To evaluate current guidelines criteria for inclusion of women in special ‘breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at ‘less than ‘moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted ‘cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45–59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence (‘NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network (‘SIGN') in defining ‘moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services.
breast cancer; familial; risk assessment
Background: Increased dietary vitamin E intake is associated with a reduced incidence of asthma, and combinations of antioxidant supplements including vitamin E are effective in reducing ozone induced bronchoconstriction. A study was undertaken to investigate the effect of supplementation with vitamin E for 6 weeks on bronchial hyperresponsiveness in atopic adults with asthma.
Methods: 72 participants from a clinical trial register of adults with asthma were randomised to receive 500 mg natural vitamin E or matched placebo for 6 weeks in a placebo controlled, double blind parallel group clinical trial. Inclusion criteria included age 18–60 years, maintenance treatment of at least one dose of inhaled corticosteroid per day, a positive skin prick test to one of three common allergens, and bronchial hyperresponsiveness to methacholine (defined as a dose provoking a 20% fall in forced expiratory volume in 1 second (FEV1) (PD20) of 12.25 µmol). Secondary outcomes were FEV1, forced vital capacity, mean morning and evening peak flow, symptom scores, bronchodilator use, and serum immunoglobulin E levels.
Results: In the primary intention to treat analysis the change in PD20 was similar in the vitamin E and placebo groups with a mean difference of +0.25 doubling doses of methacholine (95% confidence interval –0.67 to +1.16 greater with vitamin E). There was no effect of vitamin E supplementation on any other measure of asthma control, either in the intention to treat or per protocol analysis. There was also no effect of vitamin E supplementation on serum immunoglobulin levels.
Conclusion: Dietary supplementation with vitamin E adds no benefit to current standard treatment in adults with mild to moderate asthma.
Type 2 diabetes mellitus is a common multifactorial genetic syndrome, which is determined by several different genes and environmental factors. It now affects 150 million people world wide but its incidence is increasing rapidly because of secondary factors, such as obesity, hypertension, and lack of physical activity. Many studies have been carried out to determine the genetic factors involved in type 2 diabetes mellitus. In this review we look at the different strategies used and discuss the genome wide scans performed so far in more detail. New technologies, such as microarrays, and the discovery of SNPs will lead to a greater understanding of the pathogenesis of type 2 diabetes mellitus and to better diagnostics, treatment, and eventually prevention.
Keywords: diabetes mellitus type 2; genetic factors; genome screen; candidate gene
OBJECTIVES— Central nervous system haemangioblastoma (HAB) is a major feature of von Hippel-Lindau (VHL) disease, and it is estimated that about 30% of HAB patients have VHL disease. Consequently, it is widely recommended that sporadic HAB patients are screened for clinical and radiological features of VHL disease because of the risk of multiple tumours. We investigated the frequency of VHL germline mutations in patients with HAB only with no clinical or radiological evidence of VHL disease to define the role of molecular genetic analysis in the management of such patients.
METHODS—Eighty four patients with a single HAB (23 Dutch, 61 UK) and four with multiple HAB (two Dutch, two UK) were studied by direct sequencing of the coding region and quantitative Southern blotting.
RESULTS—A VHL germline mutation was found in three of 69 (4.3%) single HAB patients aged 50 years or less (three of 84 (3.6%) total single HAB patients). A germline VHL mutation was detected in a 44 year old woman with a solitary cerebellar HAB, as well as in four clinically unaffected close relatives, and in two single HAB cases presenting at the ages of 29 and 36 years. Germline VHL mutations were detected in two of four cases with multiple HAB.
CONCLUSIONS—Early detection of VHL disease is important to reduce morbidity and mortality and therefore we recommend that, in addition to conventional clinical and radiological investigations, VHL gene mutation analysis should be offered to all HAB patients younger than 50 years. HAB patients aged >50 years will have a lower a priori risk of VHL disease and further data are required to evaluate the role of routine molecular genetic investigations in late onset HAB cases. The failure to detect germline VHL mutations in some patients with multiple HAB may indicate the presence of somatic mosaicism or additional HAB susceptibility genes.
Keywords: haemangioblastoma; von Hippel-Lindau disease; VHL; germline mutation
BACKGROUND: Managing patients' requests for appointments is an important general practice activity. No previous research has systematically observed how patients and receptionists negotiate appointments. AIM: To observe appointment making and investigate patients' and professionals' experiences of appointment negotiations. DESIGN OF STUDY: A qualitative study using participant observation. SETTING: Three general practices on Tyneside; a single-handed practice, a practice comprising three doctors, and a seven-doctor practice. METHOD: Participant observation sessions, consisting of 35 activity recordings and 34 periods of observation and 38 patient and 15 professional interviews, were set up. Seven groups of patients were selected for interview. These included patients attending an 'open access' surgery, patients who complained about making an appointment, and patients who complimented the receptionists. RESULTS: Appointment making is a complex social process. Outcomes are dependent on the process of negotiation and factors, such as patients' expectations and appointment availability. Receptionists felt that patients in employment, patients allocated to the practice by the Health Authority, and patients who did not comply with practice appointment rules were most demanding. Appointment requests are legitimised by receptionists enforcing practice rules and requesting clinical information. Patients volunteer information to provide evidence that their complaint is appropriate and employ strategies, such as persistence, assertiveness, and threats, to try and persuade receptionists to grant appointments. CONCLUSION: Appointment making is a complex social process where outcomes are negotiated. Receptionists have an important role in managing patient demand. Practices should be explicit about how appointments are allocated, including publishing practice criteria.
OBJECTIVE: To assess knowledge, views, and behaviour of researchers on criteria for authorship and causes and control of gift authorship. DESIGN: Interview survey of stratified sample of researchers. SETTING: University medical faculty. SUBJECTS: 66 staff (94% response rate) comprising several levels of university academic and research appointments. MAIN OUTCOME MEASURES: Awareness and use of criteria for authorship, views on which contributions to research merit authorship, perceptions about gift authorship and strategies for reducing it, and experiences of authorship problems. RESULTS: 50 (76%) respondents supported criteria for authorship, but few knew about or used available criteria. Of the five people who could specify all three criteria of the International Committee of Medical Journal Editors, only one knew that all criteria had to be met. Forty one respondents (62%) disagreed with this stipulation. A range of practical and academic contributions were seen as sufficient for authorship. Gift authorship was perceived as common, promoted by pressure to publish, to motivate research teams, and to maintain working relationships. A signed statement justifying authorship and a published statement of the contribution of each author were perceived as practical ways of tackling gift authorship. Most researchers had experienced problems with authorship, most commonly the perception that authorship had been deserved but not awarded (49%). CONCLUSION: There seems to be a gap between editors' criteria for authorship and researchers' practice. Lack of awareness of criteria is only a partial explanation. Researchers give more weight than editors to practical research contributions. Future criteria should be agreed by researchers and not be imposed by editors.
The trio of recent government white papers heralds a new world for primary care. Many changes in the education of future primary health care professionals and in the research ethos of the discipline will be needed to realise this vision. New skills and attitudes, not least in multidisciplinary working; lifelong learning; and greater understanding of and participation in primary care research will have to emerge from educational efforts in the next few years.
A randomized controlled trial was carried out to test the effectiveness of a screening programme carried out by nurses for elderly people aged 75 years and over in a general practice. A total of 151 people were randomly allocated to the test group and 145 to the control group. The test group received a home visit from a nurse at which an assessment lasting 45 minutes was made of: activities of daily living, social functioning, sensory functions, mental and emotional problems, current medical problems, blood pressure, urinalysis, haemoglobin level and compliance with medication. Both groups completed a selection of items from four health indices before and 20 months after the intervention. At follow up, the test group scored significantly better than the control group on a morale scale. However, this trial provided no evidence for better resolution of physical problems or finding activities of daily living easier in the test group compared with the control group. It is suggested that the main benefit of such a screening process is that the special attention and education provided improves adaptation to old age and awareness of the support systems available. The government has proposed an annual review of elderly people in their own home and this study suggests that the objectives of this scheme should be clarified.
Polymorphic DNA markers can now be used for presymptomatic and prenatal diagnosis of the autosomal dominant form of polycystic kidney disease (PKD). A detailed map is known for the chromosomal region around the PKD1 gene on the short arm of chromosome 16. We present here a simple, two step procedure for diagnosis of PKD1 by family studies. Using this approach, at least 92% of random subjects are informative for polymorphic DNA markers bracketing the PKD1 gene. The recombination rate between these flanking markers is on average 10%. In non-recombinants (90% of family members), the accuracy of diagnosis using DNA markers is greater than 99%. We conclude that sufficient well defined DNA markers are now available for routine diagnosis of PKD1. We recommend, however, that prenatal diagnosis of PKD by chorionic villi sampling should be attempted only after the linkage phase of the DNA markers has been established by haplotyping the index family. Since autosomal dominant PKD has been found to be genetically heterogeneous, families should be of sufficient size to rule out the rare form of PKD not caused by a mutation on the short arm of chromosome 16.
In 288 Dutch and Belgian Duchenne and Becker muscular dystrophy families, the parental origin of 41 new deletion or duplication mutations was determined. Twenty seven of the new mutations occurred in the maternal X chromosome and nine in the grandmaternal and five in the grandpaternal X chromosome. The grandparental data are compatible with equal mutation rates for DMD in male and female X chromosomes. New mutations were defined by their presence in one or more progeny and absence in the lymphocytes of the mother or the grandparents. In one family a fraction of the maternal lymphocytes was found to carry the mutation, suggesting somatic mosaicism. In six cases out of 41, the mutation was transmitted more than once by a parent in whom the mutation was absent in lymphocytes, suggesting gonadal mosaicism as the explanation for the multiple transmission. Using our data for the recurrence of the mutations among the total of at risk haplotypes transmitted, we arrive at a recurrence risk of 14% for the at risk haplotype. The observation of this high risk of germinal mosaicism is crucially important for all physicians counselling females in DMD families. Recently, germinal mosaicism has been observed also in a number of other X linked and autosomal disorders. The implications and appropriate diagnostic precautions are discussed.
Vitreous loss is a serious complication of cataract surgery. Following vitreous loss it is common practice to perform a primary implantation of an anterior chamber lens (AC-IOL). We retrospectively analysed 642 consecutive cases of cataract extraction performed between 1983 and 1986 with special attention to those patients in whom vitreous loss occurred and an AC-IOL was placed. There were 27 such cases, and 24 of these were available for follow-up. Eighteen (75%) had visual acuity of 20/40 or better. All six patients (25%) who had a visual acuity of less than 20/40 in the operated eye had a functional visual acuity of 20/200 or less. Complications that occurred in this group are discussed. We are concerned that the complications associated with vitreous loss and with AC-IOLs may be acting in concert to cause visually disabling results.
In a large family with the fragile X syndrome, we performed linkage investigations with six probes, detecting RFLPs at both sides of the fragile site Xq27. The nearest flanking markers were cX55.7 (DXS105) on the centromeric side (theta = 0.04, lod 5.0) and St14 (DXS52) on the telomeric side (theta = 0.08, lod 4.0). Non-penetrance could be shown by the presence of the grandpaternal X chromosome in three mentally retarded fra(X) positive males. A second non-penetrant male in this family had inherited an abnormal grandmaternal X chromosome. His carrier mother had two retarded fra(X) positive brothers. Intermediate between the non-penetrant and fully penetrant males was a non-retarded male, who expressed the fragile site in 6% of his cells. His X chromosome showed the same polymorphisms as were found in his seven severely retarded brothers. In five fra(X) negative females the presence of an abnormal X chromosome could be demonstrated. Despite the existence of non-penetrance in this pedigree, there was no close linkage between a factor IX polymorphism and the fragile site (theta = 0.16, lod 1.9). However, in six descendants of a non-penetrant male, the change to penetrance appeared to be accompanied by a low recombination frequency for flanking markers.
Cytogenetic and clinical investigations were performed in 85 members of a large family, in which 18 males and seven females were mentally retarded. In the male patients the fragile site Xq27 was found in 6 to 44% (mean 22.5%) of peripheral blood lymphocytes. One non-retarded male expressed the cytogenetic abnormality in 6% of his cells. In 21 females the fra(X) was found in 3 to 28% (mean 8.7%) of their cells. Two obligate carriers did not express the fragile site. A significant difference in expression between the seven retarded (mean 16.7%) and seven non-retarded female carriers of corresponding age (mean 6.3%) was found (alpha = 0.01). No significant correlation between expression and age could be established, either in males or in females. The cytogenetic results appeared to be consistent. To avoid false positives, a cut-off point was chosen: males were considered to be fra(X) negative if no more than one in 100 cells showed the abnormality; for females the cut-off point was two in 100 cells. Segregation analysis did not detect significant deviations from the expected ratios. The putative presence of a transmitting male is discussed. The results of recombinant DNA analysis will be published elsewhere. Clinical investigations confirmed the findings of others. CT scans showed an enlargement of the ventricular system that exceeded the expected age changes.
Thirteen marker loci localised on the short arm of the X chromosome are available for use in genetic studies for Duchenne muscular dystrophy (DMD). This large number of probes detecting about 20 RFLPs encouraged us to set up a standard procedure using a sequence of selected probes and restriction enzymes for the diagnosis of DMD families. The application of DNA probe analysis for carrier detection and prenatal diagnosis, involving 61 pedigrees of both familial and isolated cases, has yielded the following results. Carrier detection using flanking markers was possible in more than 75% of the cases (104 out of 136 females) with a reliability of better than 98%. Prenatal diagnosis was possible in 95% of the cases (65 out of 68 proven carriers or women at risk). Twenty-three prenatal diagnoses were performed on male fetuses; 13 appeared to have a low risk for DMD (less than 1%) and thus the pregnancies continued. Seven have since come to term and the male infants have normal CK levels. The genetic distances of the loci relative to the DMD locus and their order on the short arm of the X chromosome were deduced from our total DMD family material and are not significantly different from those reported earlier. For 754 (DXS84) we found a genetic distance of 5 cM with a lod score of +12.4 and 95% confidence limits between 2 and 12 cM. Similar data were obtained for pERT87 (DXS164), suggesting that in our family material both loci are tightly linked. Multiply informative recombination showed that both 754 and pERT87 map proximal to the DMD mutations in the cases studied. The high frequency of DMD mutations and its relation to the observed instability in this part of the genome will be discussed. Unequal crossing over is proposed as one of the mechanisms contributing to the high mutation frequency.
The genetic locus for autosomal dominant adult polycystic kidney disease was recently assigned to chromosome 16 by the finding of genetic linkage to the alpha globin gene cluster. Further study showed that the phosphoglycolate phosphatase locus is also closely linked to both the locus for adult polycystic kidney disease and the alpha globin gene cluster. These findings have important implications for the prenatal and presymptomatic diagnosis of adult polycystic kidney disease and for a better understanding of its pathogenesis.
A prerequisite for the optimal use of the twin method in human genetics is an accurate determination of the zygosity at birth. This diagnosis is sometimes hampered by the lack of available specific markers. We report here the use of DNA variants (restriction fragment length polymorphisms) as genetic markers for zygosity determination. We have analysed the placental DNA of 22 twin pairs with known zygosity on Southern blots by hybridisation with polymorphic human DNA probes. We looked at six different polymorphic sites using four restriction enzymes and six DNA probes. Among 10 dizygotic (DZ) pairs, only one was not demonstrably different and seven had at least two discordances. Within each of the 12 monozygotic (MZ) pairs there was complete concordance. Thus, nine of 10 dizygotic and 12 of 12 monozygotic twins were assigned their correct zygosity solely by comparison of six DNA variants. The use of these highly polymorphic DNA probes may have practical importance for antenatal diagnosis and paternity testing.
The inheritance of a restriction fragment length polymorphism (RFLP) detected by a cloned DNA sequence (p754) from the short arm of the X chromosome has been studied in 14 Duchenne muscular dystrophy kindreds and six Becker muscular dystrophy kindreds. The linkage data obtained suggest that both the DMD and BMD loci are located in the same region (p21) on the short arm of the X chromosome at a distance of about 15 to 20 cM from the 754 locus. Data from families informative for both the p754 and L1.28 polymorphisms suggest that p754 is closer to the disease loci than is L1.28.
General practitioners screened 4284 asymptomatic people aged over 40 to compare the incidence of large bowel cancer and polyps with a control general practice (4288 patients). Compliance was best in young women (60%), and overall it was 42%. Twenty six patients who had a positive Haemoccult test result (1.5% of those screened) were examined by colonoscopy and 10 had polyps. The incidence of cancers in the two groups was similar but in the control (unscreened patients) practice no polyps were found.
A study of DNA restriction fragment polymorphisms and Becker muscular dystrophy has shown eight families informative for the cloned sequence L1.28, which is located on the short arm of the X chromosome between Xp110 and Xp113. Analysis of these families reveals linkage between the two loci, with the maximum likelihood estimate of the genetic distance being 16 centiMorgans (95% confidence limits between 7 and 32 centiMorgans). Since a study of DNA polymorphisms in Duchenne muscular dystrophy has shown a comparable linkage distance with L1.28, our results suggest that the locus for Becker muscular dystrophy, like that for Duchenne dystrophy, is on the short arm of the X chromosome, and further that these two loci may be closely linked or possibly allelic.
Two DNA restriction fragment length polymorphisms show genetic linkage to the Duchenne muscular dystrophy locus on the short arm of the X chromosome. Examples are given of families in which these polymorphisms can be used in the prediction of genotype for this disorder.