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Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants.To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10−13, odds ratio = 0.67, allele frequency = 0.52).9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

Obesity is a significant risk factor for the development of endometrial hyperplasia and cancer. More conservative prevention and management strategies are attractive due to the increased surgical risk and complication rates associated with obesity. The Levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena) has been shown to reduce the risk of developing endometrial cancer. The recent joint Green Top Guideline on the Management of Endometrial Hyperplasia published by the Royal College of Obstetricians and Gynaecologists (RCOG) with the British Society for Gynaecological Endoscopy (BSGE) recommends the LNG-IUS for the medical management of endometrial hyperplasia without atypia. This case study reports on the development of endometrioid adenocarcinoma despite the presence of an LNG-IUS following a negative hysteroscopy in a 56-year-old woman with morbid obesity. This report highlights the need for patients and clinicians to remain vigilant to the early warning signs of developing endometrial cancer, especially in those at an increased risk secondary to obesity.

Background Neoadjuvant chemotherapy (NAC) is increasingly used in the framework of breast-conserving therapy (BCT). Localization of the initial tumor is essential to guide surgical resection after NAC. This study describes the results obtained with I-125 seed localization in BCT including NAC. Patients and methods Between January 2009 and December 2010, 85 patients treated with NAC and BCT after I-125 seed localization were included. Radiological and pathological response and resection margins were retrospectively evaluated. Results BCT was carried out in 85 patients without secondary local excisions. Nineteen patients with unifocal tumors and seven patients with multifocal tumors showed a complete pathological response (P = 0.18). Tumor-free resection margins were obtained in 78 patients (50 patients with unifocal and 28 patients with multifocal tumors, P = 0.27). Focally involved margins were found in four patients (two patients with a unifocal and two patients with a multifocal tumor, P = 0.27). A subsequent mastectomy was carried out in three patients (two patients with multifocal tumors, P = 0.29). Conclusions BCT after NAC can be carried out successfully after initial localization with I-125 seeds in both unifocal and multifocal breast tumors with complete resection rates of >90%.

Obesity is a significant risk factor for the development of endometrial hyperplasia and cancer. More conservative prevention and management strategies are attractive due to the increased surgical risk and complication rates associated with obesity. The Levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena) has been shown to reduce the risk of developing endometrial cancer. The recent joint Green Top Guideline on the Management of Endometrial Hyperplasia published by the Royal College of Obstetricians and Gynaecologists (RCOG) with the British Society for Gynaecological Endoscopy (BSGE) recommends the LNG-IUS for the medical management of endometrial hyperplasia without atypia. This case study reports on the development of endometrioid adenocarcinoma despite the presence of an LNG-IUS following a negative hysteroscopy in a 56-year-old woman with morbid obesity. This report highlights the need for patients and clinicians to remain vigilant to the early warning signs of developing endometrial cancer, especially in those at an increased risk secondary to obesity.

Mw J. lijdt al 2 jaar aan gewrichtsklachten en is daardoor niet in staat haar werk te doen. Zij wordt begeleid door de bedrijfsarts en behandeld door haar huisarts, maar er zit niet veel verbetering in. De verzekeringsarts beoordeelt de WIA-claim van mw J. Hij meent dat niet alle behandelmogelijkheden zijn uitgeput, en stelt de huisarts voor om patiente te verwijzen naar specialist

Op vrijdag 18 april 2008 vond in Congrescentrum Figi te Zeist de jaarvergadering 2008 plaats van de Vereniging voor Gezondheidsrecht.

About 5% of colorectal cancers are associated with the autosomal dominantly inherited cancer susceptibility syndrome hereditary non-polyposis colorectal cancer (HNPCC).1,2 HNPCC is characterised by a high risk of developing colorectal cancer and endometrial cancer at a young age (cumulative lifetime risk 80-90% and 30-40%, respectively), and by an increased risk of developing various other tumour types, such as ovarian, uroepithelial, small intestine, biliary tract, stomach, brain, and skin cancers.2–5 Germline mutations in one of three mismatch repair genes ( MSH2 , MLH1 , and MSH6 ) were found to be responsible for a majority of HNPCC families.6–9 Knowledge of the causative mutation in a particular HNPCC family enables the identification of at risk family members by genetic testing. Clearly, the absence or presence of a mutation is of considerable medical and psychological significance. Subjects not carrying the mutation are relieved from a continuous anxiety and can be dismissed from medical surveillance, saving them trouble and reducing health care costs.10 Importantly, subjects with the mutation can benefit from a medical surveillance programme. For HNPCC, colonoscopy has been shown to be a potent tool for the detection and treatment of premalignant adenomas or early colorectal carcinomas in at risk subjects, reducing the risk of developing colorectal cancer and decreasing the overall mortality by about 65%.11,12 The possibility of early detection of colorectal cancer by stool analysis using the genetic markers TP53, BAT26, and K-RAS raises expectations for the development of less invasive surveillance procedures.13 Furthermore, intervention trials with non-steroidal anti-inflammatory drugs (NSAID) in subjects at risk for developing colorectal cancer are in progress.14,15 So far, studies on the use of genetic testing in HNPCC families have used families or subjects who had been registered for research purposes.10,16,17 It is …

Het bestuur van de NVAB heeft gesignaleerd dat een ontwikkeling gaande is om in het kader van de ziekteverzuimbegeleiding en re-integratie steeds vaker andere functionarissen in te zetten. Van oudsher was dit een kerndomein van de bedrijfsarts, maar verzuimcoordinatoren, re-integratiecoaches, arbeidsdeskundigen en bedrijfsverpleegkundigen worden steeds vaker gezien, niet alleen naast maar vaak ook in plaats van de bedrijfsarts.

Mutation analysis for autosomal dominant hereditary breast/ovarian cancer genes (BRCA1/BRCA2) became an important technique for women at risk of carrying these mutations. Healthy female mutation carriers have a high lifetime risk for breast and/or ovarian cancer and may opt for frequent breast and ovary surveillance or prophylactic surgery (mastectomy and/or oophorectomy). Psychological distress was assessed in 78 healthy women at risk of having inherited a BRCA1/BRCA2 mutation opting for genetic testing and 56 partners several weeks prior to ("pre-test") and after ("post-test") learning about their DNA test result. Twenty-five women were found to be mutation carriers, and 53 were non-mutation carriers. One goal of the study was to identify individuals at risk for high distress in the weeks following disclosure of the test result. Interview transcripts were used to give a fuller picture of pre- and post-test distress. High post-test anxiety was reported by 20% of the mutation carrier women and by 35% of their partners. Eleven percent of women without the mutation and 13% of their partners reported high post-test anxiety levels. High post-test anxiety in women was significantly related to 1) a high level of pre-test anxiety and 2) being a mutation carrier. Women without a mutation who had a sister identified as a mutation carrier recently had higher post-test levels of depression than the other non-mutation carriers. It is suggested to consider seriously the need for psychological support in mutation carriers who had been anxious at pre-test already. For most non-mutation carriers, psychological follow-up might be of lesser importance, but those having a sister receiving an unfavorable test result should be informed about the possibility that they might not feel relief.

Males with a BRCA1/BRCA2 mutation are not at greatly increased risk for cancer, whereas their (grand)daughters, and other female relatives who carry the mutation, are. Males from BRCA1/BRCA2 families may opt for genetic testing to confirm whether or not they may have transmitted the mutation to their children and, if so, to inform them at an appropriate age about the genetic risk and its implications. The psychological implications of genetic testing for men at risk of being a BRCA1/BRCA2 mutation carrier have received little attention. We report on 28 men requesting BRCA1 or BRCA2 testing, and their partners. Men were at 25% (n =4) or 50% risk (n =24) of being a mutation carrier, the majority with daughters and half of them with daughters aged over 20 years. Levels of psychological distress were assessed several weeks before and after disclosure of the test result. In addition, we investigated the level of intrusive thoughts and feelings about breast and ovarian cancer and the tendency to avoid these. By means of interviews and questionnaires, participants could report on (expected) emotional implications of genetic testing for themselves and their children, on experiences with cancer in the family and on personality trait optimism. Distress levels prior to the result in tested men and their partners were low. Many men and partners expected the test result to affect their children's, but not their own level of problems. Men without daughters and those with an optimistic personality had especially low distress prior to disclosure. Most men reported that they did not actively avoid the issue. Only four of the 28 men were identified as mutation carriers. High distress after disclosure of the result was reported by one mutation carrier and by three non-mutation carriers. Verbatim transcripts from interviews showed a large variation of psychological reactions in male mutation carriers (eg regarding guilt feelings). Low pre-test distress in males does not necessarily indicate avoidance of the issue. Future studies may indicate which psychological reactions occur in male mutation carriers when the problem becomes more acute, eg when a daughter is found to carry the mutation and/or is diagnosed with breast or ovarian cancer.

Twenty-six patients under treatment with the calcium channel blockers flunarizine (Fz) or cinnarizine (Cz) were examined with single-photon emission computed tomography using [123I]iodobenzamide as a ligand. The striatal dopamine D2 receptor-binding potential was determined and found to be reduced by 14 to 63% (39.5 ± 15.0%; p < 0.0001) in patients compared with age-matched control values. This reduction was larger in 12 patients with extrapyramidal symptoms and was only slowly reversible after discontinuation of treatment. Patients treated for >6 months had significantly larger reductions than patients treated for a shorter period. Parkinsonian symptoms were only seen in patients older than 50 years. Our findings prove a neuroleptic-like action of Fz and Cz, which seems to be the major reason for their extrapyramidal side effects. Older age and long-term treatment are predisposing factors for these effects.

Dopaminrezeptoren sind als Wirkorte des Dopamins sowie der Dopaminagonisten bei der Behandlung der Parkinsonkrankheit von Bedeutung. Die Darstellung und Messung der Dopamin D2 Rezeptoren ist in vivo mit der SPECT-Technik (Single-Photon- Emissions- Tomographie) sowie einem selektiven Liganden, dem J-123 markierten Jodobenzamid, moglich. Es ist von Interesse, in wieweit bei Patienten mit Morbus Parkinson sowie mit Multisystemdegenerationen eine Anderung der Dopamin D2 Rezeptordichte im Vergleich mit einer Kontrollgruppe festzustellen ist. Wir versuchten, klinische Befunde und Wirksamkeit der Therapie mit diesen Ergebnissen zu korrelieren.

Es ist seit mehreren Jahren bekannt, das die Kalziumantagonisten Flunarizin und Cinnarizin eine Parkinsonsymptomatik auslosen oder verstarken konnen (Chouza et al. 1986). Auch andere extrapyramidale Symptome wie Akathisie, tardive Dyskinesien und Dystonien scheinen von diesen Kalziumantagonisten verursacht werden zu konnen (Micheli 1989). Der Pathomechanismus dieser extrapyramidalen Nebenwirkungen ist bis jetzt noch umstritten. Tierexperimente haben sowohl Hinweise auf eine postsynaptische Dopaminrezeptorblockade im Sinne einer Neuroleptika-ahn-lichen Wirkung (Ambrosio und Stefanini 1991) als auch auf eine Interaktion auf prasynaptischer Ebene ergeben (Garcia Ruiz et al. 1992).

Die Entwicklung der Positronen Emissionstomographie (PET) und geeigneter Liganden hat es vor mehr als 10 Jahren erstmals moglich gemacht, biochemische Vorgange an Synapsen im menschlichen Gehirn in vivo zu untersuchen und sichtbar zu machen. Erst seit kurzerer Zeit konnen ahnliche Untersuchungen auch mit der leichter verfugbaren und billigeren Single Photon Emissions Computer Tomographie (SPECT) durchgefuhrt werden. Dazu werden sogenannte “Tracer” verwendet, die mit Gammastrahlen-emittierenden Isotopen, wie z.B. 123J markiert sind, sich an bestimmte biochemische Strukturen binden und mit einer Gammakamera sichtbar gemacht werden konnen. Unsere bisherigen Studien befassen sich vorwiegend mit dem dopaminergen System. Es konnte gezeigt werden, das die Substanz Jodobenzamid (IBZM) ein hochaffiner und spezifischer Ligand fur Dopamin D2 Rezeptoren ist, der sich gut fur SPECT Messungen eignet (Brucke et al. 1988). Mit dieser Substanz werden vorwiegend postsynaptische Strukturen im Striatum dargestellt. Seit 1988 wurden an unserer Klinik uber 500 Studien mit IBZM an Patienten und Kontrollen durchgefuhrt, wobei vor allem Patienten mit extrapyramidalen Erkrankungen, aber auch die pharmakologische Beeinflusung der D2 Rezeptorbindung durch verschiedene Pharmaka untersucht wurden (Brucke et al. 1991). Ein weiteres Interessensgebiet betraf Patienten mit Hypophysenadenomen. Seit kurzer Zeit steht auch fur den prasynaptischen Anteil des dopaminergen Systems ein Ligand zur Verfugung, der fur SPECT Studien verwendet werden kann.

Two patients with extrapyramidal side effects after the use of fluphenazine decanoate were evaluated by means of IBZM-SPECT. Dopamine D2 receptor occupancy 1.5 months after withdrawal still amounted to 83% and 50%. More attention should be focused on long term effects of neuroleptics.

SUMMARY Classic anti-neutrophil cytoplasmic autoantibodies (C-ANCA) are disease-specific markers of Wegener's granulomatosis (WG). The possible pathogenetic role of these autoantibodies, which are directed against Proteinase 3 (PR3), is not yet clear. We studied the effect of C-ANCA on PR3 proteolytic activity and on the complcxation of PR3 with alpha1-antitrypsin (α1AT). C-ANCA IgG from eight patients with active WG significantly inhibited PR3 proteolytic activity, particularly towards elastin (median 84.2% inhibition). C-ANCA IgG significantly inhibited the complexation of PR3 with α1AT (median 58.8% inhibition). Moreover, addition of purified PR3 to C-ANCA-positive sera from WG patients yielded less complexes with α1AT (median 44.8%) compared with sera containing perinuclear anti-neutrophil cytoplasmic autoantibodies (P-ANCA) or ANCA-negative sera. These findings indicate the existence of a hitherto unknown property of C-ANCA, which may be of importance in the pathogenesis of WG.

Determination of the efficacy of hydroquinine treatment of the restless legs syndrome.Double blind cross-over trial.University Hospital Leiden.Selection through an announcement in the press and followed by structured interview. Inclusion criteria according to the international classification of sleep disorders. Exclusion criteria defined by medication risks. Patients used either hydroquinine (200 mg in the evening and 200 mg before going to bed) or placebo in the second and fourth of four periods of two weeks duration. Severity of complaints was assessed using a daily questionnaire and a Suggested Immobilization Test (SIT) twice weekly, in which they noted the severity of complaints as experienced during a 15-minute period of immobilization.The study was completed by 59 out of 68 patients. Analysis of variance showed no significant differences between the two groups of patients (those starting with placebo and those starting with hydroquinine) for any of the questions of the daily questionnaire or of the SIT. McNemar's test showed no significant differences between the proportions of patients who wished to continue the use of either placebo or hydroquinine.This study showed no significant differences between the efficacy of placebo or hydroquinine in the restless legs syndrome.

Between September 1987 and January 1989 101 drug users in The Hague were studied for HIV seroprevalence and risky injecting behaviour. A comparison was made between this group and a group of 241 drug users who were studied in the same period in Amsterdam. All HIV-infected drug users, except for one homosexual man in Amsterdam, had a history of intravenous drug use. The HIV seroprevalence for 56 intravenous drug users in The Hague was 1.8% (95% CI: 0-5.3), and for 194 intravenous drug users in Amsterdam 26.8% (95% CI: 20.6-33.0). With regard to risky injecting behaviour no differences in frequency of borrowing or lending used needles and syringes were found between the two groups. Concluded is that further spread of HIV among intravenous drug users in The Hague (and Amsterdam) will be likely unless risk reduction in injecting behaviour will occur.

The mantle plume/rift system model developed by three of the present authors (v. C., d. T., K.) for the northern Hesperian Massif is expanded to that of an aulacogen/ensialic orogen for the entire massif. The first author (v. d. M. M.) contributes a review of the supracrustal history of the massif and its predrift adjacent areas, summarized in a time-stratigraphic table of the Cambro-Ordovician and a palinspastic-palaeogeographic sketch map of the general region in Middle Cambrian times. The infrastructural history is also reviewed, and it is concluded that the early Palaeozoic features of the Massif are consistent with those of an aulacogen oriented at a high angle to the Iapetus ocean. In the Late Palaeozoic its features changed into those of an ensialic orogen without appreciable loss of continuity as shown by the facies- and age record of sedimentary, igneous and metamorphic events.

Two patients showed occupational contact sensitization to a component present in the Nyloprint photopolymer printing plate. The component could not be identified chemically. It contains an acrylamide group. Both patients gave group-specific reactions to NN' methylene bis acrylamide. This must be a closely realted substance. Possible preventive measures are discussed. The manufacturer should have disclosed the allergic substance and instructed his customer adequately. A "philosophy" concerning this point is being developed.

Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes. Keywords: hereditary non-polyposis colorectal cancer; MSH6