Genome-wide association analysis identifies a susceptibility locus for sporadic vestibular schwannoma at 9p21.

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.

Men at risk of being a mutation carrier for hereditary breast/ovarian cancer: an exploration of attitudes and psychological functioning during genetic testing.

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.

Psychological impact of receiving a BRCA1/BRCA2 test result.

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.

Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree.

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 (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 and MLH1 carriers (32% by the age of 80 v >80%). 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.

Coping style of substance-abuse patients: effects of anxiety and mood disorders on coping change.

The authors studied the coping style of substance-abuse patients during clinical cognitive-behavioral group therapy, and the effects of mood and anxiety disorders on changes in coping style. Change in coping style was studied prospectively in a cohort of 132 residential-drug-abuse patients. In addition to pretreatment assessments, which included diagnosis of mood and anxiety disorders and addiction severity, repeated measurements of coping style were performed at predetoxification, pretreatment, and after three and six months of treatment. Considerable change in coping style between predetoxification and pretreatment was found, suggesting that coping assessment in a predetoxification phase is confounded by state factors surrounding treatment entry. Coping style of detoxified substance abusers is related to the presence of mood and anxiety disorders. Coping style was not found to be related to the severity of drug abuse. Furthermore, maladaptive coping styles decreased after three months of inpatient-substance-abuse treatment, and more-adaptive coping styles remained stable for another three months of inpatient treatment. Patients with an anxiety disorder improved less on coping style when compared to non-anxiety patients. Presence of a mood disorder had no impact on coping-style improvement. The results indicate that more attention should be focused on anxiety disorders during substance-abuse treatment in order to improve coping style. Furthermore, more studies are needed on the relation between substance abuse, coping style, and psychopathology.

Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? Rotterdam/Leiden Genetics Working Group.

Presymptomatic DNA testing for autosomal dominant hereditary breast/ovarian cancer (HBOC) became an option after the identification of the BRCA1 and BRCA2 genes in 1994-1995. Healthy female mutation carriers have a high lifetime risk for breast cancer (56-87%) or ovarian cancer (10-60%) and may opt for intensive breast and ovary surveillance or prophylactic surgery (mastectomy/oophorectomy). We studied general and cancer related distress in 85 healthy women with a 25% or 50% risk of being carrier of a BRCA1/BRCA2 gene mutation and 66 partners in the six to eight week period between genetic counselling/blood sampling and disclosure of the test result. Questionnaire and interview data are analysed. Associations are explored between levels of distress and (1) expected consequences of being identified as a mutation carrier, (2) personality traits, (3) sociodemographic variables, and (4) experiences related to HBOC. Mean pre-test anxiety and depression levels in women at risk of being a carrier and partners were similar to those of a normal Dutch population. In about 25% of those at risk of being a carrier and 10% of the partners, increased to high levels of general and cancer related distress were found. Increased levels of distress were reported by women who (1) anticipated an increase in problems after an unfavourable test outcome, (2) considered prophylactic mastectomy if found to be mutation carrier, (3) had an unoptimistic personality, (4) tended to suppress their emotions, (5) were younger than 40 years, and (6) were more familiar with the serious consequences of HBOC. Recently obtained awareness of the genetic nature of cancer in the family was not predictive of distress.The majority of the women and their partners experienced a relatively calm period before the disclosure of the test result and seemed to postpone distressing thoughts until the week of disclosure of the result. The low distress levels may partly be explained by the use of strategies to minimise the emotional impact of a possibly unfavourable test outcome. However, a minority reported feeling very distressed. Several factors were found to be predictive for increased distress levels.

Comparison of four HTLV-I and HTLV-I + II ELISAs.

BACKGROUND: Various countries require blood donor screening using assays applying specific HTLV-I and HTLV-II antigens. We evaluated the sensitivity and specificity of 4 anti-HTLV-I + II ELISAs (Abbott, Murex, Organon Teknika and Ortho). METHODS: Panel A consisted of HTLV-I-positive individuals (n = 41), panel B of Mixed Titer Performance Panel 204 (Boston Biomedica Inc. panels C and D of dilution series from HTLV-I-positive (n= 30) and HTLV-II-positive (n =20) individuals and panel E of sera from first-time blood donors (n = 1,055). RESULTS: In HTLV-I- and -II-positive samples, a sensitivity of 100% could be observed in all 4 ELISAs. In diluted HTLV-I- and -II-positive samples, probit analysis revealed that the Murex assay had the highest analytical sensitivity, followed by the ELISAs from Ortho, Abbott and Organon Teknika. In specimens from first-time donors, a specificity of 100% was observed in ELISAs from Murex, Organon Teknika and Ortho, and of 99.7% in the assay from Abbott. CONCLUSION: The 4 anti-HTLV-I + II ELISAs studied were appropriate as screening tests.

Cue reactivity and effects of cue exposure in abstinent posttreatment drug users.

After 12 months of inpatient treatment, 16 opiate-addicted patients were exposed to drug-related stimuli. The results of this study indicate that cue reactivity in opiate-addicted subjects is still present after 12 months of intensive inpatient treatment. After exposing subjects to drug-related stimuli, there is an increase in craving, feelings of depression, and anger. Because posttreatment subjects are likely to be confronted with these stimuli following discharge, a reduction of this reactivity is desirable. In the present study, cue reactivity (feelings of depression, anger, tension, craving, and physical symptoms) reduced after protocolized cue exposure treatment. This effect maintained for at least 6 weeks after the last cue exposure session.

D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study.

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.

Pharmacist-physician co-operation at a regional level.

In the Dutch region of "Betuwe" the hospital pharmacists and community pharmacists together provide short drug letters about new drugs, which are sent bimonthly to all the practising general practitioners (n = 83) and medical specialists (n = 50) in this region. A survey was conducted among these physicians in order to investigate their opinion about and reported use of the drug letters in comparison with other drug-information sources. The majority of the responding physicians (response rate 68%) was found to read the drug letter frequently and evaluated the drug letter as a useful source of information about drugs, especially its section about the advantages and disadvantages of the new drug compared to other drugs. With respect to the different stages of the drug-adoption process, the drug letter was found to be the most frequently used information source at the decision stage. At the introduction stage the pharmaceutical industry representative seems to be the most frequently used source of information, while at the information stage it is the "Geneesmiddelenbulletin" (Drug Bulletin). The majority of the responding general practitioners reported to participate in local group meetings with pharmacists. However, in only 20% of these group meetings attention is given to the drug letter. Since it is known that written information has only a limited influence on the physician's behaviour, the influence of the "Betuwe Circulaire" may increase when attention is paid to it in the local contacts between pharmacists and physicians.

[Udder infections with coagulase-negative staphylococci in freshly calved heifers]. / Uierinfecties met coagulase negatieve stafylococcen (CNS) bij nieuwmelkte vaarzen.

To determine the prevalence of udder infections in fresh calved heifers all quarters of 98 heifers on eleven commercial farms were sampled weekly during the first eight weeks of lactation. The samples during the first four weeks of this period were used for bacteriological examination and in all samples a somatic cell count was made. The prevalence of S. aureus after calving in these heifers was 12.5%. Coagulase-negative staphylococci (CNS) were isolated from half of the heifers. The predominant coagulase-negative staphylococcus species were S. xylosis and S. hyicus. The CNS, with exception of S. hyicus, had a very small effect on the cell count.

Two cases of long term dopamine D2 receptor blockade after depot neuroleptics.

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.

[No difference in efficacy of hydroquinine and placebo in restless legs syndrome]. / Geen verschil in werkzaamheid tussen hydrokinine en placebo bij het 'restless legs'-syndroom.

OBJECTIVE: Determination of the efficacy of hydroquinine treatment of the restless legs syndrome. DESIGN: Double blind cross-over trial. SETTING: University Hospital Leiden. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: This study showed no significant differences between the efficacy of placebo or hydroquinine in the restless legs syndrome.

[Relatively low HIV prevalence among drug users in The Hague in spite of risky injection behavior]. / Relatief lage HIV-prevalentie onder druggebruikers in Den Haag ondanks riskant spuitgedrag.

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.

A method for hemorrhagic shock in the rat.

Normovolemic hemorrhagic shock was induced in unanesthetized as well as anesthetized rats. The animals were bled according to predetermined schedules followed by reinfusion of all shed blood. In these models mortality during the hypovolemic phase was avoided, while practically 100% mortality ensued a number of hours after the reinfusion. To this end, a certain individualization of the bleeding procedure was necessary. The pathology induced was very similar in the two models. The survival time as well as the course of the plasma-glucose concentration (a tendency to a high degree of hypoglycemia) and the plasma-K+ concentration (extreme hyperkalemia) were also very similar. The causes of the hypoglycemia and hyperkalemia are not elucidated.