service in Greece. A study to evaluate the feasibility of an adapted version of the asthma and COPD service model from Groningen (the Netherlands) is proposed.

PhD ceremony Ms. E.A.P. de Jong-Pleij: Ultrasonography of the fetal face in the second and third trimester of pregnancy

When:We 30-01-2013 at 14:30

PhD ceremony: Ms. E.A.P. de Jong-Pleij, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Ultrasonography of the fetal face in the second and third trimester of pregnancy

Promotor(s): prof. C.M. Bilardo

Faculty: Medical Sciences

The fetal face contains a lot of information. In addition to clear anomalies with clinical relevance that can be visualised in the face, dysmorphic traits can also serve as clues to diagnose syndromes. De Jong-Pleij evaluated several aspects of three-dimensional (3D) ultrasonography for the evaluation of the fetal face. The first section of the study compared 3D multiplanar ultrasound with two-dimensional (2D) ultrasound. It appears that with 3D ultrasound the profile is more accurately displayed, thereby improving the reproducibility and measurability of structures. De Jong-Pleij introduced two objective measures to assess the profile: the maxilla-nasion-mandible angle and the profile line. Subsequently, the impact of 3D ultrasonography on three facial markers (nasal bone length (NBL), prenasal thickness (PT) and frontomaxillary facial (FMF) angle) for trisomy 21 was evaluated. In stored volumes NBL and PT were easy to measure, while the measurement of the FMF angle was much more challenging. NBL measurements were systematically smaller than in 2D ultrasound-based publications. De Jong-Pleij introduced the NBL / PT ratio which proved to be a highly sensitive marker for trisomy 21. Finally, it was shown that there was a positive effect of seeing 3D images of the fetal face on the mother-fetus bonding. Surprisingly, this effect was not significantly higher than after seeing 2D images. It is reassuring that the mothers who did not consider the 3D imaging as a positive experience, showed no measurable adverse effect on the maternal-fetal bonding.

PhD ceremony Ms. E. Piek: Depression in general practice. Underrecognition? Overtreatment? Adequate care!

When:Mo 04-02-2013 at 14:30

PhD ceremony: Ms. E. Piek, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Depression in general practice. Underrecognition? Overtreatment? Adequate care!

Promotor(s): prof. K. van der Meer, prof. W.A. Nolen

Faculty: Medical Sciences

The results presented in this thesis give an optimistic picture of the current care for depressed patients in primary care as compared to previous literature and media reports. We conclude that, in general, the care for depressed patients in primary care is mostly adequate, i.e., in accordance with ruling guideline recommendations.

The general practitioners (GPs) recognized over two-thirds of depressed patients. Patients who discuss psychological problems with their GPs, those with more depressive symptoms and with a concurrent anxiety disorder, were better recognized. Patients presenting with the atypical symptom increased appetite were less recognized. 58% of depressed patients were referred to psychological or psychiatric care. In making referrals, GPs took guideline recommendations into account; patients with preference for psychotherapy, chronic depression or suicidal tendency were referred more often. Antidepressants were also prescribed according to guideline recommendations. Only 5.4% of the patients taking antidepressants were classified in terms of overtreatment. Furthermore, more than half of these patients started antidepressants for a good reason, but were treated too long, according to guideline recommendations. From a literature review we conclude that guideline recommendations for antidepressant treatment are thoroughly based in evidence for acute treatment and relapse prevention during several months, but not for maintenance treatment. Recommendations for maintenance treatment are also less often followed. Patients taking antidepressants for maintenance are not, as the guideline prescribes, patients with chronic or recurrent depression. It does seem, however, that maintenance antidepressant users are those with a worse prognosis such as patients with comorbid dysthymia or anxiety, and patients also receiving sedatives or patients with recent psychiatric contacts.

Inaugural lecture Mr. prof. R.P. Coppes: Sparen voor later

When:Tu 05-02-2013 at 16:15

Inaugural lecture: Mr. prof. R.P. Coppes, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Sparen voor later

Chair: Radiotherapie, i.h.b. radiobiologie van schade aan normale weefsels

Faculty: Medical Sciences

PhD ceremony Ms. M.L. de Groote: Potentials and pitfalls of epigenetic editing in the gene specific re-expression of epigenetically silenced genes

When:We 06-02-2013 at 14:30

PhD ceremony: Ms. M.L. de Groote, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Potentials and pitfalls of epigenetic editing in the gene specific re-expression of epigenetically silenced genes

Promotor(s): prof. M.G. Rots

Faculty: Medical Sciences

During the research described in this thesis, a start was made with permanently altering gene expression through addition or removal of epigenetic modifications (Epigenetic Editing) to ultimately induce expression of epigenetically silenced genes such as tumor suppressor genes. To reach this goal, fusion proteins were used: gene-specific DNA binding domains fused to proteins that can add or remove epigenetic marks (epigenetic enzymes). A growing number of diseases, in addition to cancer, is associated with epigenetic changes. Epigenetic marks are inheritable modifications to the DNA or the histones that determine gene expression levels and because they are reversible, aberrant mistakes can be repaired. Moreover, as epigenetic marks are heritable, Epigenetic Editing is an interesting new therapeutic approach. Also, this way of gene expression regulation could lead to new fundamental insights. In this thesis, two tumor suppressor genes are described that are epigenetically silenced in cancer cells and to which epigenetic editing could be applied. Also, it is shown that specifically the expression of these genes can be regulated in the endogenous situation using zinc fingers fused to transcription regulating proteins. As a consequence, even a reduction in tumor cell growth was observed. Furthermore, upon targeting certain epigenetic enzymes to a predetermined site, an increased accessibility of the DNA was observed. Further research is needed to study which epigenetic enzyme(s) can be used for expression regulation of specific endogenous genes to achieve a lasting effect.

PhD ceremony Ms. E.J. Liemburg: Prefrontal networks in schizophrenia. Insights from neuroimaging

When:We 06-02-2013 at 16:15

PhD ceremony: Ms. E.J. Liemburg, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Prefrontal networks in schizophrenia. Insights from neuroimaging

Promotor(s): prof. A. Aleman

Faculty: Medical Sciences

The prefrontal cortex has an important leading role in brain function. It integrates incoming information and plans behavior. The prefrontal cortex operates within brain networks, as information is collected from all parts of the brain, and newly planned behavior is redirected to all parts of the brain. Different brain networks exist, which show slow fluctuations in fMRI signal during resting state. These fluctuations possibly represent intrinsic neural activity that is related to cognitive functions.

Dysfunction of the prefrontal networks may lead to disorders in which cognitive functions are impaired, such as schizophrenia. This thesis investigates different cognitive functions in relation to prefrontal network function in patients with schizophrenia. Prefrontal language networks indeed show altered function in schizophrenia patients. Moreover, patients with poor insight in their disease, and healthy persons with impaired emotion processing capacities, show decreased connectivity in a network involved in self-processing.

Specific focus is also given to negative symptoms which may originate from impaired prefrontal function. Findings in this thesis suggest that prefrontal activation increases following treatment with newer antipsychotics, but symptoms may not improve concurrently. Moreover, negative symptoms may consist of different subgroups, and only specific symptoms may improve from treatment. These findings may encourage research on better symptom definitions, which in turn could act as a starting point for neuroimaging research and development of novel treatment options.

PhD ceremony Mr. K.P. Rembacz: The functional relationship between peroxisomes, bile salts and lipid rafts in the liver

When:Mo 11-02-2013 at 11:00

PhD ceremony: Mr. K.P. Rembacz, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The functional relationship between peroxisomes, bile salts and lipid rafts in the liver

Promotor(s): prof. K.N. Faber, prof. H. Moshage

Faculty: Medical Sciences

The liver produces bile that solubilizes fatty compounds so that dietary fats can be absorbed in the intestinal tract and toxins and waste products are excreted with the faeces. The functional compounds in bile are bile acids. They are synthesized in the liver and after performing their function in the small intestine are absorbed in the terminal ileum and transported via the blood back to the liver. Bile acids may shuttle over 20 times between the liver and the ileum, before they escape intestinal absorption and are lost in the faeces. Liver and intestinal cells contain specific proteins in their cellular membranes that are responsible for the unidirectional transport of bile acids. Impaired bile acid transport leads to liver damage. Intestinal bacteria modify bile acids, e.g., remove their amino acid (glycine or taurine) side chain, which has to be corrected in the liver.

In this thesis we show that this reconjugation of bile acids with glycine or taurine takes place in a small organelle in liver cells, the peroxisomes. This implies that bile acid transport between liver and intestine also includes shuttling in and out peroxisomes in liver cells and is crucial to maintain functional bile. We show that a peroxisomal membrane protein, PMP70, is required for efficient bile acid reconjugation and transport, and that PMP70 exists in cholesterol-containing lipid microdomains, like other bile acid transporters. Peroxisomal lipid rafts were not detected in human peroxisomes before, but we found that they are essential for the formation of this organelle.

PhD ceremony Ms. L. Krishnappa: Proteolysis of extracytoplasmic proteins in Bacillus subtilis

When:Mo 11-02-2013 at 14:30

PhD ceremony: Ms. L. Krishnappa, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Proteolysis of extracytoplasmic proteins in Bacillus subtilis

Promotor(s): prof. J.M. van Dijl

Faculty: Medical Sciences

All living organisms have a limited lifespan and this is also true for their individual components. This thesis describes how proteolytic enzymes determine the 'life and death' of proteins that bacteria export from their site of synthesis - the cytoplasm - to the cytoplasmic membrane, the cell wall and the extracellular environment. For this purpose, the Gram-positive bacterium B. subtilis, a well-known 'cell factory' for secreted enzymes of high commercial value, was used as a model organism. Importantly, B. subtilis produces at least ten major extracytoplasmic proteases. Two of these are located in the membrane, one is located in the cell wall, and seven others are secreted into the extracellular milieu. Previous studies showed that several extracytoplasmic proteases set limits to the biotechnological use of B. subtilis, but it was not known to what extent these proteases degrade the bacterium's own proteins. Remarkably, the present investigations show that proteins in the membrane, cell wall and extracellular milieu are subject to extensive proteolysis. Unexpectedly, several proteases also attack components of the protein secretion machinery of B. subtilis, and this explains at least in part why multiple protease mutant cells have a generally improved capacity for protein secretion. On the other hand, several extracytoplasmic proteins seem to require certain proteases for their stable production. This is consistent with the view that some of the investigated proteases have important quality control functions. Altogether, these novel insights lay the foundation for the construction of next-generation super-secreting bacterial cell factories.

PhD ceremony Ms. Z. Metting: Advanced neuroimaging in mild traumatic brain injury

When:Mo 11-02-2013 at 16:15

PhD ceremony: Ms. Z. Metting, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Advanced neuroimaging in mild traumatic brain injury

Promotor(s): prof. H.P.H. Kremer

Faculty: Medical Sciences

T raumatic brain injury (TBI) is one of the most common neurological diseases and an important cause of disability and death in young adults. The majority (80-90%) sustains mild TBI. Most patients recover within weeks to months although a subgroup experiences disabling symptoms that interfere with their return to work or resumption of social activities.

One of the first and most commonly used imaging techniques in the acute phase of TBI is non-contrast computed tomography (CT). It is the most relevant imaging procedure for the detection of lesions eligible for surgical intervention. However, approximately 20% of the patients with mild TBI without abnormalities on the non-contrast CT, experience problems with work resumption. Perfusion CT is a relatively new imaging method that enables visualisation and quantification of cerebral perfusion. The purpose of this study was to provide additional prognostic factors for patients who sustained mild TBI, especially in those with normal conventional CT imaging, and to elucidate the underlying pathophysiological processes. In addition, the relation between acute phase perfusion CT imaging and diffusion tensor imaging (DTI) with neuropsychological testing in the chronic phase after injury is outlined. The study revealed cerebral perfusion changes in the acute phase after mild TBI in those with a normal conventional CT. These cerebral perfusion abnormalities, in the frontal lobes in particular, are of significant prognostic value. A relation between acute cerebral perfusion with DTI reflecting axonal injury and neuropsychological testing during follow-up could be established, indicating a pathophysiological continuum in this patient category.

Inaugural lecture Mr. prof. E.M.D. Schuuring: ‘Next Generation’ pathologie

When:Tu 12-02-2013 at 16:15

Inaugural lecture: Mr. prof. E.M.D. Schuuring, 16.15 uur, Academiegebouw, Broerstaat 5, Groningen

Title: ‘Next Generation’ pathologie

Chair: Moleculaire oncologische pathologie

Faculty: Medical Sciences

PhD ceremony Mr. K.J.J. van Hateren: Diabetes care in old age

When:We 13-02-2013 at 14:30

PhD ceremony: Mr. K.J.J. van Hateren, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Diabetes care in old age

Promotor(s): prof. H.J.G. Bilo, prof. K. van der Meer

Faculty: Medical Sciences

Read press release

PhD ceremony Mr. R.P. Vermeulen: Quality management developments in cardiology

When:We 13-02-2013 at 16:15

PhD ceremony: Mr. R.P. Vermeulen, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Quality management developments in cardiology

Promotor(s): prof. M.P. van den Berg

Faculty: Medical Sciences

In healthcare, multiple parties are involved in providing the best possible care for patients. The advance of new professions in healthcare, such as physician assistants and nurse practitioners (together ‘allied professionals’), influence the way in which healthcare is provided. To maintain and improve the quality of care, continuous close cooperation between the different partners is a prerequisite. This thesis provides several illustrations of how quality management for cardiac patients has changed in the last few years. Topics of interest are working with integrated care systems and the effect on diagnosis-to-balloon time for patients with myocardial infarction, the use of blood lactate as risk stratification tool for adverse events, finding a safe and patient friendly tool to obtain vascular closure after cardiac catheterisation, clinical performance indicators as defined by health care professionals themselves and planning and monitoring patients on the waiting list for electrical cardioversion.

PhD ceremony Mr. K.V. Haak: Computational neuroimaging of visual field loss

When:Mo 25-02-2013 at 12:45

PhD ceremony: Mr. K.V. Haak, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Computational neuroimaging of visual field loss

Promotor(s): prof. J.M.M. Hooymans

Faculty: Medical Sciences

Eye diseases such as macular degeneration damage the retina of the eye, often causing blindness. When the retina is partly damaged in both eyes, parts of the visual areas in the brain are no longer stimulated. This raises the important question of how the visual brain areas will respond: will they remain unchanged, or reorganize themselves to cope better with the new situation?

Using fMRI techniques, it was shown that the human visual brain areas are actually much more stable than generally assumed. Signs of reorganization in the presence of retinal damage were not found, and the effects previously interpreted as reorganization can also be seen in healthy individuals. This thesis also discusses the issue that, although some studies conclude that visual brain areas exhibit large-scale reorganization, the data can often be explained without having to refer to reorganization. This point is further illustrated in a case study, in which the visual brain areas of a patient with only one cerebral hemisphere are discussed. Finally, a new fMRI data-analysis is described. This new method is expected to become important for future studies investigating the (re)organization of visual brain areas. Our finding that the visual areas of the brain do not reorganize themselves is good news for individuals with retinal damage: when in the future restoration of the retina becomes possible, it is probably not necessary to undo reorganization in the brain to restore sight.

PhD ceremony Mr. V. Farshchi Andisi: Cations and oxidative stress response in Streptococcus pneumoniae

When:We 27-02-2013 at 12:45

PhD ceremony: Mr. V. Farshchi Andisi, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Cations and oxidative stress response in Streptococcus pneumoniae

Promotor(s): prof. J.M. van Dijl

Faculty: Medical Sciences

Streptococcus pneumoniae is a bacterium, which colonizes the human nasopharynx and can cause serious disease, such as pneumonia, otitis media, meningitis, and bacteremia. Generally, groups at risk for invasive pneumococcal disease are young children, elderly and immuno-compromised patients, both in developed and developing countries. Throughout the host, S. pneumoniae encounters various oxygen radicals, which can kill or damage the bacterium. The ability to withstand the damaging effects of oxygen radicals is crucial for the bacterial ability to cause disease. Our understanding of the pneumococcal defenses against oxidative stress is far from complete. In the present thesis, a novel protein complex is described, which protects the bacteria from the hazardous effects of oxygen radicals, most likely by repairing damaged proteins. Pneumococcal mutants lacking this complex were also less virulent in mouse models mimicking disease. Moreover, the presented results show for the first time that oxidative stress resistance is vital for the bacteria to survive on dry surfaces. This desiccation tolerance is thought to aid the transmission of the bacteria. Two key components necessary for the survival of desiccation stress are described in this thesis. Altogether, the present studies have provided further insights into (1) how S. pneumoniae copes with oxygen radicals and (2) the significance of oxidative stress resistance in infection and pathogenesis.

PhD ceremony Mr. W.K.H. Kuchenbecker: Obesity and female infertility

When:We 27-02-2013 at 14:30

PhD ceremony: Mr. W.K.H. Kuchenbecker, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Obesity and female infertility

Promotor(s): prof. J.A. Land, prof. B.H.R. Wolffenbuttel

Faculty: Medical Sciences

Obesity in women is associated with an increase in infertility and more pregnancy complications. The cost per live birth after fertility treatment is almost two-fold higher in women with obesity compared to women of normal weight.

Obesity related infertility and pregnancy complications are determined by body fat distribution. Accumulation of fat around the abdomen and especially accumulation of intra-abdominal fat are a risk factor for infertility and pregnancy complications. Ultrasound measurement of intra-abdominal fat is a reliable, cheap and accessible tool to study the effects of intra-abdominal fat on female reproduction. The measurement of serum adipokines, the secretory products of adipose tissue, does not adequately reflect body fat distribution parameters. Weight loss in obese and infertile women is associated with more spontaneous pregnancies and a decrease in pregnancy complications. In anovulatory women with polycystic ovary syndrome, loss of intra-abdominal fat is associated with resumption of ovulation. In structured lifestyle programmes many women who are obese and infertile show poor compliance and experience difficulty in losing weight, leading to high drop-out rates. Future studies should aim to identify risk factors for drop-out and design individualised lifestyle programmes in order to limit drop¬-out. Weight loss medication and bariatric surgery may be considered in women with severe obesity and infertility in order to achieve sufficient weight loss and limit the serious obesity related pregnancy complications. In view of the serious obesity related pregnancy complications, women with a BMI > 35 kg/m2 should not be offered fertility treatment.

PhD ceremony Ms. A. Meijer: The forest through the trees. Investigating depression in patients with cancer and patients with myocardial infarction using systematic reviews and meta-analytic techniques

When:We 27-02-2013 at 16:15

PhD ceremony: Ms. A. Meijer, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The forest through the trees. Investigating depression in patients with cancer and patients with myocardial infarction using systematic reviews and meta-analytic techniques

Promotor(s): prof. P. de Jonge

Faculty: Medical Sciences

Depression is higher prevalent among people with a medical condition than among people in the general population. Depressed patients experience a lower quality of life, and depression is associated with worsened disease outcomes. In this thesis, the results of current research into depression in patients with cancer and in patients after a heart attack were investigated by means of literature studies.

In patients with cancer, a major question is whether these patients benefit from routine screening for depression, which has been recommended by a number of important institutions. This thesis concludes that there is not enough evidence to recommend routine screening for depression. The main issue is that there are too few high-quality studies investigating screening, so there is no scientific support for routine screening. Potentially, patients may benefit more from improved depression treatment than from screening alone.

In patients after a heart attack, depression is associated with worsened cardiac outcomes. The results of several studies across the world were combined and re-analyzed. Patients suffering from depression after their heart attack, have a 2 to 3 times increased risk of, for example, a new heart attack or death than patients without depression. Part of this association can be explained by the fact that depressed patients often also have more severe cardiac disease. More research is needed to investigate why depression is dangerous in patients after a heart attack, and whether improved treatment of depression also results in improved cardiac outcomes.

Ms. D.E. Vader-van Imhoff: The management of hyperbilirubinemia in preterm infants

When:Mo 04-03-2013 at 16:15

PhD ceremony: Ms. D.E. Vader-van Imhoff, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The management of hyperbilirubinemia in preterm infants

Promotor(s): prof. A.F. Bos

Faculty: Medical Sciences

This thesis presents a variety of studies aiming to improve the management of hyperbilirubinemia in preterm infants of less than 35 weeks of gestational age. An excess amount of unconjugated bilirubin in the blood results in yellow discoloration of the skin, which can be observed in neonatal hyperbilirubinemia. Hyperbilirubinemia is very common in preterm infants and is potentially neurotoxic. Preterm infants are more prone to bilirubin neurotoxicity than their term counterparts. Treatment consists of phototherapy or a blood exchange transfusion and is based on the total serum bilirubin (TSB) concentration.

A large variation in TSB thresholds existed in the neonatal intensive care units due to lack of evidence based thresholds. Therefore we developed novel, consensus-based TSB treatment thresholds for hyperbilirubinemia in preterm infants. To further standardize the care of hyperbilirubinemia, we made recommendations on the effective use of phototherapy and we introduced a tailor made quality assessment scheme for neonatal bilirubin and albumin laboratory measurements. We also analyzed the relation of transcutaneous bilirubin (TcB) and TSB measurements during phototherapy and found that TcB levels measured on the covered hipbone can be used in preterm infants receiving phototherapy and can theoretically reduce the number of blood samples to determine the TSB concentration. Furthermore, we investigated whether the neurodevelopmental outcome of preterm infants improved when the Bilirubin/Albumin ratio was used in the management of hyperbilirubinemia next to the TSB concentration, and found no such differences.

Inaugural lecture Mr. prof. N.M. Jansonius: Oog voor de blinde vlek

When:Tu 05-03-2013 at 16:15

Inaugural lecture: Mr. prof. N.M. Jansonius, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Oog voor de blinde vlek

Chair: Oogheelkunde, i.h.b. op het gebied van glaucoom

Faculty: Medical Sciences

Ms. E. van den Berg: Nutrition and cardiovascular health in renal transplant recipients

When:We 06-03-2013 at 16:15

PhD ceremony: Ms. E. van den Berg, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Nutrition and cardiovascular health in renal transplant recipients

Promotor(s): prof. G.J. Navis, prof. R.O.B. Gans

Faculty: Medical Sciences

In the Netherlands, about 900 kidney transplantations are carried out each year. A kidney transplantation improves both quality of life and life expectancy of patients with chronic renal disease. Despite this, their risk of developing cardiovascular disease is five times higher as compared to the general population. Cardiovascular diseases not only result in increased mortality, they also lead to damage of the renal graft, even when protective drugs are being used. Therefore, it is of vital importance to prevent the occurrence of cardiovascular disease after kidney transplantation.

Studies among the general population indicate the importance of healthy food to prevent cardiovascular diseases. No data are available on the role of nutrition in the physical health of renal transplant recipients. Else van den Berg investigated the dietary habits of a large cohort of renal transplant recipients and the association of several nutrients with cardiovascular risk factors. In these patients, high salt intake was related to high blood pressure. Furthermore, an association was observed between the diet and the acidity of the blood and also between dietary patterns, such as low vegetable intake, and high cardiovascular risk.

Altogether, this study shows that with healthier foods, a large health benefit could be gained in renal transplant recipients. Based on these results, the ‘Lifestyle Medicine Program’ was recently launched in de University Medical Center Groningen. Within this framework, renal transplant recipients are counselled shortly after transplantation to improve their dietary habits. The investigators expect healthy dietary habits to contribute to both quality of life and life expectancy in this growing patient group.

Inaugural lecture Mr. prof. D.J. Reijngoud: Metabolisme - de kern

When:Tu 12-03-2013 at 16:15

Inaugural lecture: Mr. prof. D.J. Reijngoud, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Metabolisme: de kern

Chair: Laboratoriumgeneeskunde, i.h.b. de erfelijke variëteit van het metabolisme

Faculty: Medical Sciences

PhD ceremony Mr. M. Shafique: Development of a mucosal vaccine against Respiratory Syncytial Virus infection

When:We 13-03-2013 at 11:00

PhD ceremony: Mr. M. Shafique, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Development of a mucosal vaccine against Respiratory Syncytial Virus infection

Promotor(s): prof. J.C. Wilschut

Faculty: Medical Sciences

Respiratory syncytial virus (RSV) infection is an important cause of severe respiratory disease in infants and children worldwide, and also forms a serious threat in the elderly. Vaccination against RSV could reduce the burden of RSV infection, but a vaccine is not yet available. In this thesis, the efficacy and safety of a candidate mucosal RSV vaccine was explored. Reconstituted RSV virus membranes (virosomes) were used as a vaccine platform and their capacity to induce protective immune responses was evaluated after intranasal administration in animal studies. Furthermore, the capacity of Toll-like receptor (TLR) ligands and NOD2 ligands to potentiate the induction of safe and effective immune responses was evaluated. The study shows that TLR- and NOD2- ligands, incorporated in RSV virosomal membranes, boosted serum IgG and local IgA antibody responses in the respiratory tract. Immunization with virosomal RSV vaccine, containing TLR/NOD2 ligands, did not prime for enhanced respiratory disease upon challenge of the immunized animals with live virus. Furthermore, the animals were protected from infection. Incorporation of monophosphoryl lipid A, a TLR adjuvant licensed for use in human vaccines, also potentiated the capacity of RSV virosomes to induce protective antibody responses in animals, even in those with an aged immune system. Intranasal administration of RSV virosomes with built-in TLR ligands, therefore, represents a promising approach for vaccination against RSV.

PhD ceremony Ms. A.H. Arnardóttir: Regulatory benefit - risk assessment. Different perspectives

When:We 13-03-2013 at 12:45

PhD ceremony: Ms. A.H. Arnardóttir, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Regulatory benefit - risk assessment. Different perspectives

Promotor(s): prof. F.M. Haaijer-Ruskamp, prof. P.A. de Graeff

Faculty: Medical Sciences

The strict regulations of the pharmaceutical industry are aimed at ensuring that only safe, effective and high quality drugs reach the market. Regulators are pressured to balance the desire for new drugs to rapidly enter the market, with the need for an acceptable knowledge of benefits and risks at the time of approval. Such knowledge is limited, especially with regards to safety, as pre-approval clinical trials are limited in trial size, patient selection, and are focused on establishing efficacy.

This thesis aims to evaluate whether an appropriate balance is struck in the ascertainment of benefit and risk of new drugs at the time of market approval. It focuses on two issues; whether knowledge about safety issues during market authorisation is appropriately taken up, and whether regulators agree with patients and doctors when weighing benefits and risks of drugs. We found that class-related safety issues are integrated in the assessment of new drugs. Highly innovative drugs, or drugs registered with limited clinical data, were not more likely to be subject to serious post-approval safety issues. We concluded that accepting a greater uncertainty in the knowledge on risks at the time of approval, appears acceptable for drugs addressing unmet medical need. When comparing the preferences of regulators to those of patients with type 2 diabetes and their doctors regarding drug effects, no significant differences appeared. We concluded that regulators value drug effects of oral anti-diabetes drugs similar to doctors and patients when a trade-off between benefits and risks is made from a patient perspective.

PhD ceremony Ms. D.A. Abdulahad Al-Qas Alias: The role of nuclear protein High Mobility Group Box-1 (HMGB1) in the pathogenesis of Systemic Lupus Erythematosus (SLE)

When:We 13-03-2013 at 14:30

PhD ceremony: Ms. D.A. Abdulahad Al-Qas Alias, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of nuclear protein High Mobility Group Box-1 (HMGB1) in the pathogenesis of Systemic Lupus Erythematosus (SLE)

Promotor(s): prof. C.G.M. Kallenberg, prof. P.C. Limburg

Faculty: Medical Sciences

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with involvement of many organ systems in the disease process. Autoantibodies are present directed against nuclear components such as DNA, but also against other cellular constituents. One of these constituents is HMGB1 (high mobility group box-1), a DNA-binding protein that is released from apoptotic cells but also following activation of cells. This HMGB1 is a so-called alarmin that, when released, contributes to an inflammatory reaction. In this thesis, it was shown that patients with SLE produce antibodies to HMGB1 and that their levels correlate with disease activity. This is also the case for HMGB1 itself which means that levels of HMGB1 are a marker of disease activity. In addition, it was found that disease activity of SLE in the kidneys was associated with the appearance of HMGB1 in the urine. As such, measurement of HMGB1 in the urine can be a diagnostic tool for assessing renal disease activity. A next step was to assess whether exposition to sunlight (UVB) can result in release of HMGB1 from skin cells contributing to inflammation of the skin. The results of these studies indeed supported this hypothesis: SLE patients showed a much stronger release than healthy controls which may explain why SLE patients have such a strong hypersensitivity to sun exposure. In conclusion, HMGB1 is an important inflammatory protein in SLE and, additionally, an autoantigen against which antibodies are produced. Measuring levels of HMGB1 in blood and urine can be helpful for assessing disease activity in SLE. Currently we are investigating whether targeting of HMGB1 in a lupus mouse model could be a new therapeutic option for SLE.

Ms. T.A. van de Water: Potential benefits of intensity-modulated proton therapy in head and neck cancer

When:We 13-03-2013 at 16:15

PhD ceremony: Ms. T.A. van de Water, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Potential benefits of intensity-modulated proton therapy in head and neck cancer

Promotor(s): prof. J.A. Langendijk, prof. A.J. Lomax

Faculty: Medical sciences

Read press release: Proton therapy spares healthy tissue

Inaugural lecture Mr. prof. H.V. Hogerzeil: Whom do we choose to ignore? Choices in global health

When:Tu 19-03-2013 at 16:15

Inaugural lecture: Mr. prof. H.V. Hogerzeil, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Whom do we choose to ignore? Choices in global health

Chair: Global Health, i.h.b. in de geneeskunde opleiding, vanwege Jan Cornelis de Cock-Stichting

Faculty: Medical Sciences

Read press release 'Keuzes in Global Health: wie laten we buiten de boot vallen?'

PhD ceremony Ms. P.G. Serbanescu-Kele: Radiological assessment of the postoperative liver

When:We 20-03-2013 at 14:30

PhD ceremony: Ms. P.G. Serbanescu-Kele, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Radiological assessment of the postoperative liver

Promotor(s): prof. E.J. van der Jagt, prof. R.J. Porte

Faculty: Medical Sciences

Certain types of cancer, especially of colorectal origin, often metastasize to the liver. Surgical resection offers the best chance of cure, but unfortunately most patients are not suitable candidates for liver surgery. Thermoablation, for example radiofrequency ablation and microwave ablation, is a well-established alternative therapy in which tumor cells are destroyed by heat. Imaging, often performed with computed tomography (CT), is indispensable for assessing the success of thermoablation and in the follow-up. Part one of this thesis describes that the anatomical comparability of preprocedural and postprocedural CT-scans is highly important for assessment of the success of thermoablation. Volume measurements of the ablation zones proved to be valuable in the follow-up, but should not be performed on immediate postprocedural scans, since these measurements are unreliable.

The liver is a unique organ due to its remarkable regenerative capacity. Healthy liver tissue is a prerequisite for optimal liver regeneration and many other factors influence it. Animal studies revealed that platelets seem to have a pivotal role in the process of liver regeneration. Part two of this thesis describes liver regeneration after surgical resection. The regenerated volume depends strongly on the amount of resected liver tissue. Hepatic steatosis or fatty liver – an increasingly occurring condition of the liver parenchyma – negatively affects the regenerative capacity of the liver. For the first time it was shown in humans that patients with high regeneration have a stronger decrease in postoperative platelet counts than patients with poor regeneration.

PhD ceremony Ms. F.H. Jorna: Diagnostic tools and risk identification in management of hyperparathyroidism

When:We 20-03-2013 at 16:15

PhD ceremony: Ms. F.H. Jorna, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Diagnostic tools and risk identification in management of hyperparathyroidism

Promotor(s): prof. J.T.M Plukker, prof. C.A. Stegeman

Faculty: Medical Sciences

Hyperparathyroidism (HPT) is the overproduction of parathyroid hormone (PTH) by overactive parathyroid gland(s) which is treated by surgical removal of the gland(s). This thesis describes diagnostic tools that can be used before and parathyroidectomy. Various preoperative scintigraphy techniques were evaluated according to their possibilities for enabling a surgical plan. SPECT was valuable in addition to planar 99mTc-Sestamibi scintigraphy for primary HPT. Preoperative scintigraphy in case of secondary HPT was not meaningful. The value of the gammaprobe and intraoperative PTH monitoring were evaluated during an operation for secondary HPT. The probe had a limited role in guiding the resection, but was useful in confirming the resection of overactive glands. Intraoperative PTH monitoring had a high positive predictive value, but low negative predictive value. Its potential benefit is low because of high pre-test probability of surgical cure after resection of four glands and difficult interpretation of PTH in secondary HPT. Another study showed that P-gp and MRP1 had no significant role in the retention of 99mTc-Sestamibi in the parathyroid gland.

This thesis also describes risk factors for severe secondary HPT and parathyroid carcinoma. Serum PTH, phosphate and alkaline phosphatase at 1 year after the start of dialysis were independently associated with increased risk for parathyroidectomy. A palpable neck mass, PTH >3 times the upper normal limits and significantly high serum calcium, in patients presenting with HPT may indicate the presence of parathyroid carcinoma.

PhD ceremony Mr. M.T. Khan: Novel physiological and metabolic insights into the beneficial gut microbe Faecalibacterium prausnitzii. From carbohydrates to current

When:Mo 25-03-2013 at 12:45

PhD ceremony: Mr. M.T. Khan, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Novel physiological and metabolic insights into the beneficial gut microbe Faecalibacterium prausnitziii. From carbohydrates to current

Promotor(s): prof. J.M. van Dijl

Faculty: Medical sciences

The trillions of micro-organisms residing in our gut play major roles in our health and wellbeing. Changes in this so-called gut microbiota are related with disease conditions, such as obesity, chronic gut inflammation and metabolic syndromes. One of the beneficial micro-organisms that disappears when patients develop an inflamed gut is Faecalibacterium prausnitziii, a highly oxygen-sensitive bacterium with important anti-inflammatory properties. Accordingly, it was suggested to apply F. prausnitzii as a probiotic for the treatment of such patients. The research described in this thesis therefore aimed at investigating the metabolic properties of F. prausnitziii. To this end an effective procedure for isolating F. prausnitziii from human feces was developed. Studies on isolated strains led to the discovery that they can actually thrive in moderately oxygenated environments, such as the gut mucosa, by consuming oxygen and at the same time forming a protective slime layer. Hereto, the bacteria use flavins and oxidized thiols that are abundantly present in the gut. This knowledge was then applied to develop formulations that allow the survival of F. prausnitziii for at least 24 hours at ambient air, where it would normally die within two minutes. Altogether, these findings pave the way for the biomedical exploitation of this and possibly other oxygen-sensitive gut microbes in the treatment of major disorders of the human gut. Intriguingly, the present studies suggest that F. prausnitziii can also be employed in a completely different way to the benefit of mankind, namely through power generation in microbial fuel cells.

PhD ceremony Ms. G. Ghobadi: Pathophysiology of thoracic irradiation

When:Mo 25-03-2013 at 14:30

PhD ceremony: Ms. G. Ghobadi, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Pathophysiology of thoracic irradiation

Promotor(s): prof. R.P. Coppes, prof. J.A. Langendijk

Faculty: Medical Sciences

Radiation plays an important role in the treatment of thoracic tumors. The efficacy of treatment is limited by the sensitivity of unavoidably co-irradiated healthy tissues. One of the most common life threatening complications is thoracic radiation-induced respiratory dysfunction. For a more efficient thoracic radiotherapy, reduction of the chance of developing this complication is required.

Our preclinical studies showed that thoracic radiation-induced damage to the lung and the heart are very much inter-related and that respiratory dysfunction becomes manifest through physiological changes in the whole cardio-pulmonary system rather than through changes in the lung only. Lung irradiation leading to pulmonary hypertension may originate from vascular remodeling in the whole lung, possibly initiated by global loss of pulmonary endothelial cells preceding parenchymal inflammation. Radiation-induced pulmonary hypertension secondarily impairs left ventricle diastolic function and promoted pulmonary edema. Both mechanisms may contribute to the development of respiratory dysfunction. Criteria for the assessment of clinical respiratory dysfunction are subjective and non-specific. Using objective quantitative parameters, such as Computed Tomography (CT) scans of the lungs, may improve such assessments. We therefore developed a sensitive CT-based tool to assess radiation-induced lung tissue damage which showed to be superior to the previously used methods. The findings of this thesis suggest new considerations to the optimization of thoracic radiotherapy.

Inaugural lecture Ms. prof. O.C.M. Sibon: Er komt een vlieg bij de doctor

When:Tu 26-03-2013 at 16:15
Where:.

Inaugural lecture: Ms. prof. O.C.M. Sibon, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Er komt een vlieg bij de doctor

Chair: Celbiologie

Faculty: Medical Sciences

PhD ceremony Ms. J.S. Kovaleva: Microbiological safety in endoscope reprocessing

When:We 27-03-2013 at 14:30

PhD ceremony: Ms. J.S. Kovaleva, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Microbiological safety in endoscope reprocessing

Promotor(s): prof. J.E. Degener, prof. H.C. van der Mei

Faculty: Medical Sciences

The purpose of this thesis is to present an overview of the infections and cross-contaminations related to flexible endoscopy and to illustrate the impact of the presence of biofilm on endoscope reprocessing and development of post-endoscopic infection. The relevance of cleaning, high-level disinfection, drying procedures, and storage in endoscope reprocessing and the role of microbiological surveillance of flexible endoscopes are described. Finally, an overview of the impact of biofilm on endoscope reprocessing and on development of infectious complications related to endoscopy is given.

The effects of per acetic acid disinfectant with and without additional drying on biofilm formation by microorganisms isolated from contaminated flexible endoscopes were investigated. An in vitro biofilm model was applied to mimic the biofilm formation inside the endoscope channels and to imitate the disinfection and drying procedures used for reprocessing of flexible endoscopes in the UMCG. This study illustrates the high efficacy of the drying procedure after the disinfection step against different microorganisms in biofilms. However, disinfection and drying procedures may fail in the endoscope with a manufacturing defect or damaged internal channels when the decontamination process cannot reach all internal parts of the instrument, and biofilm formation will occur within the endoscope channels. Microbiological surveillance of endoscope reprocessing is appropriate to trace contaminations and to prevent contaminations and infections in patients after endoscopic procedures.

PhD ceremony Mr. M.L. Schrijvers: New prognostic markers to predict clinical outcome in patients with laryngeal cancer

When:We 03-04-2013 at 14:30

PhD ceremony: Mr. M.L. Schrijvers, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: New prognostic markers to predict clinical outcome in patients with laryngeal cancer

Promotor(s): prof. B.F.A.M. van der Laan, prof. E. Schuuring

Faculty: Medical Sciences

Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer in the world with an incidence of over 600.000 cases per year and yearly mortality of 350.000. Twenty percent of all head and neck tumours originate in the larynx, of which the majority is located in the glottic region. Most early stage (T1/T2) laryngeal carcinomas are treated with conservative (laser) surgery or (accelerated) radiotherapy. For more advanced tumours (T3/T4), surgery and/or chemoradiotherapy is the treatment of choice. Until now, the choice of treatment is mainly based on well-known clinicopathological factors, such as tumour location and tumour stage. Cell biological tumour markers associated with response to treatment or prognosis might be useful to predict clinical outcome before treatment, and thereby optimize and personalize the treatment for individual patients. In this thesis, cell biological tumour markers involved in loco regional control, overall survival, disease specific survival and lymph node status in patients with laryngeal squamous cell carcinoma treated with radiotherapy were investigated. Of these tumour markers, high pFADD expression and low HIF1a and CA-IX expression were significantly associated with better local control after radiotherapy. High EGFR expression was associated with lymph node positivity. This research reveals new insights into the molecular mechanisms of response to radiotherapy and clinical outcome in mainly early stage laryngeal carcinomas. The development of predictive molecular profiles may facilitate the optimal treatment strategy for each patient. Our results may contribute to the selection of patients who might benefit from adding chemotherapy, EGFR blocking agents or hypoxic modification to the current standard (accelerated) radiotherapy.

PhD ceremony Ms. L.V. Fortington: Enabling the elderly person with lower limb amputation through surgery, rehabilitation and long term care

When:Mo 08-04-2013 at 12:45

PhD ceremony: Ms. L.V. Fortington, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Enabling the elderly person with lower limb amputation through surgery, rehabilitation and long term care

Promotor(s): prof. J.H.B. Geertzen, prof. P.U. Dijkstra

Faculty: Medical Sciences

In the Netherlands, 80% of people undergoing lower limb amputation are over 65 years of age. Chronic peripheral vascular disease or diabetes mellitus has led to irreversible ischemia or a life threatening infection. Despite advances in preventative care, medical treatment and (peripheral) revascularisation procedures, in some cases, an amputation remains the best option for ending ongoing pain, hospitalisation and infection/ischaemia, and ultimately, enabling a person to live. It is the enabling a person to live that the research presented in this thesis focuses on. How, and how well, is the elderly population enabled from the decision to amputate and their subsequent rehabilitation and long-term care?

Key findings of the research support clinical knowledge that older age does not prevent someone achieving good mobility outcomes after amputation. However, amputation rehabilitation for the elderly person must extend beyond their limb, encompassing psychosocial elements and alternative options for mobility. Pre-amputation, research and decisions are mostly surgically focussed and may benefit from increased input of the rehabilitation team. For example, changing treatment options, particularly in respect to limb-salvage, present new questions over the timing of amputation and the population who, as a consequence, require rehabilitation. Post-amputation, measures and research of non-prosthetic outcomes are lacking and treatment from a wider group of the multidisciplinary team available in long-term care should be considered.

PhD ceremony Ms. E.M. Opmeer: Linking depression. Longitudinal and neuroimaging genetic studies in major depressive disorder

When:Mo 08-04-2013 at 16:15

PhD ceremony: Ms. E.M. Opmeer, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Linking depression. Longitudinal and neuroimaging genetic studies in major depressive disorder

Promotor(s): prof. A. Aleman

Faculty: Medical Sciences

Depression is a common disease with a high burden for the patients. For optimal treatment it is important to understand its underlying neurobiological factors. The pathogenesis of depression consists of many factors, including heritable and environmental factors. This thesis had the aim to increase our insight into the neurobiology of depression and relevant genetic influences.

The processing of negative emotional stimuli revealed a pattern of strong activation in limbic areas and less activation in the DLPFC in depressed patients. In addition, an opposite pattern of activation was seen during processing of positive emotional stimuli. Genetic association studies into vulnerability genes for depression have not led to satisfying results up to this moment. However, the studies in this thesis indicate that the association between genes and brain activation is stronger than between genes and depression. Certain genes are associated with brain activation patterns comparable to the abnormalities seen in depression. In addition, the studies in this thesis are among the first to demonstrate an influence of depression on the relation between genes and brain activation.

PhD ceremony Mr. Q. Ye: Molecular and cellular mechanism of collagen degradation in the foreign body reaction

When:We 10-04-2013 at 11:00

PhD ceremony: Mr. Q. Ye, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Molecular and cellular mechanism of collagen degradation in the foreign body reaction

Promotor(s): prof. Y. Ren, prof. R.A. Bank

Faculty: Medical Sciences

The biopolymer collagen is often used as scaffolding biomaterial in tissue engineering. Like any other biomaterials, the implantation of collagen scaffolds induces a local inflammatory reaction known as foreign body reaction (FBR). The FBR to collagen scaffolds involves a complex cascade of spatiotemporally regulated and interconnected processes that include cellular infiltration, activation of inflammatory cells, phagocytosis and proteolysis. Ultimately this results in the resolution and degradation of the implanted scaffold. Ideally, the degradation rate should match the speed of tissue regeneration. The aim of this thesis was to search for the molecular and cellular mechanisms of degradation of collagen scaffolds in the FBR. Our data have provided several striking findings regarding the nature and regulation of the enzymatic degradation and phagocytosis of collagen scaffolds. IL-10, IL-13, TIMP-1 and DDR-2 were identified as potential therapeutic factors in the regulation of MMP-based proteolysis in the extracellular enzymatic degradation of collagen. IFN-γappears to be the optimal activator for the phagocytosis of collagen by macrophages via the up-regulation of MMP-14 and Endo180. This effect can be neutralised by the addition of IL-10. Moreover, our data have also showed that it is extremely important to choose an appropriate substrate and design the physical and chemical nature of the scaffold so that its degradation can be tuned to the rate of tissue regeneration.

PhD ceremony Mr. Alkhalaf: Novel approaches in diabetic nephropathy

When:We 10-04-2013 at 16:15

PhD ceremony: Mr. Alkhalaf, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Novel approaches in diabetic nephropathy

Promotor(s): prof. G.J. Navis, prof. H.J.G. Bilo

Faculty: Medical Sciences

In patients with type 1 diabetes, CNDP1 polymorphism predicts progression to end stage renal disease (ESRD) but not mortality. In patients with type 2 diabetes, CNDP1 polymorphism did not predict progression of decline of renal function. Cardiovascular mortality was increased in female patients with 5L-5L compared to other genotypes. These results seem to contrast with those of earlier cross-sectional studies. Large prospective studies are necessary to discern whether CNDP1 indeed plays a role as a susceptibility factor of diabetic nephropathy.

In this thesis, the role of ACE I/D polymorphism as a risk factor for development of new-onset albuminuria in patients with type 2 diabetes is confirmed. The novel polymorphism CCR2 V64I might have additional value besides ACE I/D polymorphism on predicting renal outcome. Analysis of urine proteomics by capillary electrophoresis coupled with mass spectrometry (CE-MS) is a helpful diagnostic tool for the detection of diabetic nephropathy. Recent studies showed that analysis of urinary proteomics is helpful as in detection of diabetic nephropathy at an early stage. Therefore, it is tempting to speculate that using urine proteomics allows early renoprotective treatment for those at risk to developing diabetic nephropathy, with the aim to delay or prevent development of microalbuminuria.

A 12-week treatment with benfotiamine (lipid-soluble vitamin B1) did not represent a beneficial intervention in patients with diabetic nephropathy. At this moment, there are no arguments to recommend benfotiamine to patients with diabetic nephropathy.

Inaugural lecture Mr. prof. R.J.M.Groen: De klinische neurochirurgie in een veranderend landschap

When:Tu 16-04-2013 at 16:15

Inaugural lecture: Mr. prof. R.J.M.Groen, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: De klinische neurochirurgie in een veranderend landschap

Chair: Klinische neurochirurgie

Faculty: Medical Sciences

PhD ceremony Ms. K. Azijli: TRAIL-induced kinases activation and apoptosis: towards improved death receptor targeted therapy for lung cancer

When:We 17-04-2013 at 14:30

PhD ceremony: Ms. K. Azijli, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: TRAIL-induced kinases activation and apoptosis: towards improved death receptor targeted therapy for lung cancer

Promotor(s): prof. F.A.E. Kruyt, prof. G.J. Peters, prof. S. de Jong

Faculty: Medical Sciences

Lung cancer is one of the deadliest diseases amongst the different types of cancer and the incidence is expected to rise globally. The current treatment of NSCLC patients has reached a plateau since efficacy of therapy is limited by resistance to conventional chemo- and radiotherapy. New therapies are therefore urgently needed to improve lung cancer survival. Targeting the apoptotic machinery by activating Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL) receptors represents a novel approach and aims to selectively kill cancer cells by apoptosis activation while sparing normal cells. In this thesis part of the work was dedicated to examine the possible counterproductive effects of TRAIL stimulation in NSCLC and to unravel underlying mechanisms of non-canonical kinases signaling. However, the differential sensitivity for apoptosis induction and even pro-tumorigenic effects in TRAIL resistant tumor cells, requires a better understanding of the mechanisms that regulate TRAIL activity. Regardless of the more detailed molecular causes of the dichotomy in TRAIL signaling, the combined use with standard anti-cancer drugs generally results in sensitization to TRAIL-induced apoptosis. Thus, possible unwanted effects of TRAIL treatment can be overcome by combination treatments, such as the ones we presented in this thesis, TFT and Hsp90 inhibitors. Elucidation of the molecular switches that determine the settings of the TRAIL pathway will help to develop targeted strategies to make the tumor cells apoptosis prone. Another challenge for the future is to identify biomarkers that allow the preselection of patients and determination of optimal TRAIL combination strategies in order to maximize therapeutic benefit.

PhD ceremony Mr. T.A. Westra: Health-economic modelling of Human Papillomavirus vaccination

When:We 17-04-2013 at 16:15

PhD ceremony: Mr. T.A. Westra, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Health-economic modelling of Human Papillomavirus vaccination

Promotor(s): prof. M.J. Postma, prof. J.C. Wilschut, prof. C.A.H.H. Daemen

Faculty: Medical Sciences

PhD ceremony Mr. H.G. Rettke: Long-term outcomes in stroke rehabilitation: patients and informal caregivers

When:Mo 22-04-2013 at 11:00

PhD ceremony: Mr. H.G. Rettke, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Long-term outcomes in stroke rehabilitation: patients and informal caregivers

Promotor(s): prof. W.J.A. van den Heuvel

Faculty: Medical Sciences

Stroke is a leading cause of persisting disabilities. This calls for rehabilitation to restore functioning and to pave the way for community reintegration. In German speaking Switzerland a cross-sectional study was conducted on a sample of patients (n=287) suffering from first-ever stroke one to three years post-discharge and their informal caregivers. The sample was recruited from a single neuro-rehabilitation facility that had implemented a protocol for goal setting and evaluation based on the ICF. Goal categories referred to post-discharge living arrangements. Of all post-stroke patients approached, 174 filled in a questionnaire to evaluate their extent of goal attainment, community reintegration and their need of daily assistance. In addition, all medical records were screened for goal attainment during in-patient rehabilitation. The majority of patients did attain their goals at discharge, while only half of them did so post-discharge. Goal attainment at discharge was related to cognitive functioning. Post-discharge, it was related to physical functioning, help from family members and continuing therapies immediately after discharge. To assess community reintegration we applied the German version of the ‘Reintegration in Normal Living’ Index. Test results confirmed sound psychometric properties. We found community reintegration to be associated with mobility and communication at the time of questionnaire completion.

Independent from rehabilitation outcomes stroke results in a long lasting demand in daily care and assistance. Here, informal caregivers were asked to provide additional information. Among all respondents we identified 132 dyads of stroke survivors and informal caregivers. If needed, informal care is mostly provided by the partner alone. Five patterns of informal care were identified in relation to stroke survivors’ limitations and number of persons involved. Even three years post-discharge 30 patients are still in need of daily informal care giving. Providing informal care comprises a substantial burden whether caring for a circumscribed or an indefinite period. Literature reports on changes in burden over time which is seldom referred to a prolonged time period. To investigate caregiver burden we applied a German version of the ‘Caregiver Burden Inventory’ which has been validated for the first time. The psychometric properties were satisfying. The informal caregivers in our sample reported a rather low extend of burden experienced. We identified sense of mastery as a salient determining factor of caregiver burden. Longitudinal research is needed to better describe changes over time in post-stroke patients and informal caregivers. Specific interventions are needed for both to promote positive long-term outcomes.

PhD ceremony Ms. H.M. Geschwindner: Long-term outcomes in stroke rehabilitation: patients and informal caregivers

When:Mo 22-04-2013 at 12:15

PhD ceremony: Ms. H.M. Geschwindner, 12.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Long-term outcomes in stroke rehabilitation: patients and informal caregivers

Promotor(s): prof. W.J.A. van den Heuvel

Faculty: Medical Sciences

Stroke is a leading cause of persisting disabilities. This calls for rehabilitation to restore functioning and to pave the way for community reintegration. In German speaking Switzerland a cross-sectional study was conducted on a sample of patients (n=287) suffering from first-ever stroke one to three years post-discharge and their informal caregivers. The sample was recruited from a single neuro-rehabilitation facility that had implemented a protocol for goal setting and evaluation based on the ICF. Goal categories referred to post-discharge living arrangements. Of all post-stroke patients approached, 174 filled in a questionnaire to evaluate their extent of goal attainment, community reintegration and their need of daily assistance. In addition, all medical records were screened for goal attainment during in-patient rehabilitation. The majority of patients did attain their goals at discharge, while only half of them did so post-discharge. Goal attainment at discharge was related to cognitive functioning. Post-discharge, it was related to physical functioning, help from family members and continuing therapies immediately after discharge. To assess community reintegration we applied the German version of the ‘Reintegration in Normal Living’ Index. Test results confirmed sound psychometric properties. We found community reintegration to be associated with mobility and communication at the time of questionnaire completion.

Independent from rehabilitation outcomes stroke results in a long lasting demand in daily care and assistance. Here, informal caregivers were asked to provide additional information. Among all respondents we identified 132 dyads of stroke survivors and informal caregivers. If needed, informal care is mostly provided by the partner alone. Five patterns of informal care were identified in relation to stroke survivors’ limitations and number of persons involved. Even three years post-discharge 30 patients are still in need of daily informal care giving. Providing informal care comprises a substantial burden whether caring for a circumscribed or an indefinite period. Literature reports on changes in burden over time which is seldom referred to a prolonged time period. To investigate caregiver burden we applied a German version of the ‘Caregiver Burden Inventory’ which has been validated for the first time. The psychometric properties were satisfying. The informal caregivers in our sample reported a rather low extend of burden experienced. We identified sense of mastery as a salient determining factor of caregiver burden. Longitudinal research is needed to better describe changes over time in post-stroke patients and informal caregivers. Specific interventions are needed for both to promote positive long-term outcomes.

PhD ceremony Mr. R.V. Stan: Endothelial subcellular structures in vascular permeability

When:Mo 22-04-2013 at 14:30

PhD ceremony: Mr. R.V. Stan, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Endothelial subcellular structures in vascular permeability

Promotor(s): prof. G. Molema

Faculty: Medical Sciences

Vascular permeability is a cardiovascular function by which endothelial cells lining the blood vessels control the exchange of molecules between blood plasma and the interstitial fluid of different organs. Maintenance of proper vascular permeability is of utmost importance for whole organism physiology and organ function enabling nutrient delivery, waste removal and communication between organ systems. The precise molecular mechanisms controlling vascular permeability continue to elude us. Endothelial subcellular structures/organelles such as caveolae, fenestrae and transendothelial channels have been implicated in permeability over years of research. Little was known as to their molecular composition, regulation and precise function. In this thesis, we describe our work focused on insolating and characterizing the composition of caveolae, fenestrae and transendothelial channels in order to find specific molecular components, which in turn could serve as molecular targets for determining the precise function for these organelles. Our work led to the discovery and cloning of Plasmalemma Vesicle Associated Protein (Plvap/PV1). It is the first identified component of the diaphragms of caveolae, fenestrae and transendothelial channels. We further demonstrated Plvap to be a structural component of the endothelial diaphragms of caveolae, fenestrae and transendothelial channels as well as demonstrated the critical role of the fenestrae diaphragms in maintenance of basal permeability. In summary, our work opens new avenues of research into the structure, components and function of endothelial subcellular organelles involved in permeability and provides new evidence demonstrating the maintenance of vascular permeability as a critical mammalian function necessary for survival.

PhD ceremony Mr. J.W.A. Slot: Implant-supported maxillary overdentures

When:Mo 22-04-2013 at 16:15

PhD ceremony: Mr. J.W.A. Slot, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Implant-supported maxillary overdentures

Promotor(s): prof. H.J.A. Meijer, prof. G.M. Raghoebar, prof. A. Vissink

Faculty: Medical Sciences

Inaugural Lecture Mr. prof. T.P.W. Kamphuisen: Verbindende vaten

When:Tu 23-04-2013 at 16:15

Inaugural Lecture: Mr. prof. T.P.W. Kamphuisen, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Verbindende vaten

Chair: Interne geneeskunde, i.h.b. de vasculaire geneeskunde

Faculty: Medical Sciences

PhD ceremony Mr. F.A.J. de Laat: Measuring mobility in persons with a lower-limb

When:We 24-04-2013 at 12:45

PhD ceremony: Mr. F.A.J. de Laat, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Measuring mobility in persons with a lower-limb

Promotor(s): prof. J.H.B. Geertzen

Faculty: Medical Sciences

Limitated mobility following lower-limb amputation is regarded as one of the most relevant disabilities affecting the quality of life. Prosthetic devices and rehabilitation can help many people with a lower-limb amputation to restore their mobility. No gold standard exists to assess the perceived limitations in mobility for people with a lower-limb amputation. Methods to assess transfers with a prosthesis (rising and sitting down) and for climbing stairs is lacking. Ambulatory mobility requires that a person has the ability to rise and sit down first, followed by standing. Only then walking and finally climbing stairs is an option.

In this thesis the test-retest reliability and the construct validity of the Questionnaire Rising and Sitting down, Walking Questionnaire, and Climbing stairs Questionnaire were assessed. The questionnaires showed to be valid for people with a lower-limb amputation. The reliability was good for group comparisons but not for individual comparisons. The second aim was to measure the perceived ability of rising and sitting down, and climbing stairs in people with a lower-limb amputation. The perceived ability in rising and sitting down was good, but lower in older-aged and women. Climbing stairs in the house was required for 47% of the participants. While the perceived ability to climb the stairs was moderate, this was more so in older-aged persons and women who perceived less independence in climbing stairs, especially when handrails were absent. Suggestions for prosthetic training and advice for further testing are discussed.

PhD ceremony Ms. M.M. van der Kooi-Pol: In vivo and in vitro profiling of global interactions between Staphylococcus aureus and its human host

When:We 24-04-2013 at 14:30

PhD ceremony: Ms. M.M. van der Kooi-Pol, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: In vivo and in vitro profiling of global interactions between Staphylococcus aureus and its human host

Promotor(s): prof. J.M. van Dijl

Faculty: Medical Sciences

The opportunistic pathogen Staphylococcus aureus has become a major threat for human health and well-being by developing resistance to antibiotics, and by its fast evolution into new lineages that rapidly spread within the healthy human population. This calls for the development of active or passive immunization strategies to prevent and cure staphylococcal diseases. These novel strategies to combat S. aureus must be based on an integrated approach that requires the identification of invariant and immune-dominant targets. The identification of such targets requires (i) in-depth analyses on the localization of proteins and other compounds to the staphylococcal cell surface and (ii) a thorough understanding of the human immune responses to these cell surface-exposed compounds. The research described in this thesis was therefore aimed at defining the interactions between S. aureus and its human host in vivo and in vitro. In particular, studies of immune responses elicited by S. aureus colonization in patients with the genetic blistering disease epidermolysis bullosa (EB) revealed several highly immunogenic staphylococcal proteins and their epitopes. In addition, in vitro studies have pinpointed various mechanisms that are important for the cell surface exposure of different S. aureus proteins that are known to be involved in staphylococcal infections. Taken together, the findings reported in this thesis contribute to a better understanding of the interactions between humans and S. aureus during colonization and infection. The main challenges for future research now lie in the translation of the present findings into novel strategies for antistaphylococcal therapy.

PhD ceremony Mr. J.K. Smit: Response evaluation of chemoradiotherapy in esophageal cancer

When:We 24-04-2013 at 16:15

PhD ceremony: Mr. J.K. Smit, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Response evaluation of chemoradiotherapy in esophageal cancer

Promotor(s): prof. J.Th.M. Plukker, prof. R.P. Coppes, prof. H. Hollema

Faculty: Medical Sciences

The studies described in this thesis provide insight into a better assessment of recurrences and in the prediction of response following primary (chemo)radiotherapy or neoadjuvant chemoradiotherapy in esophageal cancer patients. It is well recognized that recurrence rate and time interval to recurrence are mainly related to tumor stage and several histological risk factors, including tumor type and grade. With respect to the accuracy of assessing recurrences with the traditional Tumor-Node-Metastasis (TNM)-classification, there is a particular interest in the additional information of locoregional nodal metastasis stratification in estimating recurrence free survival, as also is described in this thesis.

Data on the prediction of recurrence free survival in patients treated with neoadjuvant chemoradiotherapy and stratified/staged according to the TNM 7th edition, as collected in this thesis, is highly important for the scientific community. It became apparent that locoregional lymph node status stratification also contains important information on the prediction of recurrence in this patient category. Interestingly, the impact on (recurrence free)- survival of locoregional lymph node status (N-status in the TNM-classification) stratification is even greater than the depth of primary tumor invasion, the T-status in the TNM-classification. Indeed, in this thesis we provide intriguing data to this theory, in which neoadjuvant treated patients, who showed (nearly) complete responses, nodal micrometastatic disease had a huge negative impact on (disease free)- survival.

PhD ceremony Mr. A. Abbasi: Biomarkers and prediction models for type 2 diabetes and diabetes related outcomes

When:We 01-05-2013 at 14:30

PhD ceremony: Mr. A. Abbasi, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Biomarkers and prediction models for type 2 diabetes and diabetes related outcomes

Promotor(s): prof. R.P. Stolk, prof. G.J. Navis

Faculty: Medical Sciences

Type 2 diabetes (T2D) and its micro and macro vascular complications cause an increasing global health burden. An ageing population, obesity, and inactivity, contribute to this. Valid risk scores contribute to early identification of high-risk individuals. This is essential for (cost-)effective allocation of targeted prevention strategies. A valid risk score can also help to inform patients about future risks associated with their illness, and can guide doctors and patients in decisions on further treatment.

Many risk scores for prediction of T2D and its complications are available. The first part of this thesis is aimed at the validation of existing risk scores for T2D. The second part focuses on risk factors and added predictive value of novel biomarkers for T2D and its complications. For further insight in the development of T2D, we investigated the role of family history of diabetes and HDL-cholesterol. This thesis shows that current risk scores for future T2D are valid to identify high-risk individuals for a time frame of 5 to 10 years. We explored associations of novel biomarkers, such as procalcitonin (inflammation), copeptin (stress system), peroxiredoxin 4 (oxidative stress) with risk of diabetes, obesity, kidney dysfunction and cardiovascular disease. It appeared that addition of the novel biomarkers to existing risk scores (KORA, DESIR, FRS) can at largest lead to modest improvements in prediction of T2D and cardiovascular disease. Future studies are warranted to estimate risk of T2D and its complications over the lifetime, and improve prediction of complications.

PhD ceremony Ms. A.C. Vink: Music therapy for dementia. The effect of music therapy in reducing behavioural problems in elderly people with dementia

When:Mo 06-05-2013 at 16:15

PhD ceremony: Ms. A.C. Vink, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Music therapy for dementia. The effect of music therapy in reducing behavioural problems in elderly people with dementia

Promotor(s): prof. J.P.J. Slaets

Faculty: Medical Sciences

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PhD ceremony Mr. P.A. Smink: Biomarkers and assessment of drug efficacy in cardiovascular disease

When:We 08-05-2013 at 11:00

PhD ceremony: Mr. P.A. Smink, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Biomarkers and assessment of drug efficacy in cardiovascular disease

Promotor(s): prof. D. de Zeeuw

Faculty: Medical Sciences

In recent years, a number of large clinical drug trials which aimed to investigated whether a novel drug reduces the burden of renal and cardiovascular complications, reported no benefit and sometimes even harm. These results were unexpected since these drugs had shown to have favourable effects on a cardiovascular risk factor, such as blood pressure, cholesterol or Hba1c, so-called on-target risk factors. The explanation may be that drugs exert effects on multiple risk factors, so called off-target effects, which may beneficially or adversely affect the long-term outcome. Thus, to predict the drug effect on long-term outcome, not only the on-target but also the off-target effects should be considered and measured. In my thesis I showed that a blood pressure lowering drug influences multiple risk factors besides blood pressure. Interestingly, the changes in each of these risk factors influence long-term renal or cardiovascular outcome in opposing directions. I showed that a so called Parameter Response Efficacy (PRE) score integrating the drug effect on multiple risk factors performs significantly better in predicting drug effects on renal or cardiovascular outcome than any score based on single on-target or off-target effects. The implications of these results could be that an integrated drug response score can help the regulator to make well-informed decisions on drug efficacy (in the absence of long-term efficacy/safety data) as well as it may help the physician and patient to estimate the long-term drug effect on renal and cardiovascular outcome.

PhD ceremony Ms. E.S. Ovchinnikova: Physical-chemical interactions between bacteria and fungi

When:We 08-05-2013 at 14:30

PhD ceremony: Ms. E.S. Ovchinnikova, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Physical-chemical interactions between bacteria and fungi

Promotor(s): prof. H.C. van der Mei, prof. H.J. Busscher

Faculty: Medical Sciences

In nature, microorganisms not only form mono-species biofilms, but they also co-exist within complex polymicrobial communities, containing both commensals and opportunistic pathogens. The bacterial strains Pseudomonas aeruginosa and Staphylococcus aureus and the fungus Candida albicans often play a role in infections in the human body. Despite the fact that fungal-bacterial interactions have been investigated extensively, there is still limited information on the interplay between physico- and bio-chemical mechanisms that mediate their interaction. In this thesis the nature of the adhesion forces between P. aeruginosa, S. aureus and different C. albicans morphologies, based on surface thermodynamics and atomic force microscopy (AFM), was investigated. Thermodynamic modeling was used to evaluate the nature of the adhesion forces between two microbial surfaces by calculating the interfacial free energy of the interacting organisms. Direct measurement of adhesion forces between microorganisms were performed using AFM.

PhD ceremony Ms. L.K. Teune: Glucose metabolic patterns in neurodegenerative brain diseases

When:We 08-05-2013 at 16:15

PhD ceremony: Ms. L.K. Teune, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Glucose metabolic patterns in neurodegenerative brain diseases

Promotor(s): prof. K.L. Leenders, prof. R.A.J.O. Dierckx

Faculty: Medical Sciences

Neurodegenerative brain diseases like Parkinson’s Disease (PD), Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are brain diseases with a slowly progressive degeneration of neurons in particular brain areas. The differential diagnosis of neurodegenerative brain diseases on clinical grounds only may be difficult, especially at an early stage. In order to differentiate between neurodegenerative brain diseases, an [18F]-fluorodeoxyglucose (FDG)-PET scan could be of great assistance. It uses the radiotracer FDG (glucose) and reflects the energy needs of underlying brain neuronal systems because glucose is the only source of energy for the brain. The detected disease-related metabolic brain patterns using FDG-PET reflect the underlying pathological alterations of the affected brain regions and are different for each neurodegenerative brain disease. The main aim of this thesis was to investigate differences in glucose metabolism in neurodegenerative brain diseases. Furthermore, specific analysis techniques which can assist in the applicability of these brain patterns in clinical practice were investigated. A multivariate statistical analysis technique, called SSM/PCA, can identify relationships in relatively increased and decreased metabolic activity between different brain regions in patients and controls. Disease-specific patterns for PD, MSA and PSP were identified and highly discriminative of the three disorders. Besides group comparisons, the SSM/PCA method can quantify the expression of a covariance pattern in an individual patient. The obtained subject score indicates to what extent that individual patient expresses the disease-related pattern. These metabolic brain patterns can be a valuable aid in the differential diagnosis of individual patients with neurodegenerative brain diseases.

PhD ceremony Ms. F. Maccioni: Evaluation of Crohn's disease activity: an integrated imaging approach

When:Mo 13-05-2013 at 11:00

PhD ceremony: Ms. F. Maccioni, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Evaluation of Crohn's disease activity: an integrated imaging approach

Promotor(s): prof. A. Signore, prof. R.A.J.O. Dierckx

Faculty: Medical Sciences

This thesis describes the diagnostic value of MRI in the evaluation of the inflammatory activity of Crohn’s Disease (CD). Both T1 and T2-weighted parameters can display relevant signs of mural inflammation in CD lesions, such as hypervascularity and oedema. Gadolinum-enhancement of the wall on T1-weighted imaging, signal hyperintensity of the wall and mesenteric fat on T2-weigted imaging were extensively analyzed, quantified and statistically correlated with the “biological” scores of activity. Moreover, MRI provides CD characterization (oedema versus fibrosis) and evaluation of intestinal extent of lesions and complications in the small and large bowel, which are also relevant issues in the management of the disease. We demonstrated that these features can be fully detected in adult and paediatric patients by optimizing at the outmost MRI techniques for evaluation of the bowel. Interestingly, using MRI we observed relevant differences in intestinal lesions distribution and in their activity between adult and paediatric patients.

Using generic radio-labelled radiopharmaceuticals, nuclear medicine has always demonstrated a similar sensitivity in detecting CD inflammation. Furthermore, the recent introduction of “specific” radiopharmaceuticals enables detection of specific inflammatory cytokines “in vivo”, addressing clinicians towards the most effective biological therapy. Thanks to recent technological advances, MRI may similarly assess microscopic changes in vivo within the intestinal wall, including oedema and fibrosis, vascular perfusion, diffusion of water molecules with Diffusion Weighted Imaging and molecular architecture with MR spectroscopy. The possible association of the two imaging modalities, now achievable with the PET-MRI cameras, could lead to a more comprehensive in vivo characterization of the disease, with still unexplored potentials.

PhD ceremony Ms. F.R. Grippaudo: Imaging in dermal fillers

When:Mo 13-05-2013 at 12:45

PhD ceremony: Ms. F.R. Grippaudo, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Imaging in dermal fillers

Promotor(s): prof. A. Signore, prof. N. Scuderi

Faculty: Medical Sciences

The main topic of this thesis is the diagnostic roles of imaging techniques in dermal filler evaluation. Dermal fillers are products used to enhance soft tissues for cosmetic purposes, differing in composition and durability within the soft tissues. Complications occur that show as product migration, acute or recurrent soft tissue oedema, infection, granuloma, fistulae or fibrosis. My original contribution was to clarify the role of High Frequency Ultrasound as a first line exam to ascertain the presence of a dermal filler within the soft tissues even if not evident at clinical exam, measuring its extent and nature (different injected materials may require different treatments). Recognizing the presence of a dermal filler is of paramount importance since interactions between different fillers may cause complications. The next step was to evaluate the role of MRI in dermal filler imaging as a useful and non-invasive tool: if complication occurs, Gadolinium administration is advised for better characterization of the lesion. MRI allows the visualization of dermal fillers with respect to the anatomical structures of the face, thus easing the surgical planning in case of removal. The last innovative element of this thesis was to demonstrate the role of scintigraphy with 99mTc-labelled white blood cells for the differential diagnosis between infective processes and inflammatory reactions, in order to offer the best treatment plan to patients presenting with dermal filler complications.

PhD ceremony Mr. A.G.T. Terwisscha van Scheltinga: Molecular imaging of tumor characteristics to support targeted cancer therapies. A preclinical focus on HER2, HER3, c-Met, IGF-1R and VEGF-A imaging

When:Mo 13-05-2013 at 14:30

PhD ceremony: Mr. A.G.T. Terwisscha van Scheltinga, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Molecular imaging of tumor characteristics to support targeted cancer therapies. A preclinical focus on HER2, HER3, c-Met, IGF-1R and VEGF-A imaging

Promotor(s): prof. E.G.E. de Vries, prof. J.G.W. Kosterink

Faculty: Medical Sciences

Tumor cell biology research has resulted in novel molecular targets for anticancer treatment and the development of targeted anticancer drugs. Molecular imaging using antibodies can identify noninvasively the presence of specific targets for the drugs. Moreover, it provides whole body information about tumor uptake and organ distribution of the antibodies. Besides visualization of drug distribution, these antibodies can be used to monitor tumor status during treatment effects, thereby using the receptor or ligands as biomarker. This thesis aimed at the development and preclinical application of new tracers for molecular imaging with 89Zr-labeled radiopharmaceuticals for PET imaging and fluorescent labeled antibodies for optical imaging.

The molecular characteristics which are visualized in this thesis are receptors of growth factors HER2, HER3, c-Met and IGF-1R which are often overexpressed by tumor cells. Also the pro-angiogenic growth factor ligand VEGF-A, which is often abundantly present in the microenvironment, has been used a target for tracers. The drugs acting on these targets are radioactively labeled with zirconium-89 or made fluorescent with IRDye 800CW. With 89Zr-PET the organ distribution and specific tumor uptake of new drugs targeting HER3 or c-Met was visualized. The role of fluorescent imaging in local detection of tumors, for instance during intra-operative imaging has been analyzed. It became clear that near-infrared fluorescent labeled antibodies, targeting VEGF-A or HER2, can be used to detect a tumor. The preclinical findings as described in this thesis are currently under evaluation in clinical trials.

PhD ceremony Ms. J.M. Kerstjens: Development of moderately preterm-born children

When:Mo 13-05-2013 at 16:15

PhD ceremony: Ms. J.M. Kerstjens, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Development of moderately preterm-born children

Promotor(s): prof. A.F Bos, prof. S.A. Reijneveld

Faculty: Medical Sciences

PhD ceremony Ms. J.M. da Silva Voorham: Immature dengue virus: functional properties and potential contribution to disease

When:We 15-05-2013 at 11:00

PhD ceremony: Ms. J.M. da Silva Voorham, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Immature dengue virus: functional properties and potential contribution to disease

Promotor(s): prof. J.M. Smit, prof. J.C. Wilschut

Faculty: Medical Sciences

Dengue virus (DENV) causes the most common mosquito-borne viral infection in the world. According to WHO estimates, 50-100 million dengue virus (DENV) infections occur annually in the subtropical and tropical regions of the world. DENV comprises four serotypes. Each of the serotypes can cause a spectrum of diseases, ranging from a febrile illness to a life-threatening hemorrhagic and vascular permeability syndrome. Most of the patients who develop severe disease have antibodies against different strains of the virus as a result of previous DENV infection episodes. These antibodies not only facilitate more efficient cellular uptake of virions, they also appear to modulate the immune response in infected cells thereby favoring virus particle production. This thesis describes that in the presence of antibodies, non-infectious immature DENV can become highly infectious with titers comparable to standard DENV preparations. During a heterologous secondary DENV infection - so in the presence of cross-reactive antibodies - immature virus particles can contribute to a higher virus titer and act as a co-factor in the pathogenesis of severe disease. In summary, these results show a better understanding of the mechanisms that are important in the process of DENV infection and development of disease. Moreover, these studies have potentially important implications for the development of antiviral agents and safe dengue vaccines.

PhD ceremony Mr. K.T. Buddingh: Assessment of the biliary tree. During gallbladder surgery

When:We 15-05-2013 at 12:45

PhD ceremony: Mr. K.T. Buddingh, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Assessment of the biliary tree. During gallbladder surgery

Promotor(s): prof. R.J. Ploeg

Faculty: Medical Sciences

Cholecystectomy, the surgical removal of the gallbladder, is a frequently performed procedure. A small percentage of operations are complicated by injury of the bile ducts. This often leads to extra surgical procedures and prolonged hospital stay. In this thesis we explore different modalities to assess the biliary tract and thus decrease the chance of bile duct injury.

Some techniques have become fully integrated in daily practice in the Netherlands, such as the ‘critical view of safety’ technique. A different technique, ‘intra-operative cholangiography’ has, however, almost disappeared. This development is worrisome as there is a great deal of evidence that cholangiography reduces the chance of bile duct injury. In other countries in the developed world cholangiography is practiced more often than in the Netherlands. We furthermore advocate that the best documentation of laparoscopic surgery would be by recording the full procedure on tape, in parallel to the ‘black box recorder’ in the aviation industry. The newest technique for assessment of the biliary tree is by ‘fluorescence cholangiography’. Hereby, a fluorescent agent is instilled in the biliary tract. During surgery, this fluorescent agent emits light that is captured by specialized camera’s and processed into images. This thesis shows that the technique is effective in pig gallbladders and that it is safe for use in patients.

PhD ceremony Ms. J. Hortensius: Self-monitoring of blood glucose in insulin-treated patients with diabetes

When:We 15-05-2013 at 14:30

PhD ceremony: Ms. J. Hortensius, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Self-monitoring of blood glucose in insulin-treated patients with diabetes

Promotor(s): prof. H.J.G. Bilo, prof. R.O.B. Gans

Faculty: Medical Sciences

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PhD ceremony Ms. W. Reitsma: Pelvic high-grade serous carcinoma in women with a BRCA1/2 mutation. Carcinogenesis and early diagnosis

When:We 15-05-2013 at 16:15

PhD ceremony: Ms. W. Reitsma, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Pelvic high-grade serous carcinoma in women with a BRCA1/2 mutation. Carcinogenesis and early diagnosis

Promotor(s): prof. M.J.E. Mourits, prof. G.H. de Bock, prof. H. Hollema

Faculty: Medical Sciences

Epithelial ovarian cancer is the second most common gynecological malignancy and the deadliest in terms of absolute figures. Women with a mutation in the BRCA1 or BRCA2 gene have an increased lifetime risk to develop ovarian cancer.

A nationwide study was performed to gain more insight in the tumor and survival characteristics of ovarian cancer in BRCA1 or BRCA2 mutation carriers. Results showed a significant longer progression-free and overall survival in ovarian cancer patients with a BRCA2 mutation compared to a BRCA1 mutation. These results may have implications for future studies involving new chemotherapeutic strategies for ovarian cancer.

Seventy-five percent of the ovarian cancer cases involves the aggressive high-grade serous subtype, currently known as pelvic high-grade serous cancer (PHGSC). The cell of origin of PHGSC remains unclear. To further the debate, the prevalence of precursor lesions and early development of PHGSC were investigated. We emphasize that a precursor of PHGSC has never been found in the ovary itself. However, we did find precursor lesions of PHGSC in the distal fallopian tube, called serous tubal intraepithelial carcinoma, which appoints the fallopian tube as presumed tissue of origin of PHGSC. In addition, we demonstrated that BRCA1 and BRCA2 mutation carriers have no increased risk of developing endometrial cancer.

Finally, we investigated the expression of microRNAs. The results show that a panel of microRNAs is aberrantly expressed in PHGSC in comparison to normal fallopian tube tissue, in BRCA1 mutation carriers. Further research into the significance of microRNAs for the early detection of PHGSC is therefore potentially promising.

PhD ceremony Mr. R. Golestani: New targets in cardiovascular imaging

When:We 22-05-2013 at 12:45

PhD ceremony: Mr. R. Golestani, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: New targets in cardiovascular imaging

Promotor(s): prof. R.A.J.O. Dierckx, prof. C.J.A.M. Zeebregts

Faculty: Medical Sciences

The purpose of this dissertation was to develop and validate molecular imaging methods for visualization and measurement of molecular and cellular targets involved in atherosclerotic diseases. Potentials of cardiovascular molecular imaging were investigated in animal models of disease, ex vivo human carotid endarterectomy specimens, and abdominal aorta in individuals underwent vertebral fracture assessment.

The following aspects of molecular imaging of atherosclerotic disease were investigated in this thesis: 1) a novel method to visualize abundance of VEGF in human atherosclerotic plaque; 2) feasibility of microPET imaging of alpha5beta3 integrin using a recently developed RGD-containing tracer; 3) molecular imaging of cell-death-inhibitory effects of minocycline with apoptosis- and necrosis-detecting probes, and 4) the predictive value of abdominal aortic calcification for myocardial infarction, stroke, and transient ischemic attack.

We demonstrated promising imaging targets in preclinical and ex vivo studies for the evaluation of atherosclerotic disease. This potentially helps to advance the understanding of cardiovascular disease, design novel targeted imaging methods for better risk stratification of patients with atherosclerotic disease, and speed the drug discovery efforts that target disease progression. Availability of a noninvasive, sensitive, and specific molecular imaging technique would provide clinicians incremental value to the existing imaging modalities for assessment of individuals for cardiovascular risk.


PhD ceremony Mr. E. Burstein: COMMD1: a modulator of immunity and NF-κB activity

When:We 22-05-2013 at 14:30

PhD ceremony: Mr. E. Burstein, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: COMMD1: a modulator of immunity and NF-κB activity

Promotor(s): prof. T.N. Wijmenga, prof. M.H. Hofker

Faculty: Medical Sciences

Inflammation is a genetically programmed cellular response to injury and pathogen invasion. The NF-κB transcription factor is a central regulator of this response and plays a critical role in immunity. As such, pathways that control its activity are intensively studied. Most of the work in the field has focused on activation steps that initiate NF-κB dependent gene expression, primarily by activation of the IKK complex downstream of various signal transduction pathways. Thereafter, homeostatic pathways that inactivate NF-κB and restore back the basal state are important to avert prolonged NF-κB responses and chronic inflammation. However, this has received less attention in the field. Over the past few years it has been appreciated that ubiquitin-mediated degradation of active, DNA-bound NF-κB subunits plays an important role in controlling pro-inflammatory gene expression. This pathway constitutes a major mechanism to restore the basal state in the NF-κB system, but the mechanism responsible for mediating and regulating NF-κB ubiquitination was not initially apparent. Here we identified a new protein called COMMD1, which shows to be important to promote the termination of NF-κB activity. In this thesis we present the mechanism by which COMMD1 regulates NF-κB activity and evaluate its role in controlling inflammation in vivo. The work gives new insights in the mechanism by which inflammation is regulated and reveals new potential targets to treat inflammatory diseases.

PhD ceremony Mr. D.J.A. Lok: Novel markers in chronic heart failure

When:We 22-05-2013 at 16:15

PhD ceremony: Mr. D.J.A. Lok, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Novel markers in chronic heart failure

Promotor(s): prof. D.J. van Veldhuisen

Faculty: Medical Sciences

PhD ceremony Mr. J.L. Robertus: MicroRNA profiling in B cell non-Hodgkin Lymphoma: focus on the role of MYC

When:We 29-05-2013 at 11:00

PhD ceremony: Mr. J.L. Robertus, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: MicroRNA profiling in B cell non-Hodgkin Lymphoma: focus on the role of MYC

Promotor(s): prof. J.H.M. van den Berg, prof. P.M. Kluin

Faculty: Medical Sciences

Most non-Hodgkin lymphoma (NHL) subtypes are characterized by specific chromosomal aberrations and aberrant gene expression patterns, some of which have been shown to be particularly relevant to their pathogenesis. In the past decade, research on microRNAs (miRNAs) has further contributed to knowledge about the pathogenesis of NHL, but the picture is far from complete. MiRNAs are a group of regulatory small RNAs that belong to the non-coding RNA family. MiRNAs can post-trancriptionally regulate the expression of their target genes, which include oncogenes and tumor suppressor genes, and as such contribute to tumorigenesis. Studies on miRNAs might therefore further improve our understanding of the molecular abnormalities that underlie the pathogenesis of lymphomas and cancer in general. This thesis focused on the role of miRNAs in the pathogenesis of lymphomas, in particular that of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). We identified two miRNAs that characterize the testicular and CNS DLBCL cases. We further showed marked differences in the expression pattern of the oncogenic miRNA cluster, miR-17~92 with miR-92 being the most abundant miRNA in most cases, and miR-19b being the most significantly induced miRNA as compared to their normal counterparts. We further established specific miRNA expression profiles in different NHL subtypes and showed that the profile of BL is strongly defined by MYC. Finally, we identified seven MYC regulated miRNAs that have a remarkably strong impact on growth of BL cells.

PhD ceremony Ms. B.C.H. Huijgen: Technical skills, the key to success? A study on talent development and selection of youth soccer players

When:We 29-05-2013 at 12:45

PhD ceremony: Ms. B.C.H. Huijgen, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Technical skills, the key to success? A study on talent development and selection of youth soccer players

Promotor(s): prof. C. Visscher

Faculty: Medical Sciences

PhD ceremony Ms. B.E. Sportel: At risk for social and test anxiety. Who are at risk and how can we help?

When:We 29-05-2013 at 14:30

PhD ceremony: Ms. B.E. Sportel, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: At risk for social and test anxiety. Who are at risk and how can we help?

Promotor(s): prof. R.B. Minderaa, prof. P.J. de Jong

Faculty: Medical Sciences

The fear of negative evaluation by others plays a central role in social and test anxiety. These anxiety disorders often develop early in adolescence, have a chronic course and are associated with social isolation, substance abuse and depression. The prevention and early intervention of symptoms of social and test anxiety are thus of the utmost importance.

Esther Sportel investigated the effectiveness of two training methods, both aiming to reduce symptoms of social and test anxiety. 1800 adolescents, aged 12-14 years, were screened. This resulted in the selection of 240 individuals with mild to moderate symptoms of social and test anxiety to participate in the study. They received Cognitive Bias Modification (CBM), Cognitive Behavioural Training in a group (CBT), or participated in the control group. The follow-up period was two years. Compared to the control group, CBT showed to be effective in reducing test anxiety in the short and long term. For social anxiety CBT was only effective in the short term. CBM was effective in reducing test anxiety in the long term. In conclusion, offering CBT in schools is recommended as a method for reducing test anxiety symptoms. Furthermore, Sportel investigated risk factors for developing symptoms of anxiety, i.e., the temperamental factors attentional control, behavioural inhibition and the fight-flight-freeze-system. Despite all factors are associated with symptoms of anxiety, symptoms of anxiety themselves turned out to be the best predictor for anxiety after two years. The investigated risk factors had no unique additive value in the prediction of anxiety.

PhD ceremony Ms. C.M. Woolthuis: The biology of human hematopoietic stem and progenitor cells in acute myeloid leukemia, aging and autologous transplantation

When:We 29-05-2013 at 16:15

PhD ceremony: Ms. C.M. Woolthuis, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The biology of human hematopoietic stem and progenitor cells in acute myeloid leukemia, aging and autologous transplantation

Promotor(s): prof. E. Vellenga, prof. J.J. Schuringa

Faculty: Medical Sciences

The hematopoietic system is capable of replenishing all mature blood cells during the complete lifespan of an individual. Hematopoietic stem cells are on top of the hierarchy, followed by specialised progenitors that ultimately differentiate into mature blood cells. In this thesis the biology of human hematopoietic stem and progenitor cells was studied in various settings. By gene expression profiling of a leukemic stem cell-enriched cell population in acute myeloid leukemia, we could identify a set of genes that is highly predictive for clinical prognosis. Our studies focusing on nucleophosmin-mutated acute myeloid leukemia demonstrate that MEIS1 is an important target gene for this leukemia. Moreover, we argue to use both immunohistochemical and molecular techniqus in the detection of nucleophosmin mutations, since information can be missed if only one technique is used. Given that acute myeloid leukemia is merely a disease of the elderly and age-related effects could be a factor in leukemic development, we studied the effects of increasing age on the bone marrow of healthy individuals. The results suggest that age-related changes may not be functionally relevant in steady state conditions but can become apparent in situations of chemotoxic and replicative stress. Studying bone marrow stem and progenitor cells in patients one year following autologous stem cell transplantation revealed significant long-term effects of the transplantation, including a changed progenitor composition, a higher cycling activity and persistent gene expression changes. These effects may explain the increased vulnerability to chemotherapy, which is an important clinical concern in patients following autologous transplantation.

PhD ceremony Ms. I. Miedema: Prognostic factors of functional outcome in acute ischemic stroke

When:Mo 03-06-2013 at 16:15

PhD ceremony: Ms. I. Miedema, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Prognostic factors of functional outcome in acute ischemic stroke

Promotor(s): prof. H.P.H. Kremer, prof. J. De Keyser

Faculty: Medical Sciences

In the last decades, the development of revascularisation therapy with intravenous recombinant tissue plasminogen antigen (tPA) has greatly improved the outcome of acute ischemic stroke patients, but this therapy is only available for a selected group of patients and has safety concerns. In this thesis several possible neuroprotective agents in acute ischemic stroke and some safety aspects of tPA-treatment are discussed. In a cohort of patients with acute ischemic stroke treated with intravenous tPA no improvement of functional outcome at 3 months after the event was found in patients using selective serotonin re-uptake inhibitor (SSRI) or statin. Serum uric acid levels were also unrelated to improvement outcomes in patients with acute ischemic stroke. Concerning safety, for all stroke subtypes, hyperglycemia during admission was associated with a poor functional outcome in patients treated with tPA. Using vitamin-K-antagonist in patients with normal or slightly elevated International Normalized Ratio (INR) who are treated with tPA, is associated with the risk of symptomatic intracranial hemorrhage (SICH), but not with the actual functional outcome at 3 months after ischemic stroke. In conclusion, the studies in this thesis do not support a neuroprotective effect of SSRIs, statins and serum uric acid levels in patients with acute ischemic stroke. Treatment with tPA is still the most effective therapy for acute ischemic stroke and selection of patients to reduce treatment risks is important. Use of vitamin-K-antagonist with elevated INR and admission hyperglycemia are associated with the occurrence of SICH and poor functional outcome respectively.

PhD ceremony Ms. M.L. Hoven-Gondrie: Soft-tissue sarcomas of the extremities: aspects of survival and long-term results of isolated limb perfusion

When:We 05-06-2013 at 14:30

PhD ceremony: Ms. M.L. Hoven-Gondrie, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Soft-tissue sarcomas of the extremities: aspects of survival and long-term results of isolated limb perfusion

Promotor(s): prof. H.J. Hoekstra, prof. A.J.H. Suurmeijer

Faculty: Medical Sciences

All patients ≥18 years, diagnosed with extremity soft-tissue sarcoma between 1989 and 2008, are analysed with data from the Netherlands Cancer Registry, in order to assess time trends in presentation, treatment and survival. Furthermore, research was performed to discover differences in presentation, treatment and survival of extremity soft-tissue sarcoma patients of different age groups and to assess the impact of age on relative survival of these patients in the Netherlands. As elderly patients are at risk for over- as well as under-treatment, are less often included in clinical trials, and less often referred to a specialized sarcoma care centre, we performed this study on soft-tissue sarcoma care in the elderly to gain better insight into treatment and survival differences.

For patients with primarily irresectable locally advanced extremity soft-tissue sarcomas an established treatment strategy is isolated limb perfusion (ILP) with TNFα and melphalan, followed by delayed surgical resection and, if indicated, external-beam radiotherapy. With a long-term limb-salvage rate of 78% and a local recurrence rate of 14%, ILP appears to be a safe and effective procedure, although long-term damage to the healthy surrounding tissues cannot be prevented. Sometimes major late vascular morbidity even requires amputation. After 20 years of experience with this combined modality treatment, we evaluated the safety and effectiveness of changes in the procedure of ILP, such as dose reduction of TNFα and shorter duration of ILP, morbidity of the procedure, and long-term patient outcomes.

PhD ceremony Ms. J.E. Hartman: Physical activity in patients with chronic obstructive pulmonary disease

When:We 05-06-2013 at 16:15

PhD ceremony: Ms. J.E. Hartman, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Physical activity in patients with chronic obstructive pulmonary disease

Promotor(s): prof. H.M. Boezen

Faculty: Medical Sciences

The many health benefits of regular physical activity underline the importance of this topic, especially nowadays since a sedentary lifestyle is increasing. While physical activity has many health benefits in general, the physical activity level in COPD patients is low, compared with a healthy population but also with other patient groups. Physical activity is a modifiable risk factor and therefore an important treatment target in this patient group. This thesis investigated physical activity and its potential predictors in COPD patients in all severity stages of the disease, the suitability of general physical activity recommendations in COPD patients, and the association between decreased lung hyperinflation and physical activity.

As expected, disease-specific physical factors, like dyspnea, exercise capacity and muscle function, affected the physical activity level in COPD patients. Besides physical predictors, we also identified psychosocial, including motivational, and environmental factors that affected the physical activity level. In patients with mild to moderate COPD the predictors of physical activity were found to be more generic in contrast to the physical and disease-specific determinants in patients with more severe disease stages. Lung hyperinflation was found to be an important independent predictor of physical activity but improving lung hyperinflation with bronchoscopic lung volume reduction did not automatically increase physical activity in patients with severe emphysema. Finally, we found that applying slightly altered general physical activity recommendations, e.g., frequency, intensity or time, leads to large differences in classifying whether COPD patients are physically activity or not.

PhD ceremony Ms. N.M. Vink: The role of stress in the etiology of asthma

When:Mo 10-06-2013 at 12:45

PhD ceremony: Ms. N.M. Vink, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of stress in the etiology of asthma

Promotor(s): prof. H.M. Boezen, prof. J.G.M. Rosmalen, prof. D.S. Postma

Faculty: Medical Sciences

Asthma is a chronic inflammatory disease of the airways characterized by variable airway obstruction in association with increased airway hyper-responsiveness. Many pathways are potentially involved, including multiple genetical pathways, environmental factors, and gene-environment interactions are known to be associated with the development of asthma. However, these factors cannot fully explain the increased incidence of asthma that occurred during the past decennia. Therefore, hypotheses on determinants other than those addressing genetic predisposition, environmental exposures and gene-environment interactions have been put forward. One of these is psychological stress. Results from this thesis show that perinatal stress exposure and exposure to stressful life events before 4 years of age are significantly associated with asthma development up to age 16 years. In utero exposure to maternal smoking explains a small part of the association between perinatal stress and asthma development. The hypothalamic-pituitary-adrenal axis does not seem to play a role in the development of asthma. We found no significant association between cortisol and asthma (age 11 years) or asthma development (age 14 or 16 years). In addition, no association was observed between level of cortisol after stress and asthma (age 16 years). Also no association was observed between SNPs in receptors that binds cortisol (NR3C1 or NR3C2) and asthma or asthma development.

PhD ceremony Ms. M.J.M. Gooden: Immunologic aspects of ovarian cancer

When:Mo 10-06-2013 at 16:15

PhD ceremony: Ms. M.J.M. Gooden, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Immunologic aspects of ovarian cancer

Promotor(s): prof. H.W. Nijman, prof. C.A.H.H. Daemen

Faculty: Medical Sciences

Ovarian cancer is the most lethal gynecologic malignancy, because it is usually diagnosed at a late stage and current treatment (surgery and chemotherapy) is often not successful in eradicating the disease altogether. Thus, it is important to find new treatment options. In this context, attacking the tumor via the patient’s own immune system is a promising strategy. Immune cells are capable of recognizing cancer cells, because cancer cells differ from healthy cells. In this process of recognition and destruction of cancer cells, T-lymphocytes play a key role.

The objective of this thesis is to characterize the immune response against ovarian cancer cells. First, we determined which T-lymphocyte subsets are present in ovarian cancer. We found that the presence of cytotoxic T-lymphocytes, which are capable of destroying cancer cells directly, is predictive of a better prognosis. Moreover, a high ratio between these cytotoxic T-lymphocytes and immunosuppressive regulatory T lymphocytes is an even stronger predictor. However, the tumor has several mechanisms to counteract the immune response. We investigated components of the antigen processing and presentation pathway, which is key in recognition of tumor cells by immune cells. Also, we determined HLA-E expression, which can inhibit cytotoxic T-lymphocytes via a specific receptor which is not normally present on these T-lymphocytes. We indeed found that an intact antigen processing and presentation apparatus and a lack of HLA-E expression predicted the success of the anti-tumor immune response. Next, we investigated the role of chemokine CXCL16. The soluble form, sCXCL16, can be measured in blood. Surprisingly, it was not predictive of lymphocyte invasion in the tumor, but instead strongly predicted shorter survival. Further in vitro studies revealed that the presence of sCXCL16 was a reflection of the activity of certain protein cleaving enzymes, i.e. ADAMs. These enzymes are necessary for release of sCXCL16 in the blood stream, but also play a key role in tumor metastasis. Since ADAM activity is difficult to quantify in patients, sCXCL16 is a suitable pseudo-marker. Finally, we investigated a potentially T-lymphocyte activating glycoprotein, Galectin-9, which can be found in ascites (abdominal fluid) of ovarian cancer patients. It is thought to destroy T-lymphocytes, but we showed that in low doses, it is actually a potent activator of T-lymphocytes. Further studies are performed to determine whether Galectin-9 is indeed of potential use in (ovarian) cancer treatment.

PhD ceremony Mr. T. Klok: Determinants of adherence to inhaled corticosteroids in children with asthma

When:We 12-06-2013 at 11:00

PhD ceremony: Mr. T. Klok, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Determinants of adherence to inhaled corticosteroids in children with asthma

Promotor(s): prof. P.L.P. Brand, prof. A.A. Kaptein, prof. E.J. Duiverman

Faculty: Medical Sciences

PhD ceremony Mr. M. Bragaru: Sports and amputation

When:We 12-06-2013 at 12:45

PhD ceremony: Mr. M. Bragaru, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Sports and amputation

Promotor(s): prof. J.H.B. Geertzen, prof. P.U. Dijkstra

Faculty: Medical Sciences

Amputation of a limb usually has a negative impact on psycho-social and physical wellbeing. If clinical data from the general population are considered, one way to decrease this negative impact may be through regular participation in sports. Unfortunately, for individuals with limb amputations less is known on the influence of sports participation. The current research aimed to identify this influence and the participation rate in sports of these individuals.

Results of a systematic review identified that individuals with limb amputations may experience the same benefits of sports as the general population. Despite this, only 15% of individuals with lower limb amputations participate in sports at least 5 hours a month, while 57% of the individuals with upper limb amputations participate in sports for at least 4 hours a month. In general poor health, smoking, an age older than 60 years, and a vascular cause of amputation are negatively associated with sports participation. The desire to stay healthy, pleasure derived from sports, and psycho-social benefits represent the main reasons to start and continue participating in sports. Meanwhile, the lack of motivation, inadequate facilities, trivialization by others, and poor health were barriers commonly mentioned by the participants in this research. Support from family, sport partners or even strangers may offer the boost needed to overcome most of the barriers experienced.

In conclusion, sports should be introduced at an early stage in the rehabilitation program of individuals with limb amputations and each individual should receive a sport advice tailored to his/hers personal barriers and desires.

PhD ceremony Ms. M. van der Velde: Renal risk markers and patient prognosis in chronic kidney disease

When:We 12-06-2013 at 14:30

PhD ceremony: Ms. M. van der Velde, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Renal risk markers and patient prognosis in chronic kidney disease

Promotor(s): prof. P.E. de Jong

Faculty: Medical Sciences

Read press release Measuring albumin in urine allows early detection of chronic kidney disease

PhD ceremony Ms. A. Klooster: Thiamine, fasting and the kidney

When:We 12-06-2013 at 16:15

PhD ceremony: Ms. A. Klooster, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Thiamine, fasting and the kidney

Promotor(s): prof. H. van Goor

Faculty: Medical Sciences

In this thesis we researched the role of thiamine in ischaemia-reperfusion injury of the kidney. Thiamine is crucial for optimal amounts of reduced glutathione (anti-oxidant) and for regeneration of ATP (energy source) in cells. We describe the hypothesis that thiamine deficiency is an important determinant of the occurrence of acute tubule necrosis and delayed graft function in kidney transplantation.    

We could not show that thiamine deficiency aggravated ischaemia-reperfusion injury. Moreover, when thiamine deficiency was complicated by a decreased food intake and weight loss this prevented ischaemia-reperfusion injury. Thereby we surmised that the weight loss and reduced food may explain the unexpected protective effect.

We also investigated the hypothesis whether benfotiamine could decrease albuminuria in diabetic nephropathy. We did not find an effect of benfotiamine treatment on albuminuria and other markers of kidney damage. Also, we were unable to find an effect of peri-operative fasting on ischaemia-reperfusion injury in rats.

In renal transplant recipients we describe the protective effects of non-esterified fatty acids and malondialdehyde on graft failure. When people are fasted these markers will rise.

Therefore, we also studied whether caloric restriction in combination with ketogenic diet protects against nephropathy in a proteinuric rat model. We showed that caloric restriction lowers proteinuria and decreases renal damage. This was irrespective of ketogenesis since a ketogenic diet did not shown any changes. This suggests that other mechanisms rather than ketogenesis underlie the beneficial effects of caloric restriction.

PhD ceremony Ms. M.H.C. Theunissen: The early detection of psychosocial problems in children aged 0 to 6 years by Dutch preventive child healthcare. Professionals and their tools

When:Mo 17-06-2013 at 11:00

PhD ceremony: Ms. M.H.C. Theunissen, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The early detection of psychosocial problems in children aged 0 to 6 years by Dutch preventive child healthcare. Professionals and their tools

Promotor(s): prof. S.A. Reijneveld

Faculty: Medical Sciences

PhD ceremony Ms. I. Arends: Prevention of recurrent sickness absence in workers with common mental disorders

When:Mo 17-06-2013 at 12:45

PhD ceremony: Ms. I. Arends, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Prevention of recurrent sickness absence in workers with common mental disorders

Promotor(s): prof. J.J.L. van der Klink, prof. U. Bültmann

Faculty: Medical Sciences

Workers who returned to work after sickness absence due to common mental disorders (CMDs) frequently experience recurrent sickness absence. Standard treatment by occupational physicians (OPs) in the Netherlands has limited attention for the prevention of recurrent sickness absence. For this reason, the “SHARP-at work” intervention was developed. This is a problem solving intervention, provided by OPs to workers who returned to work after sickness absence due to CMDs, to prevent recurrent sickness absence. The intervention was compared to care as usual by OPs. The results showed that the intervention was properly applied by the OPs. Furthermore, over a period of one year, the intervention reduced the risk of recurrent sickness absence with 60%. When recurrent sickness absence occurred, the mean time to a recurrent episode was 100 days longer for the participants treated with the intervention.

In an economic evaluation, the effects of the intervention were weighed against the costs, for example due to extra care by the OP. This evaluation showed that, although the intervention was effective, it was also more costly. Important to note is that this result was extremely influenced by one participant who had very high costs due to psychiatric hospitalisation with no relationship to the intervention. When this participant was not included in the results, the intervention was cost-effective. For decision making about the implementation of the intervention into practice, the costs, effects and applicability in a specific context need to be considered.

PhD ceremony Ms. W. Annema: Understanding HDL function. Studies in preclinical models and patients

When:Mo 17-06-2013 at 14:30

PhD ceremony: Ms. W. Annema, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Understanding HDL function. Studies in preclinical models and patients

Promotor(s): prof. U.J.F. Tietge

Faculty: Medical Sciences

High-density lipoprotein (HDL) function is a novel concept in cardiovascular research. The aim of the thesis was to provide more insight into the importance of HDL function for cardiovascular risk.

A key function of HDL in cardiovascular protection is reverse cholesterol transport (RCT). HDL-mediated macrophage-to-faeces RCT was markedly impaired in mice with lipopolysaccharide-induced acute inflammation. Moreover, in mice with type 1 diabetes mellitus RCT was reduced due to decreased selective uptake of HDL cholesteryl esters in the liver. Conversely, over-expression of apolipoprotein E, which has been associated with lower atherosclerosis in different mouse models, did not affect RCT from macrophages to faeces. Additional studies in patients showed that two key anti-atherogenic functionalities of HDL were impaired in patients with a severe acute myocardial infarction and this reduction in HDL function was related to increased plasma levels of myeloperoxidase in these patients. In addition, there was a positive association between the functionality of HDL and the function of pancreatic β-cells in patients with type 2 diabetes mellitus, suggesting that HDL function may contribute to the maintenance of β-cell function. Finally, prospective studies in renal transplant recipients showed that HDL cholesterol efflux function is not associated with cardiovascular and overall mortality but is a significant independent predictor of graft failure after kidney transplantation. In conclusion, although important information can be derived from assessment of HDL function over mere HDL cholesterol mass levels, large-scale prospective population-based studies are required to conclusively test a potential causal relationship between HDL function and disease.

Inaugural Lecture Mr. prof. A.W. Friedrich: From Fibonacci to Dynamic Networks: art and science of maintaining health in a connected life

When:Tu 18-06-2013 at 16:15

Inaugural Lecture: Mr. prof. A.W. Friedrich, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: From Fibonacci to Dynamic Networks: art and science of maintaining health in a connected life

Chair: Medische microbiologie

Faculty: Medical Sciences

PhD ceremony Ms. H. Liu: Improvement of influenza vaccines by using a saponin-derived adjuvant

When:We 19-06-2013 at 11:00

PhD ceremony: Ms. H. Liu, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Improvement of influenza vaccines by using a saponin-derived adjuvant

Promotor(s): prof. A.L.W. Huckriede, prof. J.C. Wilschut

Faculty: Medical Sciences

Effective influenza vaccines should protect individuals from influenza infection and reduce the socio-economic burden imposed by the disease. Current influenza vaccines, however, show only partial efficacy and effectiveness in healthy adults. Moreover, proof of satisfactory protection among small children and the elderly, the most vulnerable populations for influenza infection, is still lacking. In this thesis, we show that the immunogenicity and protective capacity of influenza vaccines can be significantly potentiated by the incorporation of the adjuvant GPI-0100 in the vaccine. GPI-0100 is a molecule from the bark of the soap bark tree Quillaja saponaria. In mice, influenza vaccines containing GPI-0100 elicit significantly improved immune responses of higher magnitude and better quality, when compared to those induced by the same vaccines without GPI-0100. Importantly, substantial protection of the lungs can be achieved by vaccination with GPI-0100-containing influenza vaccines at an extremely low antigen dose. This can be particularly beneficial during pandemics when vaccine demand is huge, but antigen supply limited. Therefore, GPI-0100 can help to overcome the limitations concerning immunogenicity and availability of current influenza vaccines. We also show that the performance of GPI-0100-adjuvanted influenza vaccine can be further improved by choosing an optimal antigen formulation (e.g., reconstituted viral envelopes) and route of vaccine administration (e.g., pulmonary immunisation).

PhD ceremony Mr. W. Jorritsma: Disability in patients with chronic neck pain. The clinimetric properties of instruments

When:We 19-06-2013 at 12:45

PhD ceremony: Mr. W. Jorritsma, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Disability in patients with chronic neck pain. The clinimetric properties of instruments

Promotor(s): prof. J.H.B. Geertzen, prof. M.F. Reneman, prof. P.U. Dijkstra

Faculty: Medical Sciences

This thesis focussed on the study of clinimetric properties of instruments to measure disability in patients with non specific chronic neck pain (CNP) admitted for multidisciplinary out-patient pain rehabilitation in a tertiary rehabilitation setting. Disability can be assessed by means of questionnaires, clinical assessment (based on clinical history and physical examination), functional testing (for instance a functional capacity evaluation (FCE))or by a combination of these methods.

A patient’s self report of perceived disability is often assessed with region-specific and general health questionnaires. The most frequently used neck disability questionnaires are the neck pain and disability scale (NPAD) and the neck disability index (NDI). The Dutch language versions of both NPAD and NDI had acceptable clinimetric properties but the NDI was slightly better. After the start of the rehabilitation program approx. 33% of the patients dropped out. Based on global perceived effect scores, 59% of the patients who completed the program was completely or much recovered. The Short Form-36 Health Survey (SF-36) is a widely used general health questionnaire. To measure self-reported general health the Dutch language version of the SF-36 has good construct validity and can be used in patients with non-specific CNP. In conclusion, for the clinician based assessment of disability during physical examination the physical dysfunction severity and the modified cervical non organic signs may offer relevant information in the biopsychosocial diagnosis of patients with CNP. For the performance based assessment of disability the proposed neck-FCE may be useful.

PhD ceremony Mr. J.A. Stigt: Thoracic masses. From chest radiography and ultrasound guided biopsies to molecular biology

When:We 19-06-2013 at 14:30

PhD ceremony: Mr. J.A. Stigt, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Thoracic masses. From chest radiography and ultrasound guided biopsies to molecular biology

Promotor(s): prof. H.J.M. Groen

Faculty: Medical Sciences

This thesis describes explorative studies and case reports on diagnosing thoracic masses.

The diagnostic accuracy of endoscopic ultrasound (EUS) guided mediastinal lymph node sampling was compared with PET scintigraphy in restaging non-small cell lung cancer after treatment with concurrent chemoradiotherapy. An orthopedic application and a complication of EUS are described in case reports. The diagnostic performance of percutaneous ultrasound guided aspirations and biopsies was studied in patients suspected of having lung cancer. All lesions were detected with PET scintigraphy. The diagnostic accuracy of percutaneous ultrasound guided biopsies in the subcategory of patients with a mesothelioma (characterized by the absence of pleural effusion) was evaluated. The radiological and pathological characteristics of incidentally detected mediastinal lymphadenopathy on CT scans was described. A standardized diagnostic program for patients with an abnormal chest radiograph (suspected for lung cancer) was evaluated. Patients underwent PET scintigraphy in the morning followed by invasive diagnostics in the afternoon using bronchoscopy, EUS, EBUS and percutaneous ultrasound guided biopsies. Histological biopsies were compared with cytological samples (both obtained with EUS) for diagnosing masses as well as sub-typing malignancies and DNA analysis in case of adenocarcinoma. Two diagnostic strategies (pyrosequencing and HRM/Sanger sequencing) were compared in the mutation analysis of tumour DNA of archived EUS and EBUS samples. Finally, a review article describes all aspects relevant in diagnosing thoracic masses.

PhD ceremony Mr. K.P. Wevers: Progression in melanoma considerations and implications in dissecting nodal fields

When:We 19-06-2013 at 16:15

PhD ceremony: Mr. K.P. Wevers, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Progression in melanoma considerations and implications in dissecting nodal fields

Promotor (s): prof. H.J. Hoekstra

Faculty: Medical Sciences

Cutaneous melanoma, which is the most malignant skin cancer type, has one of the fastest increasing incidence rates of all cancers in the western world. In the Netherlands, its incidence has more than doubled over the past two decades. In 2013, about 5000 people in the Netherlands and will be diagnosed with melanoma.

The sentinel lymph node biopsy has enabled better selection of those melanoma patients who are most likely to benefit from dissection of their regional lymph node basin. However, still 80% of sentinel-node positive patients have no metastases found in the additionally dissected lymph nodes. Research shows that combining patient and tumour characteristics with the melanoma biomarker S-100B, enables risk stratification for narrowing the selection of patients for complete lymph node dissection. In case of clinically manifest nodal metastases, a regional lymph node dissection improves regional control and survival. Furthermore, it was shown that nodal metastases in the neck have a better prognosis compared to axillary and groin sites. Moreover, the preoperatively measured biomarker S-100B is one of the most important predictors of melanoma prognosis in these patients.

In conclusion, this thesis reveals different clinicopathological factors that improve the staging of melanoma patients with nodal metastases, as well as patient selection for lymph node dissection and experimental (neo)adjuvant systemic therapy. The results contribute to the optimization of the surgical management of melanoma patients with nodal metastases and their survival.

PhD ceremony Ms. D. Bobáková: Youth subcultures and problem behaviours in Slovakia. Hip-hop, techno-scene, metal, punk, skinheads, and Roma

When:Mo 24-06-2013 at 12:45

PhD ceremony: Ms. D. Bobáková, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Youth subcultures and problem behaviours in Slovakia. Hip-hop, techno-scene, metal, punk, skinheads, and Roma

Promotor(s): prof. S.A. Reijneveld

Faculty: Medical Sciences

Lifestyle, music preference, shared values and behaviours of young people can be understood as components of youth subcultures. This thesis captures a wide range of health- and school-related problem behaviours in youth subcultures such as Hip-hop, Punk, Skinheads, Techno-scene, Metal and, very specifically, the Roma subculture. It assesses the associations between subculture affiliation and problem behaviours (substance use, fighting, truancy, low academic achievement, and early sexual initiation) and whether peer and parent factors affect these associations.

In line with previous studies of subcultures, we found youth subcultures to be associated with various problem behaviours. Our study showed adolescents with subculture affiliation to be strongly influenced by peers regarding their behaviour. In contrast, the role of common protective factors in youth subcultures seems to be rather limited. Roma subculture differs from music-based subcultures, as we found lower levels of drunkenness and peer influence and stronger parental monitoring in Roma compared with non-Roma.

Preventive strategies could be targeted toward adolescents with a subculture affiliation, as they are at higher risk of problem behaviour, as well as their parents. Our results imply that the common cause of problem behaviour in youth subcultures might be a lack of protective factors as result of rebellion against parents and against conforming to society, which is embodied in youth subcultures. Another explanation could be that the lack of protective factors leads to problem behaviour, which gathers adolescents in youth subcultures via peer selection. These causal pathways are relevant for future research.

PhD ceremony Ms. K. Rosicová: Regional mortality in Slovakia: socioeconomic indicators and ethnicity

When:Mo 24-06-2013 at 14:30

PhD ceremony: Ms. K. Rosicová, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Regional mortality in Slovakia: socioeconomic indicators and ethnicity

Promotor(s): prof. J.W. Groothoff

Faculty: Medical Sciences

Regional differences in mortality might reflect socioeconomic and ethnic differences between regions. This study examines the contribution of selected socioeconomic indicators (education, unemployment, income, material need) and the proportion of the Roma minority on regional differences in mortality by age and gender in the Slovak Republic. Poisson regression (linear, multilevel), correlations and a non-parametric regression tree were used to analyze these data. Socioeconomic indicators, such as education, unemployment or poverty, significantly contributed to regional differences in mortality in the Slovak Republic. The male population seems to be more vulnerable to their effect, particularly in the cases of alcohol-related mortality and unemployment. A significant group of the population at risk consists of Roma living in settlements. The proportion of Roma is the strongest predictor of regional perinatal and infant mortality in the Slovak Republic and of urban mortality in Slovakia’s two biggest cities. The proportion of inhabitants in material need was the most important economic indicator associated with the mortality rate among districts in both explored periods (1997–1998 and 2007–2008). Developing and implementing policies aimed at reducing socioeconomic inequalities in mortality and addressing the health needs of the most deprived groups, and the most deprived areas, seems to be important for the country’s further economic development. Attention should therefore be paid on the population at risk – mainly the population living in Roma settlements – and successful strategies and tools (e.g. Roma mediators); their sustainability should be evaluated.

PhD ceremony Mr. J.M. Hallegraeff: Common musculoskeletal disorders in primary care physiotherapy: assessment and intervention. Acute low back pain and nocturnal leg cramps

When:Mo 24-06-2013 at 16:15

PhD ceremony: Mr. J.M. Hallegraeff, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Common musculoskeletal disorders in primary care physiotherapy: assessment and intervention. Acute low back pain and nocturnal leg cramps

Promotor(s): prof. C.P. van der Schans

Faculty: Medical Sciences

There is tension between the needs of patients with acute nonspecific low back pain and guidelines that recommend to wait with treatment. Modifiable personal factors such as expectations and perceptions should be inventoried in the acute stage of low back pain to assess the risk for transition to chronic low back pain.

Patients with negative recovery expectations to recover from acute low back pain have a twice as high risk to develop chronic low back pain, compared to patients without such negative expectations. Pain perception importantly influences a patients’ coping style. A passive or inadequate coping style was also found to increase the risk for transition to chronic low back pain. The Illness Perception Questionnaire-Brief (IPQ-B) is frequently used to measure pain perception but the psychometric properties in the population with low back pain were not yet investigated. In a cross-sectional psychometric study we showed that the B-IPQ is a reliable and valid instrument for patients with acute low back pain. In another cross-sectional study we found that the Low Back Pain Perception Questionnaire (LBPPS) did not produce adequate and acceptable results for patients with acute low back pain. We advise to use this instrument with caution.

In a RCT we investigated the effect of manual therapy in the acute stage of patients with low back pain (<16 days) without appearance of pain distal to the knee. The results showed a stronger decrease in activity limitations than physiotherapy in this acute stage of low back pain. Finally, in another RCT we investigated the effect of stretching the hamstrings and calf muscles by older patients (> 55 years) with nocturnal leg cramps (NLC) before going to bed. In the six weeks trial a significant decrease in pain and frequency of NLC was demonstrated.

PhD ceremony Ms. A. Sijtsma: Physical activity and overweight in young children

When:Tu 25-06-2013 at 11:00

PhD ceremony: Ms. A. Sijtsma, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Physical activity and overweight in young children

Promotor(s): prof. P.J.J. Sauer, prof. R.P. Stolk

Faculty: Medical Sciences

Read press release: Young children need fewer calories than previously thought

PhD ceremony Mr. V.M. van Deursen: Comorbidity in heart failure

When:We 26-06-2013 at 12:45

PhD ceremony: Mr. V.M. van Deursen, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Comorbidity in heart failure

Promotor(s): prof. A.A. Voors, prof. D.J. van Veldhuisen

Faculty: Medical Sciences

Heart failure is a clinical syndrome characterised by the heart’s inability to meet the body’s circulatory demands. Patients with heart failure have a poor quality of life and high morbidity and mortality. In recent decades, growing evidence has accumulated about other diseases and dysfunction of other organs in patients with heart failure. These ‘co-morbidities’ frequently accompany heart failure and result in worse quality of life and clinical outcome.

In this thesis we aimed to assess (i) the prevalence of individual and multiple co-morbidities in patients with heart failure and whether the prevalence is higher than in age-matched controls, (ii) the pathophysiologic mechanisms connecting heart failure with individual co-morbidities as well as determinants of multiple co-morbidities, (iii) the prognostic influence of co-morbidities. We focussed on co-morbidities in general as well as renal and liver dysfunction separately. Patients with acute and chronic heart failure were both studied. In conclusion, co-morbidities frequently accompany heart failure and worsen morbidity and mortality. In accordance, the prevalence of co-morbidities is much higher in heart failure patients compared to an age-matched population. Although heart failure has a potential causal relation, the complex pathophysiological mechanisms remain unresolved. Next to known pathophysiological factors, our research shows ate hemodynamic factors (i.e. decreased cardiac output and raised central venous pressure) are important as well.

PhD ceremony Ms. C.A.I. Stramrood: Posttraumatic stress following pregnancy and childbirth

When:We 26-06-2013 at 14:30

PhD ceremony: Ms. C.A.I. Stramrood, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Posttraumatic stress following pregnancy and childbirth

Promotor(s): prof. W.C.M. Weijmar Schultz, prof. A.J.J.M. Vingerhoets, prof. P.P. van den Berg

Faculty: Medical Sciences

Read press release: Meer dan 2000 vrouwen ontwikkelen elk jaar PTSS na de bevalling

PhD ceremony Ms. N.K.S. de Vries: Early motor repertoire of infants at risk

When:We 26-06-2013 at 16:15

PhD ceremony: Ms. N.K.S. de Vries, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Early motor repertoire of infants at risk

Promotor(s): prof. A.F. Bos

Faculty: Medical Sciences

Assessment of the quality of the spontaneous motor repertoire has proven to be valid for all infants from birth until 4-5 months as a measure for neurological function (i.e., at a particular moment in time) and neurological outcome.

In this thesis, we assessed the quality of general movements (GMs) and a detailed motor optimality score (OS) in various groups of infants. We found that abnormal GMs during the first days of life are common, both in healthy full term, and in preterm infants. In healthy full term infants normalisation of GM quality occurs from the fifth day after birth onwards. In preterm infants, and even extremely low birth weight infants (ELBW, birth weight <1000gr), we found that having at least one normal GM assessment during the first two weeks of life, was related to a high chance of a normal neurological outcome.

Chaotic features of GMs are seen early in life in several groups of infants. They are probably due to transient destabilisation of the brain and not indicative of permanent brain damage.

At term-equivalent age, we found cramped and stiff movements in ELBW infants, which appeared not to be indicative of an abnormal neurological outcome. Infants who were exposed to an antidepressant agent (SSRI) prenatally, showed neurological effects that reflected a more abnormal GMs with lower OS in the first days after birth. After 3-4 months after term these effects persisted as more monotonous movements; they were independent of maternal mood.

PhD ceremony Ms. P.Y.W. Dankers: Renal regenerative medicine. Bioengineering of cell-based membranes and anti-inflammatory drug delivery

When:Mo 01-07-2013 at 12:45

PhD ceremony: Ms. P.Y.W. Dankers, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Renal regenerative medicine. Bioengineering of cell-based membranes and anti-inflammatory drug delivery

Promotor(s): prof. M.J.A. van Luyn

Faculty: Medical Sciences

Deterioration of kidney function is typically slow but progressive, and occurs in every person upon aging. Fortunately, not everybody develops chronic kidney disease (CKD). Kidney disease is often diagnosed in a late stage, and not until renal function has dropped below 10%, replacement therapy is needed. Kidney transplantation provides a solution for long-term replacement of kidney function. Nevertheless, because of the shortage of sufficient donors, most end-stage renal disease (ESRD) patients receive dialysis therapy. Dialysis is life-saving at short term, but falls short of long-term efficacy and most dialysis patients remain in poor health. Consequently, innovative strategies towards new kidney therapies for patients with CKD or ESRD, based on regenerative medicine approaches are needed.

In this thesis we explore two renal regenerative medicine approaches. The first strategy is based on the amelioration of dialysis using cell-based membranes to be applied in a bioartificial kidney in conjunction with the conventional dialysis apparatus. We introduced new, synthetic membranes and investigated the source of human epithelial cells and endothelial cells to be applied on these membranes. This strategy ultimately aims at a solution for ESRD patients. The second approach consists of the local, intrarenal drug delivery of a proteinaceous anti-inflammatory and anti-fibrotic drug from a hydrogel carrier implanted under the kidney capsule. This may in future be applied for kidney transplantation patients, who develop post-operative ischemia/reperfusion injury and/or severe inflammation leading to graft failure and/or rejection.

PhD ceremony Mr. V. Kannan: Modulation of microglial activity

When:Mo 01-07-2013 at 14:30

PhD ceremony: Mr. V. Kannan, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Modulation of microglial activity

Promotor(s): prof. H.W.G.M. Boddeke

Faculty: Medical Sciences

Microglia are the primary immune cells of the central nervous system. Microglia are important for neuronal support, tissue homeostasis, antigen presentation and removal of apoptotic cells. Normally, microglia are highly ramified and are responsible for immune surveillance. Under pathological conditions, microglia can become activated and transform to an amoeboid shape with an increased expression of surface markers and release of inflammatory cytokines for repair and tissue regeneration. Excessive microglia activation is associated with neurodegenerative conditions and ageing.

Therefore, it is important to identify factors that can modulate microglia inflammatory responses. Here, histone deacetylases (HDACs) were studied as factors modulating inflammatory responses in primary microglia and in experimental autoimmune encephalomyelitis, a demyelinating disorder. Microglia express a variety of receptors to monitor their surroundings, including purinergic and chemokine receptors. Purinergic receptors are important sensors of neuronal stress and the purinergic P2X7 receptor is involved in neuronal protection. The neuroprotective effect of the P2X7 receptor, and the effect of HDAC inhibitors on P2X7 expression by microglia was investigated in hippocampal slice cultures. Chemokine receptors and chemokines are important for the regulation of microglia migration. Inhibition of CXCR3-mediated microglia chemotaxis by chemokine-like receptor CCX-CKR was determined.

Summarizing, the data presented in this thesis show that HDACs have an important role in the glial inflammatory response and are possibly important targets in demyelinating disorders. Purinergic and chemokine receptors were demonstrated to have an important role in the regulation of inflammatory responses in microglia and other immune cells.

PhD ceremony Ms. D.M. Zelle: Lifestyle, the next target for intervention in renal transplant recipients

When:Mo 01-07-2013 at 16:15

PhD ceremony: Ms. D.M. Zelle, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Lifestyle, the next target for intervention in renal transplant recipients

Promotor(s): prof. G.J. Navis, prof. R.P. Stolk

Faculty: Medical Sciences

PhD ceremony Mr. M.R. Kapma: Outcomes and costs of endovascular and open repair in patients with a ruptured abdominal aortic aneurysm

When:We 04-09-2013 at 11:00

PhD ceremony: Mr. M.R. Kapma, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Outcomes and costs of endovascular and open repair in patients with a ruptured abdominal aortic aneurysm

Promotor(s): prof. C.J.A.M. Zeebregts

Faculty: Medical Sciences

Endovascular Aneurysm Repair (EVAR) is feasible for treatment of Ruptured Abdominal Aortic Aneurysm (RAAA), together with conventional Open Repair (OR). This thesis describes the outcomes and costs of EVAR versus OR in RAAA. The excellent first results of this technique were analyzed. The necessary logistics for this minimally invasive technique were described. The results of risk-predicting scoring methods were studied. To evaluate the cost-effectiveness of EVAR versus OR in the treatment of RAAA two studies were performed, a Groningen study and a the Amsterdam AJAX trial.

When these two studies are evaluated together a clear view on the cost-effectiveness of EVAR in the treatment of RAAA can be postulated: a preferential strategy by EVAR for RAAA patients can be cost effective, although there will always be a role for open repair.

In conclusion: the introduction and widespread implementation of EVAR has been worthwhile in the treatment of RAAA.

PhD ceremony Mr. A.E. de Vries: The use of computer decision support systems and telemonitoring in heart failure

When:We 04-09-2013 at 12:45

PhD ceremony: Mr. A.E. de Vries, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The use of computer decision support systems and telemonitoring in heart failure

Promotor(s): prof. H.L. Hillege, prof. T. Jaarsma, prof. R.J.J.M. Jorna

Faculty: Medical Sciences

This thesis focuses on two examples of innovative ICT developments in health care that can be used for patients with heart failure: telemonitoring (TM) and computer decision support systems (CDSS). This thesis shows that innovative information and communication technologies such as telemonitoring and computer decision support systems are promising tools that may help to support and improve care for heart failure patients. However, TM and CDSS are not 'one size fits all "solutions and TM does not automatically reduce readmissions, mortality and improve the quality of life.

PhD ceremony Ms. G.M. de Kuijper: Aspects of long-term use of antipsychotic drugs on an off-label base in individuals with intellectual disability

When:We 04-09-2013 at 14:30

PhD ceremony: Ms. G.M. de Kuijper, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Aspects of long-term use of antipsychotic drugs on an off-label base in individuals with intellectual disability

Promotor(s): prof. R.B. Minderaa, prof. H.M. Evenhuis

Faculty: Medical Sciences

Read press release: Decrease in Problem Behaviour following discontinuation of antipsychotics in Individuals with Intellectual Disability

PhD ceremony Mr. H.G. van Keeken: Model and measurement studies on stages of prosthetic gait. Predictions on how not to walk symmetrically with a mechanical prosthetic limb

When:We 04-09-2013 at 16:15

PhD ceremony: Mr. H.G. van Keeken, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Model and measurement studies on stages of prosthetic gait. Predictions on how not to walk symmetrically with a mechanical prosthetic limb

Promotor(s): prof. E. Otten, prof. K. Postema

Faculty: Medical Sciences

In the current thesis, entitled ’Model and measurement studies on stages of prosthetic gait - Predictions on how not to walk symmetrically with a mechanical prosthetic limb’, we used several two dimensional inverse and forward dynamics mathematical models to investigate principles of transfemoral amputee prosthetic gait. For four specific stages of prosthetic gait, namely gait initiation, weight bearing, prosthetic limb swing and gait termination, mathematical models were designed which allowed us to conceptually analyze phenomena observed in the real world.

PhD ceremony Ms. O.M. Laceulle: Programming effects of adversity on adolescent adaptive capacity

When:Mo 09-09-2013 at 12:45

PhD ceremony: Ms. O.M. Laceulle, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Programming effects of adversity on adolescent adaptive capacity

Promotor(s): prof. J. Ormel, prof. M.A.G. van Aken

Faculty: Medical Sciences

PhD ceremony Mr. T.E. Rams: Antibiotic resistance in human periodontitis and peri-implant microbiota

When:Mo 09-09-2013 at 16:15

PhD ceremony: Mr. T.E. Rams, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Antibiotic resistance in human periodontitis and peri-implant microbiota

Promotor(s): prof. A.J. van Winkelhoff, prof. J.E. Degener

Faculty: Medical Sciences

The extent of in vitro antibiotic resistance of subgingival bacterial pathogens in chronic periodontitis and peri-implantitis patients in the United States was studied in this thesis.

Study 1 found clindamycin most active against periodontal Streptococcus constellatus, and amoxicillin most active against periodontal Streptococcus intermedius. Study 2 found substantial in vitro resistance of periodontal Enterococcus faecalis to tetracycline, erythromycin, clindamycin, and metronidazole, but 100% susceptibility to ampicillin, amoxicillin/clavulanate, vancomycin, and teicoplanin. Study 3 revealed 52.1% of 564 chronic periodontitis patients yielded β-lactamase enzyme producing subgingival bacterial test species, which raises questions about the therapeutic potential of β-lactam antibiotics in periodontal therapy. Study 4 found subgingival periodontal pathogens resistant in vitro to doxycycline, amoxicillin, metronidazole, or clindamycin, in 55%, 43.3%, 30.3%, and 26.5%, of 400 chronic periodontitis subjects, respectively. However, only 15% of subjects harbored subgingival pathogens resistant to both amoxicillin and metronidazole. Study 5 found considerable in vitro spiramycin resistance among subgingival periodontal pathogens, but that spiramycin in combination with metronidazole had an antimicrobial potential similar to amoxicillin plus metronidazole. Study 6 found peri-implantitis patients to frequently harbor submucosal bacterial pathogens resistant in vitro to individual therapeutic concentrations of clindamycin, amoxicillin, doxycycline or metronidazole, but only rarely to both amoxicillin and metronidazole.

These findings indicate that chronic periodontitis and peri-implantitis patients in the United States frequently yield subgingival periodontal pathogens resistant in vitro to therapeutic concentrations of individual antibiotics, but less so with antibiotic combinations, and demonstrate a wide variability in periodontal pathogen antibiotic resistance patterns.

PhD ceremony Ms. M.M.A. Lensvelt: The endoluminal bypass for occlusive lesions of the superficial femoral artery

When:We 11-09-2013 at 11:00

PhD ceremony: Ms. M.M.A. Lensvelt, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The endoluminal bypass for occlusive lesions of the superficial femoral artery

Promotor(s): prof. C.J.A.M. Zeebregts

Faculty: Medical Sciences

Peripheral arterial disease (occlusive disease of the arteries) is a growing concern in the ageing population. It leads to calf pain when walking (intermittent claudication) and can even develop to chronic ulcers. Bypass surgery is still considered the golden standard when treating long lesions (>10cm in length) of the artery of the upper leg. This is major surgery associated with complications such as wound infections and oedema.

A less invasive alternative could be a good option in the population with frail arteries. For short lesions of the arteries (occlusions/stenosis <10 cm in length) balloon angioplasty (dilatation of the stenosis using a balloon) is a good option. But for longer lesions, balloon angioplasty alone shows worse results. Combining balloon angioplasty with a new kind of stent (a tube placed inside the vessel) greatly improves the results of this minimal invasive technique for long lesions of the arteries. This stent placement results in less complications and a shorter time spent in hospital than the surgical bypass.

This thesis describes the first results of the new stent in patients with peripheral arterial disease. It has also laid the foundation for a large trial that is still including patients, in which a direct comparison is made between patients with the new stent and bypass surgery.

PhD ceremony Mr. C. Wu: Ultra-high-resolution quantitative multi-pinhole small-animal SPECT

When:We 11-09-2013 at 12:45

PhD ceremony: Mr. C. Wu, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Ultra-high-resolution quantitative multi-pinhole small-animal SPECT

Promotor(s): prof. F.J. Beekman, prof. R.A.J.O. Dierckx

Faculty: Medical Sciences

Small-animal single photon emission computed tomography (SPECT) allows imaging the dynamic 3D distribution of radio labeled molecules (“tracers”) in rodents at sub-half-millimeter resolution. This allows e.g. to study function of cell populations non-invasively, and to develop new tracers, pharmaceuticals and clinical imaging procedures.

The thesis first explains the technology of small-animal SPECT and SPECT/computed tomography (CT) including applications in cardiovascular research, and continues with a study on methods for reducing cardiac image blur caused by animal breathing. Furthermore, in order to quantify precisely the amount of tracers in certain locations of animal bodies using their SPECT images, the thesis describes and evaluates a fast and practical method to correct for attenuation of gamma-radiation by tissue on trajectories between the locations of the tracers and SPECT detectors. Finally the influence of the attenuation map inaccuracy on the quantitative accuracy of reconstructed tracer uptake in SPECT images has been thoroughly investigated and discussed.

The research shows that highly quantitative (uncertainty < 2%) small-animal SPECT imaging can be achieved, which was previously thought to be possible for positron emission tomography (PET) only. Together with its ultra-high resolution (quarter mm), small-animal SPECT reveals possibilities for many novel preclinical applications with a broad selection of SPECT tracers, which are likely to benefit research into diseases and drug exploration.

PhD ceremony Mr. J.J. Meeuse: Aspects of pain in measurement, management and health care utilization

When:We 11-09-2013 at 14:30

PhD ceremony: Mr. J.J. Meeuse, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Aspects of pain in measurement, management and health care utilization

Promotor(s): prof. R.O.B. Gans

Faculty: Medical Sciences

This thesis describes various aspects of pain. It aims to contribute to improve pain measurement, treatment, and the relationship between pain and health care consumption.

To develop an instrument for patients who are not able to indicate their pain intensity, the association between heart rate variability with pain intensity was studied in 75 healthy volunteers. Although changes occurred in heart rate variability during pain, these changes were not correlated with the perceived pain intensity.

Radiotherapy is effective for painful bone metastases. Since pain relief is not always immediate and is sometimes preceded by an increase in pain, we examined whether radiotherapy is useful in patients with a short life expectancy. In a subanalysis of 274 patients from the Dutch Bone Metastases Study, who deceased within 12 weeks after radiotherapy, 45% showed a decrease in pain. Nonetheless, in 60% of them the pain remained moderate to severe.

The hypothesis that people experience less pain if they are distracted, eg by music, was studied in 245 patients who underwent sigmoidoscopy. Whether or not you listen to music did not affect the perceived pain intensity.

Care during the last weeks of life is preferably provided at the patients’ home, according to the Dutch model. In a subanalysis of the Dutch Bone Metastases Study we found, that during these weeks an increase in GP contacts was not accompanied with a reduction in hospital based care. A transmural multidisciplinary palliative team may help to avoid unnecessary hospital visits.

PhD ceremony Ms. M. Sie: Angiogenesis in pediatric brain tumors: therapeutic possibilities?

When:We 11-09-2013 at 16:15

PhD ceremony: Ms. M. Sie, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Angiogenesis in pediatric brain tumors: therapeutic possibilities?

Promotor(s): prof. E.S.J.M. de Bont, prof. W.A. Kamps

Faculty: Medical Sciences

Brain tumors are the most frequent pediatric tumors and are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic modalities including neurosurgery, chemotherapy and radiation. Moreover, morbidity can be serious, mainly because of the localization of the tumor and its subsequent chance of surgical morbidity and dismal effect of chemotherapy and/or radiation. So to reduce this morbidity as well as mortality, stimulating healthy ageing, new therapeutic modalities are needed.

As angiogenesis, the formation of vessels from a pre-existing vasculature, is highly crucial in tumor growth and progression, this mechanism has been extensively investigated and different anti-angiogenic therapies have been developed. However these studies are limited in pediatric brain tumors. So the present thesis obtained to increase insight into the angiogenic profile, tumor vasculature and growth-factor-driven resistance to angiogenic inhibitors in pediatric brain tumors including low grade astrocytoma and ependymoma. This thesis suggested a therapeutic window for anti-angiogenic therapy in these tumors at the one site and at the other site highlighted the possible tumor escape mechanisms that can arise in response to anti-angiogenic therapy. To further increase insight into these mechanisms and to test potential angiogenic agents, preclinical analyses need to be optimized, making translation into clinical trials more rational. Eventually, more individualized anti-angiogenic therapy will be a worthwhile future perspective in pediatric brain tumors.

PhD ceremony Ms. Y. Zhao: Lung nodule assessment in low-dose CT lung cancer screening. Validation of detection and volumetric measurement

When:Mo 16-09-2013 at 14:30

PhD ceremony: Ms. Y. Zhao, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Lung nodule assessment in low-dose CT lung cancer screening. Validation of detection and volumetric measurement

Promotor(s): prof. M. Oudkerk

Faculty: Medical Sciences

Early detection by computed tomography (CT) could improve the survival in lung cancer. The Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON). investigates whether screening by low-dose multi-detector CT in high risk subjects will decrease lung cancer mortality. The NELSON trial is the first in which lung nodule management is based on nodule volume at first detection, and volume doubling time on follow-up examinations.

As described in this thesis, over 7500 participants at high risk of lung cancer underwent CT screening in the NELSON trial. In the baseline round, 2.6% of the participants had a positive test result. 0.9% had lung cancer, the majority being an early stage of disease. A negative test ruled out the probability of lung cancer. Secondly, computer-aided detection (CAD) software detected more lung nodules than double reading. The combination of CAD and nodule size cut-off considerably reduces the false positive rate of CAD. Semi-automated software tools for volumetry yielded different nodule volumes. Variations between software results may lead to false-positive or false-negative screening results. Different software tools should not be used in a single screening trial. Lastly, the 3 month follow-up CT for intermediate-size nodules greatly reduced false-positive findings as many nodules show no or slow growth, or have disappeared. The NELSON strategy diminishes the need for further (invasive) work-up in participants with an intermediate-size nodule.

In conclusion, CT lung cancer screening based on volume and volume-doubling of lung nodules, with short-term repeat CT for intermediate-size nodules, is efficient to detect lung cancer.

PhD ceremony Mr. X. Xie: CT biomarkers in lung cancer screening

When:Mo 16-09-2013 at 16:15

PhD ceremony: Mr. X. Xie, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: CT biomarkers in lung cancer screening

Promotor(s): prof. M. Oudkerk

Faculty: Medical Sciences

Interest in computed tomography (CT) screening for early detection of lung cancer is increasing. Aging and smoking, risk factors for lung cancer, are also major risk factors for cardiovascular disease and chronic obstructive pulmonary disease (COPD). The screening CT also yields quantitative information on coronary calcification, expressed in a calcium score, and on emphysema and bronchial wall thickening. The focus of this thesis is the validation of these CT biomarkers. This thesis was performed within the context of the Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON).

Research shows that low-dose CT reliably detects lung nodules with diameter of at least 5 mm. Semi-automated volumetry is more accurate than manual diameter assessment. The variability in volumetry becomes small at larger nodule size. With these findings, the lung nodule management protocol in CT screening can be optimized. Secondly, increasing calcium score categories based on chest CT are associated with higher risk of cardiovascular events. A high calcium score fairly reliably indicates high cardiovascular risk; however, a zero calcium score does not exclude the presence of coronary calcification. Thirdly, CT evaluation of emphysema and peripheral airway thickness correlates with lung function test results. Also, individuals with respiratory symptoms generally have thicker walls of large bronchi on CT. These findings confirm a morphological basis of lung function and respiratory symptoms, which can be evaluated by CT. In conclusion, integrated evaluation of CT biomarkers for coronary artery disease and COPD, on top of lung cancer, may enhance the cost-effectiveness of CT screening.

PhD ceremony Ms. M. Aparicio Vergara: TNF signaling in nonalcoholic fatty liver disease

When:We 18-09-2013 at 12:45

PhD ceremony: Ms. M. Aparicio Vergara, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: TNF signaling in nonalcoholic fatty liver disease

Promotor(s): prof. M.H. Hofker

Faculty: Medical Sciences

The dramatic increase in obesity has been paralleled to a rise in its adverse health outcomes, including type 2 diabetes, insulin resistance, heart disease, cancer and fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver-related disorders, ranging from a benign and reversible state of fat accumulation in the hepatocytes (hepatic steatosis) to hepatic inflammation (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although the mechanisms underlying the pathogenesis of NAFLD are not fully understood, a central role for pro-inflammatory cytokines and their receptors in its development has been elucidated. Indeed, it is generally accepted that Tumor Necrosis Factor alpha (TNFα) and its receptor TNFR1 are involved in the development of NAFLD and insulin resistance. In this thesis, we aimed to establish the exact role of TNFR1 signaling in the pathophysiologies of NAFLD and insulin resistance. We used young and aged knock-in mice expressing a mutated TNFR1 ectodomain ( p55Δns ), incapable of shedding and dampen the inflammatory response. The studies described in this thesis show that TNF-signaling via TNFR1 plays a pivotal role in the pathogenesis of NASH. Moreover, in contrast to the alleged association between inflammation and insulin resistance, we report dissociation between the development of macrophage-associated inflammation and the onset of insulin resistance in a mouse model with persistent TNFα signaling, thereby breaking an important dogma.

PhD ceremony Mr. G.Sidorenkov: Predictive value of treatment quality indicators on outcomes in patients with diabetes

When:We 18-09-2013 at 14:30

PhD ceremony: Mr. G.Sidorenkov, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Predictive value of treatment quality indicators on outcomes in patients with diabetes

Promotor(s): prof. F.M. Haaijer-Ruskamp, prof. D. de Zeeuw

Faculty: Medical Sciences

Quality indicators are tools for measuring the quality of health care. An important requirement for measuring quality of care is credible evidence linking higher quality estimates to better patient outcomes. This thesis presents an overview of current knowledge and new findings about the relationship between indicators measuring the quality of drug treatment and outcomes in patients with diabetes. Although it may seem obvious that better treatment leads to better outcomes, quality indicators that are not correctly defined or indicators using wrong assumptions will not result in better outcomes, and may even stimulate suboptimal treatment. In this thesis, a number of treatment quality indicators are identified that are related to better patient outcomes. For example, the indicator measuring lipid-lowering treatment in patients with diabetes was associated with better cholesterol control and a lower risk of complications. Indicators measuring whether treatment was intensified when indicated were mainly associated with better short-term outcomes, e.g. HbA1c. There were also indicators that should be restricted to specific patients groups, for example, the indicators measuring the quality of glucose-lowering treatment. Finally, there were several indicators that were not related to better outcomes, especially the ones trying to measure the quality of blood pressure treatment. The important implication of this research is that some of the currently used or proposed quality indicators may stimulate care which is not equally beneficial for all patients. Therefore, quality of care indicators for diabetes may require restriction or stratification on patient characteristics, such as age or level of risk factor control.

PhD ceremony Ms. M.J. Siebelink: The child as a donor. A multidisciplinary approach

When:We 18-09-2013 at 16:15

PhD ceremony: Ms. M.J. Siebelink, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The child as a donor. A multidisciplinary approach

Promotor(s): prof. H.B.M. van de Wiel, prof. P.F. Roodbol

Faculty: Medical Sciences

PhD ceremony Ms. J. Jezierska: Genetic and molecular mechanisms underlying spinocerebellar ataxias

When:Mo 23-09-2013 at 11:00

PhD ceremony: Ms. J. Jezierska, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Genetic and molecular mechanisms underlying spinocerebellar ataxias

Promotor(s): prof. R. Sinke, prof. H.H. Kampinga

Faculty: Medical Sciences

Patients with spinocerebellar ataxia (SCA) suffer from balance and coordination problems caused by neuronal cell loss and damage to the small brain. SCA is caused by genetic defects and the disease can be transmitted with 50% chance to the offspring. Up to date, 31 SCA types are known and each type correlates with a different defect in a different gene. We discovered the genetic defects underlying two new types of SCA, SCA19 and SCA23. Additionally, we generated cellular models and mouse models mimicking the disease in humans in order to have a tool in which the disease mechanism can be studied. The identification of novel SCA genes does not only improve the diagnostic possibilities for ataxia patients, but also provides additional insights into the mechanism of disease contributing to new therapeutic developments.

PhD ceremony mr. S. Klein: The significance of preoperative vascular mapping of donor- and acceptor vessels in free flap surgery

When:We 25-09-2013 at 12:45

PhD ceremony: mr. S. Klein, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The significance of preoperative vascular mapping of donor- and acceptor vessels in free flap surgery

Promotor(s): prof. P.M.N. Werker

Faculty: Medical Sciences

Parallel to the elucidation of the vascular anatomy of the tegument of the human body, composite tissue (free) flaps are increasingly being developed for application by plastic surgeons in the reconstruction of congenital defects or wounds resulting from trauma or tumor ablation. The biggest advancement of the past 25 years is that surgeons can now isolate composite tissue flaps on a small side branch of the source vessels thereby limiting damage at the donor-site. It is therefore conceivable that the preoperative identification of the supplying (perforator) vessels is of paramount importance for successful flap transfer with limited morbidity. This thesis deals with various aspects of the identification process of the donor and recipient sites of flaps, including a discussion about the pro’s and con’s of methods for preoperative vascular mapping. These include Hand-held Doppler, colour duplex, digital subtraction angiography (DSA), computed tomographic angiography (CTA) and magnetic resonance angiography (MRA). Furthermore, various aspects of the applicability of the Ankle-Arm Index (AAI) as a tool for assessment of the vascular supply of the lower limb are assessed.

Each method was found to have its specific indication. DSA proved more reliable for preoperative vascular mapping of the free fibula than AAI. CTA and MRA are in this respect a good alternative for DSA and are the preferred methods for perforator flaps. Atherosclerotic or irradiation damage to vessels cannot always be detected pre-operatively by angiography, and not even by direct intra-operative examination.

PhD ceremony Ms. A.T. van der Goot: Genetic modifiers of aging and age-related proteotoxicity

When:We 25-09-2013 at 14:30

PhD ceremony: Ms. A.T. van der Goot, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Genetic modifiers of aging and age-related proteotoxicity

Promotor(s): prof. E.A.A. Nollen

Faculty: Medical Sciences

Neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington disease, are caused by the loss of neurons. Why neurons die is not clear yet but sticky disease proteins seem to play an important role. This is based on the finding that brains of patients contain accumulations of these proteins, also called aggregates. In healthy individuals, these aggregates are not present in such amounts. The aggregates contain disease-specific proteins. How these sticky proteins, or aggregation-prone disease proteins, cause neuronal toxicity, how they accumulate in aggregates, and how cells cope with such proteins is largely unknown.

Focus of the PhD study was to search for genes that can influence the formation and toxicity of protein aggregation in the small nematode C. elegans in which we modelled disease protein aggregation. The loss of at least two genes resulted in a reduction and a delay of toxicity of protein aggregation. These genes regulate the production of two proteins, namely of tryptophan 2,3-dioxygenase (TDO-2) and of modifier of aggregation 4 (MOAG-4). TDO-2 is essential for the degradation of the essential amino acid tryptophan, suggesting that tryptophan metabolism might play a role in toxicity caused by sticky disease proteins. In another study we found that MOAG-4 can enhance the formation of aggregates, most likely through a direct interaction with disease proteins. Together, these studies increased our understanding of how cells and organisms deal with protein damage. The genes that were indetified, provide interesting starting points for follow-up research for possible therapies to treat or delay neurodegenerative diseases.

PhD ceremony Mr. G.K. Yakala: Diet-associated metabolic and vascular (dys)function. Dietary strategies for prevention

When:Mo 30-09-2013 at 12:45

PhD ceremony: Mr. G.K. Yakala, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Diet-associated metabolic and vascular (dys)function. Dietary strategies for prevention

Promotor(s): prof. P. Heeringa, prof. G. Molema

Faculty: Medical Sciences

Obesity has turned into a worldwide epidemic. The development of obesity is closely associated with multiple metabolic disorders such as insulin resistance, hyperlipidaemia and hypertension which increase the risk for developing type 2 diabetes mellitus and cardiovascular diseases (CVD). The prevalence of these cardio-metabolic diseases is increasing mainly because of rapid changes in dietary intake patterns and unfavourable lifestyles. The main aim of this thesis was to investigate whether (dietary) strategies can be developed and implemented to prevent or reduce the occurrence of high-fat or high-cholesterol-induced cardio-metabolic complications. Treatment strategies studied in this thesis include: 1. Life style changes (calorie restriction). Despite the beneficial health effects of caloric restriction, most individuals find it difficult to comply with such strict regimens. We demonstrated that an alternative form of daily calorie restriction i.e. alternating low-fat / low-cholesterol and high-fat / high-cholesterol, instead of continuous consumption of a high-fat or high-cholesterol diet is beneficial in terms of reducing CVD risk factors. 2. Dietary intake changes (diet enriched with polyphenols). From epidemiological studies it is evident that regular intake of plant-derived products, especially polyphenols, inversely correlates with CVD. Chocolate is a rich source of polyphenols, but we demonstrated that dietary supplementation of chocolate did not show any beneficial effects on cardiovascular health. 3. Pharmacological interventions. Metabolic stress induced by high-fat or high-cholesterol induces systemic inflammation that can adversely affect cardiovascular health. We demonstrated that attenuation of inflammation caused by metabolic stress using an anti-inflammatory drug (Rosiglitazone) improved cardiovascular health.

PhD ceremony Mr. E.M. Bos: Therapeutic properties of hydrogen sulfide in ischemia / reperfusion injury

When:Mo 30-09-2013 at 16:15

PhD ceremony: Mr. E.M. Bos, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Therapeutic properties of hydrogen sulfide in ischemia / reperfusion injury

Promotor(s): prof. H. van Goor, prof. R.J. Ploeg

Faculty: Medical Sciences

The gas hydrogen sulfide (H2S) is known for its penetrant odor – that of rotten eggs – and its toxic properties. Recently, newly found features of H2S produced by the body have resulted in renewed scientific interest.

Our research focused on a remarkable effect of H2S: it can induce a hibernation-like state in mice, during which oxygen consumption is reduced by more than 90%. We used this effect to protect organs during periods of oxygen deprivation, like the hypoxia that occurs during organ transplantation. When inducing this hibernation-like state with H2S, the kidneys, livers and hearts that were temporarily without blood supply (ischemia or reperfusion injury) showed largely reduced amounts of damage.

We also investigated whether cystathionine γ-lyase (CSE), one of the H2S-producing proteins in the body, influenced ischemia/reperfusion injury. We used mice that do not produce CSE in the body, and therefor little H2S, and compared them to normal mice. We showed that mice missing CSE had increased amounts of damage after ischemia, which indicates that CSE is involved in the protection against hypoxia. Also, the amount of CSE in human kidney transplants was associated with a better renal function after transplantation. This points to a role for endogenously produced H2S in the protection against oxygen deprivation.

This research may lead to novel therapies involving H2S as a protective substance during periods of hypoxia, such as during organ transplantation, and may lead to a better functioning of transplanted organs.

Inaugural Lecture Mr. prof. T. Hortobagyi: Learning from our past: the future of successful ageing

When:Tu 01-10-2013 at 16:15

Inaugural Lecture: Mr. prof. T. Hortobagyi, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Learning from our past: the future of successful ageing

Chair: Bewegen en gezond ouder worden

Faculty: Medical Sciences

Read Opinion ‘Inactivity is creeping into every walk of life’

PhD ceremony Ms. S. Piening: Communicating Risk Effectively

When:We 02-10-2013 at 12:45

PhD ceremony: Ms. S. Piening, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Communicating Risk Effectively

Promotor(s): prof. S.M. Haaijer-Ruskamp, prof. P.A. de Graeff

Faculty: Medical Sciences

This thesis focuses on risks of side effects of drugs. Once a drug is allowed on the market serious safety problems may arise, possibly leading to hospitalization, disability, or even death of patients. Paper based warning letters, so-called Direct Healthcare Professional Communications (DHPCs) are sent to inform healthcare professionals of these side effects. However DHPCs have not always been successful. Following a third of DHPCs we observed a significant decrease in the long-term use of the drugs. DHPCs proved to be specifically effective in case of well-structured information, and very serious side effects. Healthcare professionals preferred to receive safety information via e-mail and from an independent source. An additional e-mail that was sent by the Dutch Medicines Evaluation Board appeared to enhance the effect of the written DHPC. Healthcare professionals were more aware of the side effect and took more action in response to the issue. Risk communication of side effects should be improved by addressing several factors. Communication methods should be improved, for example, by communicating through new channels such as e-mail, and by an independent source. Healthcare professionals and professional associations should be involved in the DHPC drafting process. Also, it should be determined at which point a DHPC may be considered sufficiently effective. Evaluation of safety warnings is useful only when thresholds are set and additional measures will be demanded if these thresholds are not reached. Currently, the DHPC has a clear added value, but future developments will need to be monitored.

PhD ceremony Mr. J. van Ark: Role of circulating vascular progenitor cells in the development of macrovascular disease in diabetes

When:We 02-10-2013 at 14:30

PhD ceremony: Mr. J. van Ark, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Role of circulating vascular progenitor cells in the development of macrovascular disease in diabetes

Promotor(s): prof. J.L. Hillebrands, prof. B.H.R. Wolffenbuttel

Faculty: Medical Sciences

Cardiovascular diseases are the number one cause of death in industrialised countries. Macrovascular disease (MVD) contributes to this to a considerable extent. Type 2 diabetes is associated with a 2- to 4-fold increase in rates of MVD. The underlying causes of the accelerated progression of MVD in diabetes are incompletely understood. Therefore, new insights into the mechanisms behind the development of MVD are essential to develop effective therapies for the prevention and treatment of MVD in patients with diabetes. Circulating vascular progenitor cells (VPCs) contribute to the health and maintenance of blood vessels. Different types of VPCs are described which have different effects on the development of MVD. Endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs) inhibit the progression of MVD. On the other hand, smooth muscle progenitor cells (SMPCs) are able to stimulate the progression of MVD. In this thesis we investigated the role of circulating VPCs in the development of MVD in patients with type 2 diabetes. We demonstrate that the number of protective EPCs and CACs is decreased in the blood of diabetic patients. In contrast, the number of damaging SMPCs is slightly increased in these patients. Therefore, the balance between protective and damaging VPCs is disturbed in favour of the latter. This may contribute to the accelerated development of MVD in patients with diabetes. This makes VPCs a potential therapeutic target to inhibit the progression and prevent the complications of MVD in patients with type 2 diabetes.

PhD ceremony Ms. M. Abdoli: Development and evaluation of metal artifact reduction and image segmentation techniques in PET/CT

When:We 02-10-2013 at 16:15

PhD ceremony: Ms. M. Abdoli, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Development and evaluation of metal artifact reduction and image segmentation techniques in PET/CT

Promotor(s): prof. H. Zaidi, prof. R.A. Dierckx, prof. J. Pruim

Faculty: Medical Sciences

The production of artifact-free and quantitative PET images requires metal artifact reduction (MAR) of the CT images prior to application of the CT-based attenuation correction procedure. The various MAR methods are discussed in this thesis. The general conclusion is that sinogram-based MAR approaches are more accurate in obtaining reliable attenuation coefficients. Chapter 3 demonstrates that different implantable cardiac pacing devices can give rise to varying magnitudes of metal artifacts on CT images. The misalignment between PET images and attenuation maps produced more severe artifacts.

We describe various MAR methods, i.e. sinogram-based methods applying different interpolation techniques, ranging from a 1D spline interpolation method to a 2D Clough-Tocher interpolation technique. Each proposed technique improved the performance of the preceding one.

Delineation of target volumes on PET images is known to be a challenging task due to the inherent noisy and low-resolution characteristic of PET images. We assessed the performance of different categories of 18F-FDG PET image segmentation techniques. The deformable active contour model proposed in this thesis handles the intrinsic high noise level of PET images and the heterogeneity of the tumor uptake appropriately. Application of ADF makes the handling of the high level of noise in PET images feasible without influencing PET quantification. Moreover, integrating the contourlet transform of the image to the energy functional formulation makes the fitting terms more potent in attracting the evolving curve towards the object boundaries due to the enhancement of the TBR.

PhD ceremony Ms. J. Smolonska: The many faces of chronic obstructive pulmonary disease

When:We 09-10-2013 at 12:45

PhD ceremony: Ms. J. Smolonska, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The many faces of chronic obstructive pulmonary disease

Promotor(s): prof. H.M. Boezen, prof. C. Wijmenga

Faculty: Medical Sciences

This thesis is an investigation of several phenotypes of COPD: airway obstruction, emphysema, lung function decline. We were interested not only in these phenotypes, but also their shared genetic background. Airway obstruction and emphysema can occur together, asthma and COPD despite being separate diseases share many features, and therefore we searched for common genes underlying these phenotypes. GWA studies were the main tools used, but we also looked beyond GWA studies and used other tools, like analysis of epistasis. The pathways that emerge from our findings are worth investigating further, as not all of them were considered to be involved in COPD before, for example the cell adhesion pathway. Although the results did not reach genome-wide significance, they still can be valid and worth investigating further.

PhD ceremony Ms. A. Kunnen: Periodontitis & preeclampsia

When:We 09-10-2013 at 14:30

PhD ceremony: Ms. A. Kunnen, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Periodontitis & preeclampsia

Promotor(s): prof. F. Abbas, prof. J.G. Aarnoudse, prof. C.P. van der Schans

Faculty: Medical Sciences

There are strong indications that periodontitis is involved in pregnancy complications, such as preterm birth and low birth weight. This thesis shows that periodontitis is also associated with preeclampsia. This association is most evident in early-onset preeclampsia (<34 weeks of gestation). This thesis also shows that one of the most important periodontopathic micro-organisms, Porphyromonas gingivalis, appears to play a role in the development of maternal hypertension, placental and foetal growth restriction and miscarriage in a rat experiment. It is unlikely, however, that periodontitis plays a causal role in the pathogenesis of preeclampsia, because the pro-inflammatory lipopolysaccharide of P. gingivalis did not induce proteinuria or a generalised systemic inflammatory response in the pregnant rat. Moreover, P. gingivalis did not induce pro-inflammatory cytokine production in blood of pregnant and non-pregnant women in in vitro and ex vivo experiments. Periodontal therapy performed at about 20 weeks of gestation does not lead to a reduction in preeclamptic pregnancies. However, it is possible that periodontal treatment performed at about 20 weeks of gestation is too late in pregnancy to prevent preeclampsia, because periodontal pathogens may enter the maternal blood stream and reach the placenta early in pregnancy. Further research on treatment earlier in pregnancy, or perhaps even before conception, is recommended. Irrespective of an aetiological role of periodontitis in pregnancy complications, the state of pregnancy increases the susceptibility to periodontal infections. Therefore, early detection and treatment of periodontitis prior to or during pregnancy remain unquestionably of benefit to the mother and should be performed at all time.

PhD ceremony Mr. E.D. Telenga: On phenotyping in asthma and COPD

When:We 09-10-2013 at 16:15

PhD ceremony: Mr. E.D. Telenga, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: On phenotyping in asthma and COPD

Promotor(s): prof. D.S. Postma

Faculty: Medical Sciences

Inhaled corticosteroids (ICS) are frequently used medications in obstructive pulmonary diseases. ICS are the cornerstone of treatment in asthma. The role of ICS is less clear in COPD. COPD patients respond less to ICS treatment than asthma patients. There are also asthma patients who respond less or not at all to ICS. Since smoking is the main risk factor for COPD, we investigated if smoking influences corticosteroid sensitivity in asthma patients. We showed that current- and ex-smoking asthma patients have a lower short-term response to ICS treatment than never-smoking asthma patients. However, the long-term response of current- and ex-smoking asthma patients appears similar to that of never-smokers. Additionally, we investigated the ICS response in obese asthma patients. After a short-term treatment with ICS, obese asthma patients (BMI >30) showed significantly less improvement in lung function than patients with normal weight (BMI < 25).

We also investigated the association between small airways and bronchial hyper responsiveness with impulse oscillometrie. We showed that in healthy subjects the airway wall thickness, measured with high resolution CT-scans, decreases with increasing age, but increases in smokers. Finally, we investigated the lipid profile in sputum of COPD patients and healthy subjects. We showed that multiple lipids are differentially regulated in COPD patients than in healthy smokers. This suggests a role for changes in the lipid profile in the development of COPD.

PhD ceremony Mr. J. van Zaane: Bipolar disorder and alcohol. Double trouble or just co-occurrence?

When:We 16-10-2013 at 12:45

PhD ceremony: Mr. J. van Zaane, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Bipolar disorder and alcohol. Double trouble or just co-occurrence?

Promotor(s): prof. W.A. Nolen, prof. W. van den Brink

Faculty: Medical Sciences

Bipolar (manic-depressive) disorders (BD) and substance use disorders (SUD) are “co-travelers”. About 50% of the patients with BD have a comorbid SUD during live.

This thesis addresses two important questions. The first question refers to the problem of early detection of BD in patients who seek treatment in addiction centers. The validity of the screening instrument for BD, the Mood Disorder Questionnaire (MDQ), was tested in this population. The results showed that the MDQ is not a suitable instrument to rule in BD in a treatment seeking addiction population. Many patients who tested positive on the MDQ had another diagnosis than BD, such as borderline personality disorder. In contrast, the MDQ could be used to rule out BD in patients who seek treatment in addiction centers.

The second question in this thesis addresses the effect of moderate (social) use of alcohol on the course and outcome in patients with BD. This issue has never been thoroughly examined. The results of our study showed that moderate use of alcohol did not have a negative effect (more and longer episodes, faster recurrence) on the course and outcome. However, patients with excessive use of alcohol also showed no negative effect on the course and outcome. Our results are not in line with other studies that showed a lot of negative effects when BD patients used excessive alcohol. Our main explanation is that our patients, in contrast to the patients of the other studies, were very adherent to their medication.

PhD ceremony Mr. B.W. Peterson: Visco-elastic properties of biofilms

When:We 16-10-2013 at 14:30

PhD ceremony: Mr. B.W. Peterson, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Visco-elastic properties of biofilms

Promotor(s): prof. H.C. van der Mei, prof. H.J. Bosscher

Faculty: Medical Sciences

While mathematical models for biofilms have been available for many years, there has yet to be a definitive physical connection between mathematical terms and physical or biological functions. It was determined that a connection between the underlying properties of initially adhering bacteria and the resulting relaxation properties of biofilms exists. Stress relaxation of biofilms could be described mathematically in three Maxwell elements, which also linked to their structural composition and antimicrobial penetration. Extracellular DNA had a distinguishable role in biofilm stress relaxation, making it a primary target for future research into bioacoustics-associated treatments. Throughout this thesis, the length of the relaxation time constants was used to distinguish between Maxwell elements and determine their associations to biofilm structure and antimicrobial penetration. These time constants could be converted to frequencies for bioacoustics as a useful tool against bacterial biofilms, however we have not tested the efficacy of these frequencies. A potentially successful biofilm treatment would combine antimicrobials with a mechanical frequency that would resonate the bacterial biofilm while leaving neighboring cells and tissues unaffected.

Inaugural Lecture Ms. prof. B.M. Bakker: Modellen voor jong en oud

When:Tu 22-10-2013 at 16:15

Inaugural Lecture: Ms. prof. B.M. Bakker, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Modellen voor jong en oud

Chair: Kindergeneeskunde, i.h.b. medische systeem biologie

Faculty: Medical Sciences

PhD ceremony Mr. M.T.R. Roofthooft: Pediatric and neonatal pulmonary hypertension. Epidemiology, management, risk stratification and outcome

When:We 23-10-2013 at 14:30

PhD ceremony: Mr. M.T.R. Roofthooft, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Pediatric and neonatal pulmonary hypertension. Epidemiology, management, risk stratification and outcome

Promotor(s): prof. R.M.F. Berger

Faculty: Medical Sciences

The national expertise center for diagnosis and treatment of children with pulmonary hypertension (PH) is situated in the University Medical Center Groningen.

In an epidemiological study, we were able to assess the incidence and prevalence of all forms of paediatric PH. We studied the outcome of children with pulmonary arterial hypertension (PAH), treated with available targeted PAH medication. Moreover, a comparison between treatment of children and adults with PAH was performed.

The impact of persistent pulmonary hypertension of the newborn (PPHN) in children with transposition of the great arteries was studied, in addition to the general impact of PPHN on morbidity and mortality in children. The role of echocardiography and the symptom hemoptysis were examined to assess disease severity and outcome. The incidence and hemodynamic factors influencing PAH in patients with an atrial septal defect (ASD) were analysed and a search for risk factors in resolution of PAH after defect closure was performed. In the last part of the thesis, we present a new mutation in TBX4 gene, responsible for childhood-onset PAH. We report our experiences in the combination of pediatric PAH and renal trombotic microangiopathy, caused by a Cobalamin C deficiency.

PhD ceremony Ms. K. Klauke: Epigenetic regulation of normal and malignant hematopoiesis

When:We 23-10-2013 at 16:15

PhD ceremony: Ms. K. Klauke, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Epigenetic regulation of normal and malignant hemotopoiesis

Promotor(s): prof. G. de Haan

Faculty: Medical Sciences

Stem cells are required for the formation of all cells in our body throughout our entire lifespan. They were discovered in almost every organ. These cells have the unique capacity to self-renew relatively unlimited, producing two stem cells upon division. In addition, stem cells can specialize (differentiate) into the mature cells of which the tissue is composed. A precise balance between self-renewal and differentiation of HSCs is essential to maintain a proper-sized HSC pool throughout life. Unbalanced stem cell divisions can result in diseases, such as cancer.

A protein complex has been identified that acts as a switch to determine the fate of blood stem cells. The so-called ' Polycomb complex’ can modify the manner in which the DNA is packed in the nucleus of stem cells, which determines the genetic information in the DNA that is used for the function of the cell. Polycomb proteins function together in a large protein complex. The proteins compete with each other for every position in the complex. Depending on which proteins integrate into the complex , stem cells self-renew or specialize in mature blood cells. In this way, the complex functions as a 'switch'. This discovery is a step forward in understanding the balance between health and disease . If the switch results in too much renewal of stem cells leukemia can develop (blood cancer). If the switch results in too much maturation and loss of stem cells, blood cell deficiency might occur.

By manipulation of this protein complex, and by marking individual stem cells with a ‘barcode’, this study also gave more insight into the development and the heterogeneity of leukemia. Leukemia can be maintained by multiple ‘leukemia stem cells’ (mother cells that produce the bulk tumour cells)with different properties with respect to growth rate and differentiation. These leukemia stem cells can also react differently to stresses, such as chemotherapy. This study therefore highlights the usefulness of combination therapy with multiple chemotherapeutic agents to treat leukemia.

The results of this research have been published in Nature Cell Biology

PhD ceremony Ms. S. Chalavi: The traumatized brain. Gray and white matter morphology in dissociative identity disorder and posttraumatic stress disorder

When:Mo 28-10-2013 at 12:45

PhD ceremony: Ms. S. Chalavi, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The traumatized brain. Gray and white matter morphology in dissociative identity disorder and posttraumatic stress disorder

Promotor(s): prof. A. Aleman, prof. D.J. Veltman

Faculty: Medical Sciences

Despite the mentioning of dissociative identity disorder (DID) in the DSM-3 through DSM-5, there is ongoing debate about its diagnosis, aetiology, and theoretical basis. This may be related to the lack of empirical research of the neurobiological correlates of DIS. This thesis aims to provide such neuroscientific knowledge using structural imaging techniques.

We found that both patients with dissociative identity disorder and patients with posttraumatic stress disorder had smaller gray matter of the frontal, temporal and insular cortices and whole cortex and abnormality of the white matter of the brain. In addition, hippocampus was smaller in patients with dissociative identity disorder compared to healthy volunteers and the severity of hippocampal reduction correlated with the severity of childhood traumatisation. Furthermore, we found that dissociative identity disorder was associated with structural abnormality of the inferior parietal cortex and dorsal striatum compared to patients with posttraumatic stress disorder and healthy volunteers and these abnormalities were linked to the dissociative symptoms. Findings presented in this thesis mainly provide objective empirical support in favour of a trauma-related aetiology for DID and thereby may help in better understanding the neural mechanism underlying dissociative identity disorder.

PhD ceremony Ms. J. Riphagen-Dalhuisen: Influenza vaccination of health care workers

When:Mo 28-10-2013 at 14:30

PhD ceremony: Ms. J. Riphagen-Dalhuisen, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Influenza vaccination of health care workers

Promotor(s): prof. E. Hak

Faculty: Medical Sciences

Read press release Flu-shot for hospital staff prevents patients from infection

PhD ceremony Mr. M.O. Hoeke: The role of vitamin A in bile bile acid synthesis and transport and the relevance for cholestatic liver disease

When:Mo 28-10-2013 at 16:15

PhD ceremony: Mr. M.O. Hoeke, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of vitamin A in bile bile acid synthesis and transport and the relevance for cholestatic liver disease

Promotor(s): prof. K.N. Faber, prof. H. Moshage

Faculty: Medical Sciences

Absorption of fat-soluble vitamin A depends on bile salts, which are synthesized in the liver and give bile its emulsifying properties. Bile salts are potentially toxic compounds, so their synthesis and transport in the enterohepatic circulation are tightly regulated. Bile acids are ligands for the bile acids sensor FXR (farnesoid X receptor), a ligand activated transcription factor. Via FXR bile acids regulate key genes involved in bile salt synthesis and transport. In order to regulate transcription of its target genes, FXR dimerizes with the retinoid X receptor (RXR). Via RXR vitamin A could influence bile salt homeostasis. Moreover, vitamin A is stored in the liver and liver diseases are often accompanied by vitamin A deficiency (VAD). This demonstrates a network of interactions between bile salts and vitamin A.

The research described in this thesis shows that vitamin A influences expression of FXR target genes and thus bile salt homeostasis. The bile salt export pump (BSEP) in the liver shows maximal expression in the absence of vitamin A, while other FXR-target genes such as SHP (small heterodimer partner) en FGF19 (fibroblast growth factor 19), which both inhibit bile salt synthesis, are maximally expressed in the presence of vitamin A. VAD alone increased plasma bile salt concentrations in rats. The other way around, cholestasis is often accompanied by VAD and these results suggest that VAD might contribute to a cholestatic phenotype. Therefore, we studied the effect of VAD in an animal model of obstructive cholestasis. VAD dramatically aggravated the clinical symptoms, while vitamin A therapy normalized the clinical symptoms in vitamin A deficient rats.

These results show that vitamin A is an important co-regulator of bile salt homeostasis and urge the close monitoring of vitamin A levels in cholestatic patients, as vitamin A shortage could rapidly deteriorate the patient’s condition.

PhD ceremony Ms. S. Post: House dust mite and the integrity of the airway epithelium. Mechanisms involved in the development of the allergic asthma

When:We 30-10-2013 at 11:00

PhD ceremony: Ms. S. Post, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: House dust mite and the integrity of the airway epithelium. Mechanisms involved in the development of the allergic asthma

Promotor(s): prof. A.J.M. van Oosterhout

Faculty: Medical Sciences

The airway epithelium forms the first barrier against aeroallergens, including house dust mite (HDM). It exerts pro-inflammatory activity when damaged, and is a key player in the initiation of allergic responses. Although it was initially thought that the serine proteolytic activity of HDM contributes to loss of the cell-cell contacts including E-cadherin, barrier dysfunction and pro-inflammatory reaction of the airway epithelium, we recently observed that the HDM-induced epithelial responses are independent on their serine protease activities. Additionally we investigated the role of protease-activated receptor-2 (PAR-2) in a HDM mouse model and found that HDM extracts that widely differed in protease activity evoked highly similar allergic reactions in Wt and PAR2 KO mice, with the exception of the IgE response. Instead, our experiments showed that HDM initiates the influx of calcium, which is responsible for both barrier dysfunction and secretion of the pro-inflammatory cytokine CCL20. Furthermore, we found that primary bronchial epithelial cells (PBECs) from asthmatics are more prone to develop barrier dysfunction and secretion of pro-inflammatory cytokines then healthy control PBECs in response to HDM. To test the role for loss of E-cadherin in allergic sensitization and airway remodelling, we generated a lung-specific E-cadherin deficient mouse where E-cadherin deficiency was induced in respiratory epithelial cells during development of the respiratory epithelium using doxycycline. These mice developed spontaneously goblet cell metaplasia, inflammation and bronchial epithelial aplasia when mice reached an adult age, and will be used in future experiments for additional investigations regarding the role of E-cadherin in the development of allergic asthma.

PhD ceremony Mr. J.B. Terra: Studies on clinical symptoms, diagnosis and treatment in pemphigoid diseases

When:We 30-10-2013 at 12:45

PhD ceremony: Mr. J.B. Terra, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Studies on clinical symptoms, diagnosis and treatment in pemphigoid diseases

Promotor(s): prof. M.F. Jonkman

Faculty: Medical Sciences

Read press release Hormone cream is a safe and effective treatment for blistering diseases with and without blisters

PhD ceremony Ms. M.J. Noordzij: Skin autofluorescence and atherosclerosis

When:We 30-10-2013 at 14:30

PhD ceremony: Ms. M.J. Noordzij, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Skin autofluorescence and atherosclerosis

Promotor(s): prof. R.O.B. Gans, prof. A.J. Smit

Faculty: Medical Sciences

Advanced glycation end products (AGE) are harmful substances that slowly accumulate in our body during lifetime. This is part of the normal aging process, but in several diseases the accumulation of these harmful AGE is accelerated and increased. This is well known for diabetes mellitus, kidney failure and several rheumatic diseases. Accumulation of AGE proved to be an important factor in causing the long term complications and early mortality in these diseases. AGE accumulation can be estimated by an advanced light technique called skin autofluorescence (SAF). My thesis has two main conclusions. First, SAF measurement can be influenced by several factors. These disturbing factors must be avoided to ensure a reliable measurement. Secondly, AGE play an important role in atherosclerotic disease. SAF, as a measure of AGE accumulation, is markedly elevated in several manifestations of atherosclerosis. My studies show a markedly elevated SAF in patients with carotid stenosis, patients with peripheral artery disease and in patients with type 2 diabetes who have macro vascular disease. SAF therefore seems a reliable indicator of atherosclerosis. Previous research in type 2 diabetic patients showed that SAF was a good risk indicator of future cardiovascular disease, in addition to, and independent of classical cardiovascular risk factors (such as blood pressure, cholesterol, and smoking). Because SAF measurement is very easy and quick, it has great potential to be widely used in medical practice for estimating atherosclerosis and future cardiovascular risk.

PhD ceremony Ms. M.J. de Boer: Living with chronic pain. Mechanisms and interventions

When:We 30-10-2013 at 16:15

PhD ceremony: Ms. M.J. de Boer, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Living with chronic pain. Mechanisms and interventions

Promotor(s): prof. M.M.R.F. Struys, prof. R. Sanderman

Faculty: Medical Sciences

Read press release Interpretation of pain determines pain perception

PhD ceremony Ms. F.J. van Apeldoorn: The treatment of panic disorder. Psychotherapy, pharmacotherapy, or the two combined?

When:Mo 04-11-2013 at 16:15

PhD ceremony: Ms. F.J. van Apeldoorn, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The treatment of panic disorder. Psychotherapy, pharmacotherapy, or the two combined?

Promotor(s): prof. J.A. den Boer

Faculty: Medical Sciences

PhD ceremony Ms. T. Wu: Influence of genes, environment and their interaction on risk factors for asthma and cardiovascular disease

When:We 06-11-2013 at 09:00

PhD ceremony: Ms. T. Wu, 9.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Influence of genes, environment and their interaction on risk factors for asthma and cardiovascular disease

Promotor(s): prof. H. Snieder

Faculty: Medical Sciences

In this thesis we applied different gene-environment interaction methods to study risk factors for asthma and cardiovascular disease. It starts with a prospective candidate gene study, which gives more insight in interaction between maternal passive smoking and maternal metabolic enzyme genes on infant birth weight. The greater part of this thesis consists of several twin studies, which improve and extend the application of twin modeling to explore gene-environment interactions. Univariate structural equation modeling was performed in chapter 3 to examine heritabilities of responses to environmental challenges, such as bronchial hyper responsiveness. Similarly, in chapter 4, heritabilities of overnight urinary excretion rates of norepinephrine and epinephrine, which reflect basal sympathetic activity levels as a measure of chronic exposure to stress, were explored by the same twin modeling. A Meta-analysis that pooled the results of all published twin studies on heritablities of heart rate or blood pressure (BP) reactivity to the cold pressor test or various mental stress tasks was presented in chapter 5. In chapter 6, we used bivariate modeling to estimate the contribution of genes and environment to the individual differences in levels of BP and underlying hemodynamic characteristics at rest and during stress. Finally, in chapter 7, Purcell’s GxE model was applied to examine the extent to which body mass index as a measure of adiposity and treated as an environment factor in this model, may modify the genetic influence on BP. These results have implications and provide guidance to further gene finding efforts for underlying risk factors of asthma and cardiovascular disease.

PhD ceremony Ms. A. Funke: The role of hepatic inflammation in the development of hepatic steatosis and insulin resistance

When:We 06-11-2013 at 11:00

PhD ceremony: Ms. A. Funke, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of hepatic inflammation in the development of hepatic steatosis and insulin resistance

Promotor(s): prof. M.H. Hofker

Faculty: Medical Sciences

It is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. However, several studies have shed doubt on this view, which questions the causality of this association. Therefore in this thesis, we used 3 different mouse models, i.e. the Ldlr-/- mice, Myd88-/- mice and Csf1op/+ mice to investigate the role of hepatic inflammation in the aetiology of NAFLD and insulin resistance. We have demonstrated that short-term HFC-induced hepatic inflammation does not lead to the development of systemic insulin resistance in lean Ldlr-/- mice. In addition, sustained hepatic inflammation induced by long-term HFC feeding did not aggravate the development of insulin resistance in obese Ldlr-/- mice compared to HF control diets. Furthermore, we have shown that reduced hepatic inflammation in the Myd88-/- mice does not lead to the protection from obesity-induced insulin resistance. In addition, lower inflammatory levels in the liver, adipose tissue and plasma in Csf1op/+ mice are not associated with protection against the development of systemic insulin resistance. Therefore we conclude that hepatic inflammation is not causally linked to the pathogenesis of insulin resistance. Our data clearly show that the current knowledge about the role of inflammation in the development of insulin resistance is far from understood. In addition, we have also shown that cross-talk between Kupffer cells and hepatocytes is important for protecting hepatocytes from the development of hepatic steatosis. These data suggest that a fine balance of inflammatory mediators is necessary for the optimal metabolic control in the liver.

PhD ceremony Mr. S. Arsov: Advanced glycation end-products in hemodialysis patients

When:We 06-11-2013 at 12:45

PhD ceremony: Mr. S. Arsov, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Advanced glycation end-products in hemodialysis patients

Promotor(s): prof. G. Rakhorst, prof. A.J. Smit

Faculty: Medical Sciences

End-stage renal disease (ESRD) represents a serious health and social problem. In this thesis we focused on hemodialysis (HD), the most frequently used method of renal replacement therapy in ESRD patients. Advanced Glycation End-products (AGEs) are metabolic end-products that belong to the group of protein-bound uremic toxins. Skin AGEs can be measured by means of Skin Autoflourescence (AF). This dissertation aimed at finding factors that influence the skin and plasma AGEs and possible strategies in reducing the AGEs levels in HD patients.

The mean one year increase of Skin AF of the HD patients was around 7-9 fold higher than of healthy subjects. One year increase of Skin AF proved to be a strong predictor of mortality in HD patients. Although plasma AF decreased significantly after a single HD session, this did not lead to instant differences in Skin AF. AGEs accumulation measured by means of Skin AF did not differ in HD patients with and without hepatitis C. It appeared that calorie, protein and AGEs intake hardly influenced the one year increase of Skin AF in HD patients. However, Body Mass Index (BMI) was a predictor of the one year increase of Skin AF which is a strong predictor of mortality of HD patients. The BMI of HD patients of around 24 kg/m2 resulted in the lowest one year increase of Skin AF.

It appears that optimizing the nutritional level of HD patients might result in reduced accumulation of AGEs and thus reducing the mortality risk of these patients.

PhD ceremony Mr. P.C. van den Akker: Dystrophic epidermolysis bullosa. Novel insights into the genotype-phenotype correlation and somatic mosaicism

When:We 06-11-2013 at 14:30

PhD ceremony: Mr. P.C. van den Akker, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Dystrophic epidermolysis bullosa. Novel insights into the genotype-phenotype correlation and somatic mosaicism

Promotor(s): prof. M.F. Jonkman, prof. R.M.W. Hofstra

Faculty: Medical Sciences

Read press release Prospects for treatment of skin disorder epidermolysis bullosa

PhD ceremony Ms. M.L. Fokkema: Outcome after percutaneous coronary intervention

When:We 06-11-2013 at 16:15

PhD ceremony: Ms. M.L. Fokkema, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Outcome after percutaneous coronary intervention

Promotor(s): prof. A.A. Voors

Faculty: Medical Sciences

This thesis describes outcomes after percutaneous coronary intervention (PCI) in patients with different presentations of coronary artery disease. A PCI procedure, usually consisting of balloon dilatation and/or stenting, is often part of the standard treatment in these patients. During the past decades, technical, procedural and pharmacologic developments have resulted in improvements in clinical outcome after PCI.

The first part of this thesis describes population trends and clinical outcomes after PCI in patients with different presentations of coronary artery disease. This was investigated in a national registry study of all PCI procedures performed in Sweden over the last 20 years. The PCI population and their risks substantially changed over time. Outcomes after PCI considerably differed between the different indications of PCI. Based on outcome, it was suggested that improvements in therapy are needed in the acute phase as well as on the long term after PCI.

In the second part, different parameters influencing outcome after primary PCI in patients with ST-elevation myocardial infarction (STEMI) were investigated. One of the findings was that STEMI patients, whose time from symptom onset until treatment was more than 5 hours, had worse prognosis than patients who were treated earlier.

In the third part, clinical effects of erythropoiesis-stimulating agents were investigated, as additional treatment after primary PCI in STEMI patients. This was done in a randomized controlled trial as well as in a meta-analysis on individual patient data. The administration of these agents did not result in an improved clinical outcome after PCI.

PhD ceremony Mr. F. Iovino: Streptococcus pneumoniae interactions with endothelial cells leading to invasive pneumococcal disease

When:Mo 11-11-2013 at 16:15

PhD ceremony: Mr. F. Iovino, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Streptococcus pneumoniae interactions with endothelial cells leading to invasive pneumococcal disease

Promotor(s): prof. J.M. van Dijl, prof. G. Molema

Faculty: Medical Sciences

Meningitis is a serious invasive disease causing considerable mortality and morbidity worldwide. How bacterial pathogens cross the blood brain barrier and enter the CNS is currently unclear. Receptor-mediated adhesion of the bacteria to the brain endothelium is considered a key event leading to meningitis development. Streptococcus pneumoniae (the pneumococcus) is the main causative agent of bacterial meningitis in Europe and in the USA and is thought to invade the brain via the bloodstream by crossing the vasculature of the blood-brain barrier (BBB). The aim of this PhD research was to elucidate the spatio-temporal interactions of blood-borne S. pneumoniae with the blood-brain barrier endothelium during the events leading up to meningitis, and to characterize the receptors involved. The studies described in this thesis show that adhesion to the blood brain barrier is spatiotemporally controlled at different sites throughout the brain and that the local immune system is activated immediately upon entry of the bacteria into the bloodstream. They also provide evidence that pIgR, a well-known epithelial receptor for pneumococci, is also expressed by brain endothelial cells and may be a novel adhesin for the bacteria on the BBB. The research described in the last experimental chapter indicates that PECAM-1 could well be another novel receptor for S. pneumoniae on the BBB endothelium. Altogether, the research described in this thesis has provided novel insights in the adhesion of S. pneumoniae to the brain vascular endothelium, a crucial step in the passage of pneumococci across the BBB leading to meningitis.

PhD ceremony Ms. C. de Jong: The Groningen LCPUFA study. Associations between neonatal and early postnatal fatty acid status and developmental outcome at 9 years

When:We 13-11-2013 at 11:00

PhD ceremony: Ms. C. de Jong, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The Groningen LCPUFA study. Associations between neonatal and early postnatal fatty acid status and developmental outcome at 9 years

Promotor(s): prof. M. Hadders-Algra

Faculty: Medical Sciences

Fatty acids, in particular the so-called Long-Chain PolyUnsaturated Fatty Acids (LCPUFA) are essential in child development, but it is unclear whether supplementing formula with LCPUFA is beneficial for later development. The current thesis addresses this issue. The effect of supplementing formula with the LCPUFA docosahexaenoic acid (DHA) and arachidonic acid (AA) during the first two months of life in healthy, term-born children on development at age nine was studied. Additionally, the relationship between various fatty acids in the umbilical cord and development at age nine is analyzed. The current study is the first to study the effects of early LCPUFA status on development at school age. Attention was paid to neuromotor, cognitive and behavioral development, height, weight, head circumference, blood pressure and heart rate.

LCPUFA supplementation of formula did not affect neuromotor, behavioral and physical development. It affected cognition in a complex way. Some cognitive abilities in children exposed to maternal smoking during pregnancy improved by LCPUFA supplemented formula, while some cognitive abilities of children not exposed to maternal smoking deteriorated slightly. The study confirmed the small positive association between breastfeeding and neuromotor and cognitive development and heart rate. Finally the study demonstrated a positive association between DHA level in the umbilical cord and neuromotor development. The study indicates that LCPUFA status prior to birth matters more for child development than LCPUFA supplementation of infant formula.

PhD ceremony Ms. N.A. Hosper: The use of mesenchymal cells in fetal and adult tissue repair

When:We 13-11-2013 at 12:45

PhD ceremony: Ms. N.A. Hosper, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The use of mesenchymal cells in fetal and adult tissue repair

Promotor(s): prof. P.P. van den Berg, prof. R.A. Bank

Faculty: Medical Sciences

In this thesis cellular processes involved in fetal and adult tissue repair were studied. Such knowledge can be useful for the design of novel therapies with regard to e.g. spina bifida. Spina bifida is a congenital closure defect of the neural tube leading to neural damage. Such neural damage is caused by two hits; the ‘first’ is the failure of the neural tube to close and the ‘second’ hit is the exposure of the neural tissue to the amniotic fluid during pregnancy. Intra-uterine tissue engineering might reduce neural damage in spina bifida patients. We used collagen I matrices to close skin defects in a fetal sheep model. In this study we have demonstrated that collagen scaffolds can be used to treat fetal skin defects and that the combination of collagen scaffolds with growth factors vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF2) had a beneficial effect on fetal wound healing. Another option to improve wound healing can be the addition of stem cells to a scaffold. We have shown that human amniotic fluid cells from healthy fetuses can be used to repair skin defects. For future therapy it is important that autologous cells are used to prevent immunological complications. We found that neural tube defect amniotic fluid cells do not deposit collagen type I in vitro. This is a disadvantage when such cells are used for fetal tissue engineering. More research is required to conclude whether these cells are suitable for the treatment of spina bifida.

PhD ceremony Mr. A.J. Borghuis: Core stability in soccer: it's a matter of control!

When:We 13-11-2013 at 14:30

PhD ceremony: Mr. A.J. Borghuis, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Core stability in soccer: it's a matter of control!

Promotor(s): prof. K.A.P.M. Lemmink, prof. C. Visscher

Faculty: Medical Sciences

The first aim of this thesis was to take a closer look at the concept of core stability from a scientific perspective. An attempt was made to provide a universal definition of core stability, in order to stimulate that future discussions regarding the subject concern one and the same concept.

The second aim was to present valid and reliable measurement methods to quantify core stability, based on the definition that was formulated. A sitting balance task was developed, which was used to compare core muscle response times and balance measures between amateur soccer players and non-players. The soccer players reacted faster in response to sudden balance perturbations. Subsequently, the measurement methods were further refined and their reliability was investigated.

The third aim was to study the effect of a soccer specific neuromuscular training program (NMTP) on core stability in elite youth soccer players, using these measurement tools. Besides, as a secondary aim, the effect of the training program on standing balance and agility as performance measures and on injury occurrence was investigated. Although positive trends in the data indicated that the NMTP had a positive effect on reactive core stabilizing control, standing balance capacity and slalom sprint performance, no significant differences in improvement were found between the intervention and control group.

Although a common view exists that a stable core is important with respect to performance optimisation and injury prevention, further research is needed for scientific substantiation.

PhD ceremony Ms. S. Op den Dries: Bile duct injury in liver transplantation. Study on etiology and the protective role of machine perfusion

When:We 13-11-2013 at 16:15

PhD ceremony: Ms. S. Op den Dries, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Bile duct injury in liver transplantation. Study on etiology and the protective role of machine perfusion

Promotor(s): prof. R.J. Porte, prof. J.A. Lisman

Faculty: Medical Sciences

Non-anastomotic biliary strictures (NAS) are a major complication after liver transplantation. The development of strictures (narrowing) of the bile ducts is characteristic of this complication, often leading to morbidity and the need for re-transplantation. The studies described in this thesis resulted in a better understanding of the causes of NAS and provide new strategies to prevent bile duct injury and the subsequent formation of NAS.

The high incidence of NAS after donation after cardiac death (21-33%) compared to donation after brain death (1-13%), demonstrates the significant role of lack of oxygen (ischemia) in the development of NAS. In this thesis, severe injury to the bile duct epithelium (the lining of the bile duct) was discovered in the majority of donor livers at the end of the cold preservation period. Moreover, it was discovered that the lack of regeneration of bile duct epithelium, rather than the amount of injury, determines whether a liver will develop NAS after transplantation. In order to maintain this regeneration capacity of the bile ducts, it is essential to protect vulnerable livers (older, fatter, donation after cardiac death) from injury induced by cold ischemia.

This thesis demonstrates that machine perfusion creates new opportunities for improved donor organ preservation, including the protection of vulnerable bile ducts by providing an oxygen-rich environment. It was demonstrated that machine perfusion allows human donor livers to be kept ‘alive’ outside the human body. Machine perfusion allows assessment of donor livers, which can be used to decide whether a liver is suitable for transplantation.

Read also the press release: http://www.umcg.nl/EN/corporate/News/Pages/UMCGperformstestrunondonorliversbeforetransplantation.aspx

PhD ceremony Mr. M.M.H. Lahr: Organisational models for thrombolysis in acute ischaemic stroke. A simulation exemplar

When:Mo 18-11-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. M.M.H. Lahr

Dissertation: Organisational models for thrombolysis in acute ischaemic stroke. A simulation exemplar

Promotor(s): prof. E. Buskens

Faculty: Medical Sciences

Read press release Improve acute care for stroke victims by improving the chain as a whole

PhD ceremony Mr. M.E. Sutton: Studies on injury and repair of donor bile ducts after liver transplantation

When:Mo 18-11-2013 at 16:15

PhD ceremony: Mr. M.E. Sutton, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Studies on injury and repair of donor bile ducts after liver transplantation

Promotor(s): prof. R.J. Porte, prof. J.A. Lisman

Faculty: Medical Sciences

Orthotopic liver transplantation (OLT) is a well-accepted treatment option for patients with acute liver failure and end-stage chronic liver disease. An important challenge in OLT is the reduction in the incidence of non-anastomotic biliary strictures (NAS) after OLT. Damage to biliary epithelial cells is thought to play a key role in the development of NAS.

This thesis focuses on the regenerative capacity of bile ducts in response to initial biliary damage. A review of the literature on mechanisms leading to biliary epithelial damage and the development of NAS is given. In addition, we have identified novel risk factors for NAS within two subpopulations of OLT recipients; patients transplanted with a liver obtained after cardiac arrest of the donor (DCD), and patients transplanted for primary sclerosing cholangitis.

Experimental studies described in this thesis indicate that (extrahepatic) bile ducts possess an endogenous regenerative potential, in which the peribiliary glands play a pivotal role after severe biliary damage, as is observed after OLT.

Based on a porcine model, we conclude that hypothermic (10°C) machine perfusion of liver grafts leads to an improved preservation of arterial vessels of the bile duct compared to static cold storage and is associated with a better recovery of bile ducts. In addition, for the first time we provide evidence that bile production is a suitable biomarker to assess hepatic viability of discarded human livers during normothermic (37°C) machine perfusion. The application of such a selection criterion to judge discarded human donor livers could potentially expand the donor pool.

Inaugural Lecture Ms. prof.dr. H. Bootsma: Systeemziekten: ‘‘response - ability’’

When:Tu 19-11-2013 at 16:15

Inaugural Lecture: Ms. prof.dr. H. Bootsma, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Title: Systeemziekten: ‘‘response - ability’’

Chair: Reumatologie

Faculty: Medical Sciences

PhD ceremony Ms. I.F.A. Bocca-Tjeertes: Growth of preterm-born children

When:We 20-11-2013 at 11:00

PhD ceremony: Ms. I.F.A. Bocca-Tjeertes, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Growth of preterm-born children

Promotor(s): prof. A.F. Bos, prof. S.A. Reijneveld

Faculteit: Medical Sciences

The main goal of the research reported in this thesis was to describe normal growth in preterm-born children and to determine growth and its influence on development in (pre)term children according to their birth weight, gestational age, and type of fetal growth restriction.

Growth can be seen as a biomarker for the general well-being of a child. It is also one of the accessible outcomes of preterm birth. Studies showed that preterm birth is associated with poorer growth in the long-term. Prematurity thus seems to affect growth directly, although growth is influenced by many other factors, such as genetic and hormonal profiles, morbidity, and social conditions.

In summary we found that growth in preterm-born children differed from that of full term children. It was dependent of a child’s gestational age and body proportions at birth. Catch-up growth was seen in preterm-born children, but it was mostly limited to the first year after birth. Growth was mostly insufficient to provide catch-up towards the median for children that were growth restricted at birth compared to their preterm-born counterparts. Even so, preterm children born with an appropriate birth weight for their gestational age were also at risk for growth restriction in the long-term.

Both ends of the birth weight spectrum had different consequences regarding development of preterm-born children. Growth restriction resulted in a two-fold increase of the risk for developmental delay whereas fetal overgrowth did not.

PhD ceremony Mr. G. Bocca: Effects of a multidisciplinary treatment program in overweight and obese preschool children

When:We 20-11-2013 at 12:45

PhD ceremony: Mr. G. Bocca, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Effects of a multidisciplinary treatment program in overweight and obese preschool children

Promotor(s): prof. P.J.J. Sauer, prof. R.P. Stolk

Faculty: Medical Sciences

PhD ceremony Ms. J.E.A. Verschuren: Sexuality and limb amputation: perspective of patients, partners and professionals

When:We 20-11-2013 at 14:30

PhD ceremony: Ms. J.E.A. Verschuren, 14.30 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Sexuality and limb amputation: perspective of patients, partners and professionals

Promotor(s): prof. J.H.B. Geertzen, prof. P.U. Dijkstra, prof. P. Enzlin

Faculty: Medical Sciences

The focus of this thesis is on the possible influence of an upper or lower limb amputation on someone’s sexuality. People with a limb amputation, their partners, and professionals working with people with a limb amputation, were interviewed and/or filled out a questionnaire about their views and experiences concerning the topic of sexuality and amputation.

Following a review about the influence of a chronic disease/disability on someone’s sexual functioning or sexual well-being, revealing that there is (limited) information available about this topic, and following interviews with both patients and partners, a large scale quantitative study about sexuality and limb amputation was set up. Twenty percent of all participants in this quantitative study (n=301) indicated that they experienced at least one sexual problem. In the interview studies both people with an amputation and their partners reported that their sexual lives had changed after the amputation. This change could be both positive and negative. Despite these changes, many of the participants of the quantitative and qualitative studies reported that sexuality was seldom discussed during their rehabilitation process. Most of these participants would have liked to have been (better) informed about sexuality after a limb amputation. Therefore, professionals were also asked to fill out a survey on ‘sexuality and limb amputation’. The participating professionals indicated that sexuality indeed needs to be discussed during the rehabilitation process, but at the same time they indicated that they felt rather insecure about doing so, since they experienced a lack of knowledge and conversation skills concerning this topic.

PhD ceremony Ms. Y.L. Gu: Intracoronary therapies and myocardial reperfusion in acute myocardial infarction

When:We 20-11-2013 at 16:15

PhD ceremony: Ms. Y.L. Gu, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Intracoronary therapies and myocardial reperfusion in acute myocardial infarction

Promotor(s): prof. F. Kuipers

Faculty: Medical Sciences

Coronary heart diseases are a major cause of death in the Western world. Acute myocardial infarction (AMI, or heart attack) is a major contributor. AMI is caused by formation of a clot and, subsequently, blockage of a coronary vessel. This results in irreversible damage to the heart muscle tissue that is supplied by the vessel, unless treatment is initiated timely. In recent years, steep progress has been made in the treatment of AMI, especially through the use of angioplasty to unblock the coronary vessel and additional drugs during this procedure. Yet, restoration of blood flow to the heart muscle is impaired in a considerable number of patients with AMI, which can lead to reduced muscle function and higher mortality. During this PhD project, we studied two treatments that were used directly in the diseased coronary vessel to improve restoration of blood flow to the heart muscle. The first part compares sucking out the blood clot with the usual method to restore blood flow through the diseased coronary vessel by dilating the vessel with a balloon. The second part studies additional treatment with abciximab, a drug that blocks an early step in the formation of a blood clot. Based on promising findings from previous studies, we investigated whether administration of this drug directly into the diseased coronary vessel is more effective than the conventional treatment through an infusion. Third, we evaluated a novel computer program, the Quantitative Blush Evaluator (QuBE), to measure blood flow through the heart muscle after treatment.

PhD ceremony Ms. P.A. Erba: Imaging cardio-vascular infection

When:Mo 25-11-2013 at 09:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. P.A. Erba

Dissertation: Imaging cardio-vascular infection

Promotor(s): prof. A. Signore, prof. G. Mariani, prof. R.A.J.O. Dierckx

Faculty: Medical Sciences

The introduction of a hybrid system for combining functional and anatomical imaging gave the opportunity to expand our clinical experience with 99mTc-HMPAO radio labelled leukocytes scintigraphy in the field of infectious disease, by applying these technologies to new challenging clinical setting as in the presence of cardiovascular system infections. We applied 99mTc-HMPAO SPECT/CT hybrid imaging to patients with infectious endocarditis (IE), cardiovascular implanted electronic device (CIED) infections, or late and low-grade late vascular graft infections (VPI). In addition, we tried to establish how the use of standardized imaging acquisition protocols and new, bacterial specific, radiopharmaceuticals may improve the scintigraphic accuracy. Our results demonstrate that the use of 99mTc-HMPAO-WBC scintigraphy is beneficial in patients with a high clinical probability of IE, CIED and VPI infections with the following main clinical indications: i) the confirmation of diagnosis in doubtful circumstances, ii) defining the extent of device involvement, and iii) detecting associated complications and septic embolisms, thus impacting on treatment strategy . SPECT/CT combined technology is preferred to visualize infection by 99mTc-HMPAO-WBCs . Our findings support the use of 99m Tc-HMPAO-WBC scintigraphy also to monitor the response to antimicrobial treatment . From a methodological perspective, we demonstrated that the most accurate imaging acquisition protocol for 99mTc-HMPAO-WBC scintigraphy is scanning at 3-4h and at 20-24h after 99mTc-HMPAO-WBCs injection, corrected for isotope decay. Semi-quantitative analysis might be deserved to doubtful cases. In view of the research on new radiopharmaceuticals to image infectious processes, our results suggest 68Ga-DOTA-Biotin as a suitable candidate for further clinical development.

PhD ceremony Ms. M. Majernikova: Self-rated health and mortality after kidney transplantation

When:Mo 25-11-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. M. Majernikova

Dissertation: Self-rated health and mortality after kidney transplantation

Promotor(s): prof. J.W. Groothoff

Faculty: Medical Sciences

This study focuses on self-rated health (SRH), morbidity and mortality in kidney transplant (KT) recipients and shows the possibilities for SRH as a potential indicator of future health status after KT. We found the change in graft function over time to be a significant predictor of SRH at one-year follow-up after KT and at longer follow-up. Medical factors, such as late acute rejection episodes, chronic renal allograft dysfunction and post-transplant anemia, were found to be independent predictors of SRH worsening at different times after transplantation, depending on the stage of Chronic Kidney Disease (CKD). Previously, mild and severe anemia during the first year after KT were found to be a predictor of patient mortality independently of kidney function in patients with CKD stages 1-2; on the other hand, severe ? but not mild ? anemia increased mortality risk in transplanted patients with CKD stages 3-5. Moreover, SRH at early time after transplantation was shown to be an independent predictor of a patient?s mortality and graft loss. We found that average SRH was associated with a 4-fold higher and poor SRH with an 11-fold higher risk of mortality at up to ten years follow-up. Up to now, average SRH has been associated with a 3-fold higher risk of graft loss and poor SRH with a 6-fold higher risk of graft loss at up to ten years follow-up. Improving long-term post-transplantation outcomes should be a priority for the management of transplanted recipients in order to reduce the risk of morbidity and mortality.

PhD ceremony Mr. S. Piersma: Applications of quantitative fluorescence microscopy for systems level gene expression analyses in Bacillus subtilis

When:Mo 25-11-2013 at 14:30
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. S. Piersma

Dissertation: Applications of quantitative fluorescence microscopy for systems level gene expression analyses in Bacillus subtilis

Promotor(s): prof. J.M. van Dijl

Faculty: Medical Sciences

The present PhD research was aimed at the development of novel tools for quantitative fluorescence microscopy. These were needed for systems-level gene expression analyses in the soil bacterium Bacillus subtilis, a popular model organism for research on bacterial gene expression. The studies were rooted in the EC-funded BaSysBio project and started with the construction of an arrayed collection of more than 1000 different fusions between promoters of B. subtilis and the Green Fluorescent Protein (GFP). Each GFP fusion was expressed in a different strain and, together, this strain collection formed a so-called Live Cell Array (LCA). The LCA was then employed in genome-wide gene expression analyses in response to changing nutritional conditions. These analyses were performed at the population level in microtiter plate readers, and at the single-cell level using high-throughput time-lapse fluorescence microscopy. For the latter purpose, a dedicated data processing pipeline (TLM-Quant) was developed based on open-source software. The BaSysBio project culminated in a publication in Science describing the regulatory network of B. subtilis at the transcriptome, proteome and metabolome levels. Here, the LCA and TLM-Quant were employed to verify gene expression homogeneity in exponentially growing cells. Subsequently, the developed tools were applied in several other investigations on the origin of heterogeneous expression of an antimicrobial agent, the bacterial responses to limited water availability, the secretion of proteins, and bacterial responses to a novel antimicrobial compound. Altogether, this PhD research expanded the toolbox for quantitative microscopy especially through the development of methods for faster data processing and visualization.

PhD ceremony Mr. L. Pitel: Sociocultural determinants, gender and health-related behaviour in adolescence

When:Mo 25-11-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. L. Pitel

Dissertation: Sociocultural determinants, gender and health-related behaviour in adolescence

Promotor(s): prof. S.A. Reijneveld

Faculty: Medical Sciences

The aim of this thesis is to contribute to a better understanding of the relationship between the health-related behaviours of Slovak adolescents and their socioeconomic position, the degree of urbanisation of their environment and their religiosity.

Adolescents from lower socioeconomic positions tended to have certain unhealthy behaviours (smoking, physical inactivity, poor nutritional behaviour) more frequently than those from the highest socioeconomic position, but the differences were relatively small. In poor fruits and vegetables consumption the socioeconomic differences were larger among girls. The degree of urbanisation was related to health-related behaviour only among girls. The prevalence rates of substance use among girls increased with an increasing degree of urbanisation, while among boys no association was found. Religiosity was inversely associated with unhealthy behaviours regarding substance use, having breakfast, soft drinks consumption, screen-based activities and sexual intercourse. However, no such association was found for physical inactivity, fruits and vegetables consumption, tooth brushing and fighting. Regarding substance use, associations were significantly stronger among girls than among boys.

In conclusion, the associations between sociocultural characteristics and health-related behaviour were particularly strong among girls, among whom the most vulnerable groups were those from bigger cities, those from a low socioeconomic background and those who were non-religious. Among boys, these factors mostly played a less important role, though their associations with health-related behaviours were present in some cases (socioeconomic position in physical inactivity, religiosity in substance use and sexual debut). These results should be considered in the planning of prevention activities and public health policies.

PhD ceremony Mr. M.G. Dickinson: Pulmonary arterial hypertension. The role of increased blood flow and Egr-1

When:We 27-11-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. M.G. Dickinson

Dissertation: Pulmonary arterial hypertension. The role of increased blood flow and Egr-1

Promotor(s): prof. R.M.F. Berger

Faculty: Medical Sciences

Pulmonary Arterial Hypertension (PAH) is a leading cause of morbidity and mortality in patients with CHD. In these patients increased pulmonary blood flow (due to systemic-to-pulmonary shunting) is seen as an essential trigger for the formation of pulmonary neointimal lesions and thus PAH development. To date, neointimal lesions are regarded incurable, making PAH irreversible once these lesions occur. To develop new therapies, the molecular mechanism of this specific form of pulmonary vascular remodeling must therefore be unraveled.

The research identified gene expression profiles specifically related to the addition of increased pulmonary blood flow in experimental PAH. In this profile, 1 gene was of particular interest: Early Growth Response protein 1 (Egr-1). The spatiotemporal analysis of Egr-1 expression in this PAH model reveals that Egr-1 is up-regulated in the pulmonary arteries directly after induction of increased flow, but also later in the disease process. Specific oligonucleotides were used as a method to down-regulate vascular Egr-1 expression in the PAH model. In this study intravenous administration of catalytic oligodeoxynucleotides attenuated pulmonary vascular remodeling, including the development of occlusive neointimal lesions. Patients with PAH associated with CHD were studied, and pulmonary vascular Egr-1 expression was specifically increased in neointimal remodeling compared to medial hypertrophy remodeling in hypoxic PH and control vessels. Catheter related complications are described in 111 consecutive patients with pulmonary hypertension who were treated with long-term, continuous epoprostenol using a TIAP. TIAP complication rates in this study compare favorably with reported findings for tunneled catheter use (Hickman or Broviac).

PhD ceremony Ms. A.K. Muszanska: Functional polymer brush-coating to prevent biomaterial associated infections

When:We 27-11-2013 at 14:30
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. A.K. Muszanska

Dissertation: Functional polymer brush-coating to prevent biomaterial associated infections

Promotor(s): prof. W. Norde, prof. H.J. Busscher, prof. H.C. van der Mei

Faculty: Medical Sciences

Read press release Smart coating to prevent implant infections

PhD ceremony Ms. V.J. Goosens: Bacillus systems exporting folded proteins and folding exported proteins

When:We 27-11-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. V.J. Goosens

Dissertation: Bacillus systems exporting folded proteins and folding exported proteins

Promotor(s): prof. J.M. van Dijl

Faculty: Medical Sciences

Protein translocation across a membrane is an essential component of many cellular functions in all kingdoms of life. However, simply moving a protein over the membrane does not guarantee an operational protein - functional proteins need to be correctly folded and occasionally require co-factors. Bacillus subtilis, the model organism used to examine protein translocation in this study, is a Gram-positive bacterium relevant in both application-oriented and fundamental scientific settings. The research described in this thesis was focused on systems either involved in the membrane translocation of cargo proteins where folding and co-factor-attachment takes place prior to translocation, or involved in the post-translocational folding of proteins that are translocated in an unfolded state. These systems are known as the Twin-arginine translocation (Tat) and Thiol-disulphide oxidoreductase (TDOR) pathways, respectively. In the studies presented here, mass spectrometric techniques were firstly applied, and by observing the presence of proteins in various genetic backgrounds novel interacting partners and substrates were identified in both the Tat and the TDOR systems. The newly identified Tat-dependent substrate QcrA was investigated further, and by mutating residues associated with folding and co-factor insertion, requirements for QcrA-Tat processing were identified. The Tat system is made up of TatA and TatC proteins, and in this thesis a role for the third, and until recently enigmatic, TatA component TatAc was unveiled. Therefore, the research presented in this thesis led to novel insights into the processing, substrates and systems associated with the translocation of folded proteins (Tat) and folding of proteins post-translocation (TDOR).

PhD ceremony Ms. Y. Liu: Novel insights in the pathogenesis of Hodgkin lymphoma. Microenvironment, genetic landscape and regulation of HLA expression

When:Mo 02-12-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. Y. Liu

Dissertation: Novel insights in the pathogenesis of Hodgkin lymphoma. Microenvironment, genetic landscape and regulation of HLA expression

Promotor(s): prof. J.H.M. van den Berg

Faculty: Medical Sciences

Classical Hodgkin lymphoma (cHL) is a B cell malignancy consisting of neoplastic Hodgkin Reed-Sternberg (HRS) cells, which generally comprise less than 1% of the total cell population, and a large majority of non-malignant reactive immune cells. This highly characteristic histology makes cHL a disease that is difficult to study. In our group we have a longstanding interest in the molecular, pathological and immunological background of cHL. The focus of this thesis is on the tumour microenvironment, gene mutations, and the regulation of HLA expression.

In summary, the most important outcomes are: 1) The microenvironment in cHL is actively shaped and an essential component of the tumour; 2) The complete loss of HLA class I in HL might be related to gene mutations affecting β2-m or the classical HLA genes themselves; 3) Special PML isoforms and SATB1 partially affect HLA expression in cHL.

Inaugural lecture Mr. prof. R.H. Sijmons: Genomic Medicine: een toekomstige zorg?

When:Tu 03-12-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

Inaugural lecture: Mr. prof. R.H. Sijmons

Title: Genomic Medicine: een toekomstige zorg?

Chair: Medische translationele genetica

Faculty: Medical Sciences

PhD ceremony Ms. S.L. Della Penna: Pathophysiological effects of the excess of sodium in renal and vascular tissues

When:We 04-12-2013 at 09:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. S.L. Della Penna

Dissertation: Pathophysiological effects of the excess of sodium in renal and vascular tissues

Promotor(s): prof. H. van Goor, prof. B.E. Fernández

Faculty: Medical Sciences

An acute or chronic sodium overload is able to regulate the expression of AQP-1 and AQP-2 and thus the water balance through intrarenal Ang II and oxidative stress in vivo. Early renal inflammation produced by an acute excess of sodium is a process that can be prevented and/or reversed. Chronic inflammation may be reversible in the absence of histopathological lesions. Inflammation by sodium is linked to ROS (due to flux, stretch and/or transport) more tan to tubular Ang II, which could be more related to sodium and water transport. Triggering of the cascade of inflammatory events is due to an increase of the cellular work when it reabsorbs sodium, which produces relative hypoxia (HIF), increase of renal Ang II and NF-kB expression and develops oxidative stress. This cascade can be prevented or reverted by cutting the chain in any of its links: a) decreasing sodium reabsorption (ANP), b) inhibiting local Ang II (losartan) or c) the oxidative stress (tempol). In vitro, sodium can affect the expression of the Ang II receptor (AT1R) and the endothelium protecting enzyme E-NTPDase. These molecules are downregulated on the endothelium when it is co-cultured with peripheral blood mononuclear cells. A better understanding of the mechanisms involved in the regulation of water and sodium handling, especially when the body is exposed to an excess of salt, would lead to improved prevention of renal and cardiovascular diseases and would increase treatment efficacy.

PhD ceremony Ms. J. Han: The microenvironment of the inflammatory type hepatocellular adenoma

When:We 04-12-2013 at 11:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. J. Han

Dissertation: The microenvironment of the inflammatory type hepatocellular adenoma

Promotor(s): prof. A.S.H. Gouw, prof. G. Molema

Faculty: Medical Sciences

Benign hepatocellular tumours are characterized by a hepatocyte proliferation without invasion and metastasis. Hepatocellular adenoma (HCA) is a benign tumour arising in an otherwise non-diseased liver with an incidence of 3-4/100,000 people with long term use of oral contraceptives. It is the second most common hepatocellular benign tumour next to focal nodular hyperplasia (FNH). HCA sub-typing is based on the genotypes and the inflammatory HCA (IHCA), which is associated with overweight/obesity, is the most frequent subtype of HCA.

In this thesis, we investigated the microenvironment in which IHCA develops and explored the possible molecular link between obesity with IHCA. We found foci of micro-adenomas in the non-lesional liver and frequent presence of steatosis suggesting that the liver in which IHCA develops can be regarded as a “sick” liver. When we analysed the status of adipokines receptors in IHCA we found an increased expression of leptin-receptor and decreased adiponectin-receptor in the tumour which may stimulate tumour growth and induce the inflammatory phenotype of IHCA via leptin/leptin-receptor activation. These findings may represent the link of IHCA with obesity due to hyperleptinemia and hypoadiponectinemia in obesity. We also investigated the nature of biliary ductules in IHCA and found that they represent hepatic progenitor cells (HPC) mediated regeneration associated with the inflammation within IHCA. We also found subclonal cell populations in the tumour that probably are generated by stem cells, independent of the inflammatory status.

Summarizing, the liver in which IHCA develops harbours microadenomas and obesity may contribute to the growth and IHCA phenotype.

PhD ceremony Mr. H. Kusano: Prognostic aspects of hepatocellurar carcinoma

When:We 04-12-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. H. Kusano

Dissertation: Prognostic aspects of hepatocellurar carcinoma

Promotor(s): prof. A.S.H. Gouw, prof. G Molema, prof. H. Yano

Faculty: Medical Sciences

This thesis addresses two issues that influence the prognosis of hepatocellular carcinoma (HCC), microvascular invasion (micro-VI) (part I) and interferon (IFN) therapy (part II). In a review of the current status of methods to predict micro-VI preoperatively we concluded that currently there is no reliable method to predict micro-VI before surgery. We investigated a molecular profile of micro-VI positive HCC that may yield a predictive factor of micro-VI. Results of these studies indicated the importance of peritumoral tissue as a compartment that contains changes related with micro-VI. This was represented partly in altered angiogenic characteristics as witnessed by upregulation of placental growth factor and vascular endothelial growth factor receptor-1 expression and partly in decreased numbers of ductular structures that probably undergo phenotype switching during progression of HCC as part of cancer related epithelial-mesenchymal transition. The decreasing numbers of ductules may serve as a predictive factor of micro-VI in tumour biopsies.

In part II, we evaluated pegylated IFNs (PEG-IFNs) as a promising drug combined with sorafenib. As 70% to 80% of patients with HCC are diagnosed at the advanced stage, effective systemic therapy options are still sought for. We demonstrated the anti-proliferative effect of PEG-IFNs with or without sorafenib in various HCC cell lines. Sensitivity to each combination varied leading us to conclude that molecular tumour profiling will be necessary to improve the sensitivity of therapies based on the matching of the tumour with certain drugs or combination of drugs.

PhD ceremony Mr. S. Sobhani: Rocker shoes for ankle and foot overuse injuries: a biomechanical and physiological evaluation

When:We 04-12-2013 at 14:30
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. S. Sobhani

Dissertation: Rocker shoes for ankle and foot overuse injuries: a biomechanical and physiological evaluation

Promotor(s): prof. K. Postema, prof. E.R. van den Heuvel

Faculty: Medical Sciences

Reducing the high loads on the Achilles tendon and the metatarsophalangeal joint during the active phase of running, could be valuable in both prevention and treatment of Achilles tendinopathy and forefoot overuse injuries. Internal plantar flexion moment (PFM) is a biomechanical parameter that is directly related to Achilles tendon loading. In walking activities, rocker shoes were shown to be effective in reducing the PFM. Rocker shoes were also found to be capable of reducing plantar pressure in the forefoot region during walking. In this thesis we examined these biomechanical effects of rocker shoes primarily for running activities.

We found that the use of rocker shoes reduced PFM during the late stance phase of slow running and walking in both healthy people and patients with chronic Achilles tendinopathy. We also found that the rocker shoes significantly reduced plantar pressure in the forefoot region during running. Another finding of this thesis was that oxygen consumption rate during running with rocker shoes was 4.5% higher than with standard shoes and 5.6% higher than with minimalist shoes.

These findings suggest that rocker shoes might be useful in unloading the Achilles tendon and forefoot region during running, and therefore they might be beneficial for runners who are recovering from Achilles tendinopathy and forefoot overuse injuries. A poor running economy, however, is expected as a side-effect of wearing rocker shoes.

PhD ceremony Mr. R.P.E. Pollard: B cell targeting in Sjögren's syndrome. Clues to pathogenesis

When:We 04-12-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. R.P.E. Pollard

Dissertation: B cell targeting in Sjögren's syndrome. Clues to pathogenesis

Promotor(s): prof. A. Vissink, prof. F.G.M. Kroese, prof. F.K.L. Spijkervet

Faculty: Medical Sciences

Sjögren’s syndrome (SS) is an autoimmune disorder that is characterized by inflammatory infiltrates in the exocrine glands, particularly in the salivary and lacrimal glands. Most of the patients suffer from dry mouth and dry eyes. Other clinical manifestations such as fatigue, joint and muscle pain are often present. Along with the dryness complaints, these events lead to a reduced quality of life. A major complication of SS is the development of a malignant lymphoma in the salivary glands, mostly a mucosa associated lymphoid tissue (MALT) lymphoma.

There is no recognized causal treatment for SS. Recently, new treatment options are introduced in order to, through the use of antibodies, inhibit the disease activity and to prevent further progression. Rituximab, a monoclonal antibody directed against the protein CD20 on B cells, showed favorable results in several clinical studies. This research has focused on the immuno(histo-)logical effects of B-cell depletion by rituximab in patients with SS. My research shows that a treatment with rituximab leads to an improvement of the inflammatory process in the salivary gland. Furthermore, several additional therapeutic targets (BAFF, IL -6 ) are described in this thesis. In addition, a study how a patient with SS MALT lymphoma can be treated best is described. The study shows that in SS patients with MALT lymphoma, under certain conditions, a "watchful waiting" is justified.

PhD ceremony Ms. U.M. Domanska: Tumor microenvironment: preclinical insights into therapy resistance and targeting strategies

When:Mo 09-12-2013 at 09:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. U.M. Domanska

Dissertation: Tumor microenvironment: preclinical insights into therapy resistance and targeting strategies

Promotor(s): prof. E.G.E. de Vries

Faculty: Medical Sciences

Activation of treatment resistance mechanisms in cancer are a major hurdle in developing an ultimately successful treatment. A body of preclinical research indicates that tumour adaptation to therapy is largely influenced by changes in the tumour microenvironment. In this thesis, two cell-surface receptors mediating interactions of cancer cell with its microenvironment - chemokine receptor 4 (CXCR4) and formylated-peptide receptor 1 (FPR1) - were studied. Both receptors may be overexpressed on cancer cells and primarily mediate their migration. The aim was to gain a better understanding of the role of CXCR4 and FPR1 in the biology of solid cancers, with a particular focus on the role of CXCR4 in the interactions of tumour cells with stromal microenvironment and its influence on the anti-cancer therapy response. Preclinical studies described in this thesis reveal the contribution of CXCR4/CXCL12 signaling to the microenvironment-mediated resistance of solid tumour cells to classical therapies. Up-regulated by anti-cancer treatment, involved in tumour resistance, survival, metastasis and vascularization, this chemokine receptor/ligand pair may be a valuable target for therapy of solid tumours. In addition, FPR1 receptor is investigated as an important inducer of migration of high-grade brain tumour cells. The effects of the recently identified FPR1 ligands, present in the necrotic tumour microenvironment, and the potent inhibitory effects of the FPR1 antagonist, are shown in preclinical models of high-grade glioma. These step-by-step advances in understanding the functions and dynamics of G protein-coupled receptors in tumour microenvironment should help to define novel, rational strategies for more successful cancer treatment.

PhD ceremony Ms. F. Cui: Distinguishing and connecting self and others. A social neuroscience perspective

When:Mo 09-12-2013 at 11:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. F. Cui,

Dissertation: Distinguishing and connecting self and others. A social neuroscience perspective

Promotor(s): prof. C.M. Keysers

Faculty: Medical Sciences

If you have seen the movie starred by Will Smith “I am legend” you might be shocked by the feeling of desperation and loneliness. Born as social animals, it is curial for our survival to be able to distinguish and connect self and others. “How does our brain work when performing these social functions?” This is the question we want to answer in this thesis using a combination of functional Magnetic Resonance Imaging (fMRI), ElectroEncephaloGraphy (EEG) and ElectroMyoGraphy (EMG) technologies. Here, you will find out how our brain differentiates active and passive body movement; how fMRI and EEG were used to discover how you share the actions of others; why you feel the pain of others more when you are fully responsible for their suffering compared to when you are not or partly responsible; and why knowing that the suffering person receives monetary compensation makes you feel better. This thesis will shed light on some of the mystery of our social nature.

PhD ceremony Ms. P. Brummelman: Cognition in patients treated for pituitary diseases

When:Mo 09-12-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. P. Brummelman

Dissertation: Cognition in patients treated for pituitary diseases

Promotor(s): prof. B.H.R. Wolffenbuttel, prof. O.M. Tucha

Faculty: Medical Sciences

Pituitary diseases are characterized by abnormalities related to undersecretion or oversecretion of pituitary hormones with or without local mass effects. The cause of these diseases is often a pituitary tumour, which is usually benign and emanates from the anterior pituitary. In general, treatment of pituitary adenomas consists of surgery, which may be followed by radiotherapy in cases of a significant tumour remnant or regrowth. Due to the pituitary disease itself, or after treatment with surgery and/or radiotherapy, hormonal therapy may be necessary in case of new or persistent hormonal disturbances. Literature suggests that these different treatment options may have an effect on cognition. However, reported results were inconsistent and mostly derived from small and heterogeneous patient groups according to diagnose and treatment. Therefore, we studied the effects of radiotherapy and hormonal and medical therapy on cognition in large and homogenous groups of patients treated for pituitary diseases. We found that multiple field radiotherapy techniques and fractionated radiation dose regimens did not have a major effect on memory and executive functioning in patients treated for a non-functioning pituitary macroadenoma. In patients treated for acromegaly, we found that previous growth hormone excess and growth hormone suppressive medication were not associated with impaired cognitive functioning. Further, in a large study with extensive neuropsychological evaluation, we found that patients treated for secondary adrenal insufficiency had selective impairments in the cognitive domains of memory, attention, executive functions and social cognition.

PhD ceremony Mr. F.T.G. Rahusen: The athletes elbow

When:Mo 09-12-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. F.T.G. Rahusen

Dissertation: The athletes elbow

Promotor(s): prof. R.L. Diercks

Faculty: Medical Sciences

This thesis deals with research for medical doctors and paramedics, for instance physiotherapists, who treat athletes suffering from elbow problems.

Various pathophysiological conditions are described, including the most common anatomical, biomechanical and pathophysiology conditions of the elbow. Chapter 2 specifically focuses on the most common elbow problems of tennis players. Chapter 3 summarizes an experimental muscle contusion model in mice, and advises on treatment of muscle injuries. Chapter 5 is an article about a novel technique for injecting into the elbow. Specific conditions as osteochondral defects and posterior impingement are described in chapter 6 and 7. Finally, chapter 8 describes considerations for treating patients with a Medial collateral ligament reconstruction.

Through this dissertation medical and paramedical professionals who treat patients with athletic elbow disorders are better prepared in doing so.

PhD ceremony Mr. N. Li: Novel mechanisms for prevention and treatment of type 2 diabetes

When:We 11-12-2013 at 11:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. N. Li

Dissertation: Novel mechanisms for prevention and treatment of type 2 diabetes

Promotor(s): prof. M. Hofker, prof. C. Wijmenga

Faculty: Medical Sciences

Type 2 diabetes(T2D) has become one of the most common chronic diseases worldwide in the past 20-30 years. Although the discovery of insulin was an epoch-making achievement in the history of treating diabetes, we still face problems that insulin and treatments to improving insulin signaling cannot solve. The focus of this thesis is mechanisms for preventing and treating T2D. 50 putative genes associated with T2D were reviewed and classified based on current knowledge of their presumed molecular functions; these genes, mainly discovered by recent genome-wide association studies, will be potential targets for anti-diabetic drugs in the future. We also discussed whether hypertriglyceridemia and low-HDL cholesterol can be causal factors in the development of insulin resistance. If this is true, we could prevent T2D by intervening in the hypertriglyceridemia and low-HDL cholesterol. Furthermore, we tested association of 95 lipid loci collectively and individually with glucose-related traits in two independent cohorts (LifeLines, 10,995 subjects and PREVEND, 2,438 subjects). And there are other, new, problems arising as side-effects from the use of insulin, which also need to be treated. We introduced an improved regimen for treating insulin allergy, which indicates novel mechanism of T2D related to immune tolerance. Anti-insulin antibody induced dysglycemia was also described, and we suggest a new classification for insulin-related-antibody-induced dysglycemia based on the pathophysiological mechanisms involved. There is still much to do before T2D is defeated and we have shown that the current genetics approaches are excellent for the urgently needed insight into the mechanisms.

PhD ceremony Mr. J.F. de Boer: Novel insights into the pathogenesis of metabolic syndrome-related disease

When:We 11-12-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. J.F. de Boer

Dissertation: Novel insights into the pathogenesis of metabolic syndrome-related disease

Promotor(s): prof. U.J.F. Tietge

Faculty: Medical Sciences

Patients with the metabolic syndrome, but also those with type 1 diabetes, have a strong increased risk of cardiovascular disease. The aim of this research project was to provide a better understanding of the pathophysiology leading to insulin resistance and to explore a potential role for altered HDL functionality in diabetes as a contributing factor to increased cardiovascular disease risk.

Data obtained from one study revealed that lack of 12/15-lipoxygenase, especially lack of this enzyme in immune cells, leads to more severe development of diet-induced insulin resistance. Another study showed that mice lacking the enzyme MK2 have a reduced insulin sensitivity, most likely due to decreased expression of an insulin-stimulated glucose transporter. In addition, it was shown that lower HDL levels in type 2 diabetic patients lead to a reduction of the protection against the harmful oxidation of LDL particles, a phenomenon that is strongly linked to the development of atherosclerosis. A study that aimed to investigate the effect of type 1 diabetes on transport of cholesterol from immune cells, via the liver, out of the body, revealed that this so called ‘reverse cholesterol transport pathway’ is impaired in type 1 diabetic conditions. Also, it was found that a recently discovered HDL-associated protein does not impact on the atheroprotective functions of these ‘good’-cholesterol particles although it is preferentially present on these particles in the blood stream.

PhD ceremony Mr. L.R. Cornelius: A view beyond the horizon. A prospective cohort study on mental health and long-term disability

When:We 11-12-2013 at 14:30
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. L.R. Cornelius

Dissertation: A view beyond the horizon. A prospective cohort study on mental health and long-term disability

Promotor(s): prof. J.J.L. van der Klink, prof. J.W. Groothoff

Faculty: Medical Sciences

PhD ceremony Mr. H.J. Santing: Provisional implant-supported restorations in the aesthetic zone. Assessment of material properties and biofilm

When:We 11-12-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. H.J. Santing

Dissertation: Provisional implant-supported restorations in the aesthetic zone. Assessment of material properties and biofilm

Promotor(s): prof. H.J.A. Meijer, prof. G.M. Raghoebar, prof. A. Vissink

Faculty: Medical Sciences

To achieve a harmonious peri-implant soft tissue and excellent aesthetics, an anatomical provisional implant-supported restoration can be used. Provisional implant-supported restorations should be strong enough to withstand functional forces (i.e. have high fracture strength and low wear) and should not be harmful to surrounding peri-implant soft tissues. Little information is available on these topics.

The general aim of the research described in this thesis was to assess a number of material properties of provisional implant-supported restorations in the anterior zone of the mouth. Furthermore, the clinical performance of the Straumann Bone Level Implant System was evaluated and a new method for design and production of provisional implant-supported restorations was described.

Results of the in vitro studies reveal that indirect laboratory composite resin provisional implant-supported restorations are suitable for prolonged use in the anterior zone of the mouth with regards to fracture resistance and occlusal wear. It was concluded that more bacteria (both alive and dead) reside on indirect laboratory composite resin provisional implant-supported restorations compared to definitive zirconia/porcelain restorations. However, the clinical implications of these findings are unknown. Additional clinical studies are required to warrant prolonged use of provisional implant-supported restorations.

Furthermore, the radiographic, clinical and aesthetic outcomes and patient satisfaction of cases treated with platform-switched single implant restorations in the aesthetic region of the maxilla were evaluated. From this prospective, clinical study it can be concluded that the Straumann Bone Level Implant shows an excellent survival rate, marginal bone stability and good clinical and aesthetic results.

PhD ceremony Ms. H. Yu: Exploring AKIP1 function in the heart

When:We 18-12-2013 at 09:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. H. Yu

Dissertation: Exploring AKIP1 function in the heart

Promotor(s): prof. W.H. van Gilst

Faculty: Medical Sciences

Heart failure (HF) is the common end stage syndrome of many cardiac disorders, which is associated with altered ventricular wall stress triggering cardiac remodeling. Cardiomyocyte growth (hypertrophy), which is often accompanied by energetic reprogramming, is an important process that contributes to cardiac remodeling and HF development. Induction of hypertrophy is accompanied by marked changes in gene expression profiles. The aim of this thesis was to generate an inventory of gene expression changes specific for cardiomyocyte hypertrophy and to further investigate the role of these changes in hypertrophy development . In particular, we explored the function of A kinase interacting protein 1 (AKIP1), which was identified in the inventory as a novel hypertrophy associated gene. We reviewed the current knowledge on gene expression regulation during hypertrophy development. In order to identify novel HF associated genes, we performed a whole genome analysis on several cardiac hypertrophy/HF models and compared the gene expression profiles with their corresponding control groups. Then we investigated the role of AKIP1 in hypertrophy development in NRVCs. Furthermore the effect of AKIP1 on the oxygen consumption rate (OCR) in cardiomyocytes was described. To translate the in vitro findings to the in vivo situation, we generated a cardiac specific AKIP1 transgenic (Tg) mouse line and further investigated the role of AKIP1 in hypertrophy by a TAC mediated pressure overload model.

PhD ceremony Mr. S. Daghighi: Bio-optical imaging of host-bacteria interactions in biomaterial-associated infection

When:We 18-12-2013 at 11:00
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. S. Daghighi

Dissertation: Bio-optical imaging of host-bacteria interactions in biomaterial-associated infection

Promotor(s): prof. H.J. Busscher, prof. H.C. van der Mei

Faculty: Medical Sciences

The first aim of this thesis is to gain a better understanding of the host immune system interaction with bacteria in a biomaterials-associated infection (BAI). Furthermore, we want to develop an in vivo implant BAI models based on bioluminescence and fluorescence imaging.

We discuss a number of hypotheses to explain the decreased infection risk associated with the use of degradable versus non-degradable biomaterials. In a murine model we compared staphylococcal persistence on and around a degradable and non-degradable surgical mesh. Bioluminescent staphylococci persisted on and around non-degradable meshes up to the 28th day, whereas the bacteria disappeared from surrounding tissues once a degradable mesh had fully dissolved. Bioluminescent flux from S. aureus Xen29 was quantified in absence and presence of different antibiotics. Staphylococcal bioluminescence at sub-inhibitory concentrations seemed to be enhanced when measured 24 h after incubation. Therefore, antibiotic pressure may impact the relationship between bacterial numbers and their bioluminescence. We investigated the relationship between MMP- and integrin-expression and the clearance of infecting S. aureus around implanted biomaterials in a murine model. MMP- and integrin-expression were equally enhanced in presence of staphylococci or biomaterials up to 7 days post-implantation, but bacterial clearance was higher in absence of biomaterials. MMP- and integrin-expression were enhanced in presence of staphylococci and biomaterial, but the immune system remained hampered in eradicating bacteria during the first 7 days post-implantation. Finally, different subjects of our findings are discussed.

PhD ceremony Ms. L. Mohseninejad: Uncertainty in economic evaluation: implications for healthcare decisions

When:We 18-12-2013 at 12:45
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. L. Mohseninejad

Dissertation: Uncertainty in economic evaluation: implications for healthcare decisions

Promotor(s): prof. E. Buskens

Faculty: Medical Sciences

Economic evaluations, especially cost-effectiveness analyses, play an increasing role in supporting policy making in health care. In these methods, additional costs and health benefits of a new drug/health intervention are compared to the standard of care. When the additional costs and benefits of the new technology are balanced in a way that the adoption is worthwhile, the health policy can change in favor of the new technology. Different diseases with various specifications and progression stages would need different ways of calculating the long term costs and health effects. However, since any assessment of the effects as well as costs will remain uncertain to some degree, any decision based on cost-effectives will also be uncertain. This uncertainty arises from different sources, and can have an important effect on the results.

The objective of this thesis is to explore different ways of handling the uncertainty in economic evaluation of new medical technologies and to extend the methods of the uncertainty analysis. Beside the methodological contribution, I explore different policy options in uncertainty management and contribute to the methods of linking reimbursement of medical products to the collection of additional evidence.

PhD ceremony Ms. A. Holwerda: Work outcome in young adults with disabilities

When:We 18-12-2013 at 14:30
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Ms. A. Holwerda

Dissertation: Work outcome in young adults with disabilities

Promotor(s): prof. J.J.L. van der Klink, prof. J.W. Groothoff

Faculty: Medical Sciences

Read press release Policy to increase employment opportunities for young adults with a disability is essential

PhD ceremony Mr. B.H. Bosker: Pitfalls in traditional and innovative hip replacement surgery

When:We 18-12-2013 at 16:15
Where:Academiegebouw, Broerstraat 5, Groningen

PhD ceremony: Mr. B.H. Bosker

Dissertation: Pitfalls in traditional and innovative hip replacement surgery

Promotor(s): prof. S.K. Bulstra

Faculty: Medical Sciences

Instability, increased wear, and reduced motion range are important complications of total hip arthroplasty (THA) and associated with cup malpositioning. Despite modern alternatives like computer navigation, most cups are still implanted by using a freehand technique. Because cup malposition is associated with shortened survival and dislocation, the accuracy of this freehand technique is questioned.

The first part of this thesis describes a prospective cohort study on the accuracy of freehand cup positioning in THA. Factors contributing to the inaccuracy were further investigated. Dislocation of the prosthesis resulting from cup malposition is a serious complication. Revisional surgery is frequently indicated to treat recurrent dislocations. The results of a less invasive procedure by using an augmentation ring are discussed in a retrospective cohort study.

The second part of the thesis discusses the problems associated to metal-on-metal total hip arthroplasties. We found a much higher incidence of pseudotumors than as earlier described in the literature. Risk factors for pseudotumor formation and revision were investigated. The specific design and corrosion of the prosthesis might play an important role in the high incidence of pseudotumors, and might lead to early failure and fracture of the implant.

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