Integration of linkage analyses and disease association studies

The REGD procedure of the S.A.G.E. [1994] system was used to determine the mode of inheritance of the rare disease given in Problem 1. The likelihood ratio test statistic indicated that we should reject the hypotheses of dominant and recessive inheritance at the 0.01 level, so codominant inheritance was assumed. The estimated penetrance values computed from the β estimates given by the S.A.G.E. output were 1.0, 0.7, and 0.0 for the AA, AB, and BB genotypes respectively. A sample of three markers from each chromosome was used to determine which chromosome(s) gave evidence of having loci linked to the disease locus. The lod minus 0.83 support interval, which has been shown to provide the best approximation to 95% coverage among interval estimates [Nemesure et al., in press], was obtained for each of these markers. The criterion for rejecting the hypothesis of close linkage using the support interval methodology required that the left side of the lod minus 0.83 support interval about the maximum likelihood estimate, $ {\rm \hat \theta } $, includes only values greater than θ = 0.10. This criterion suggested that chromosomes 2, 3, and 6 did not contain the disease genes. Classical lod-score linkage analysis using the usual criteria of 3.0 for linkage and -2.0 for exclusion did not result in any regions being identified. On dropping the required lod score to 1.0, chromosomes 1, 3, and 6 gave results in favor of linkage with lod scores of 1.94 (θ = 0.19), 1.20 (θ = 0.24), and 1.30 (θ = 0.23), respectively. Association studies comparing unrelated cases to unrelated controls were done for all markers on all chromosomes. Two associations were observed which were significant at the 0.05 level after adjusting for the large number of multiple comparisons being made. The strongest association observed was between allele 7 of marker 23 on chromosome 5 and the disease (χ = 52.20, or = 4.7) and the second strongest was between allele 8 of marker 31 on chromosome 1 (χ = 20.10, OR = 3.4). ©1995 Wiley-Liss, Inc.     

An Inter- and Intra-University Comparison With Short Case-Based Testing

Comparisons between PBL and non-PBL medical schools on problem-solving ability often show no differences. This could be either due to the fact that no difference in problem-solving skills exists or that the instruments used are inadequate. In this study a key-feature approach case-based examination was used to compare two medical schools in the Netherlands, one of which has a PBL curriculum (Maastricht) and one which has a program half way a transition from a non-PBL towards a PBL curriculum (Groningen). Differences were found both in proficiency scores and in the pattern of response times, both supporting the assumption that a PBL approach would lead to a higher level of problem solving ability. The effect size, however, is not as large as originally assumed by the PBL proponents. Conclusions must be drawn with caution, but it seems likely that a test based on large numbers of short cases is the most sensitive in detecting differences in problem solving ability between students of different curricula. This revised version was published online in June 2006 with corrections to the Cover Date.     

Supine Bicycle Exercise Echocardiography: A Potent Immediately Available Tool for Detection and Localization of Myocardial Ischemia for the Initial Cardiologist

Background: Exercise echocardiography (EE) is being used increasingly as an investigative technique now that dynamic images can be captured digitally. Its equivalent reliability with scintigraphic methods has been demonstrated in a hospital setting. This study analyzes its impact on daily practice. Materials and Methods: Standardized progressive stress was produced by supine bicycle ergometry. Echocardiographic images of complete cardiac cycles were obtained in standard apical and parasternal short-axis views before, during, and after maximum effort, and digitized for simultaneous analysis of synchronized images at rest and during exercise. Two hundred sixteen patients (175 men and 41 women; mean age 58 ± 10 years) were studied. Results: Image quality was suboptimal in 4 cases. In the remaining 212 cases, ischemia was detected in 91 cases, and the test was negative in 114 cases and doubtful in 7 cases. Control by selective coronary angiography, as indicated by the clinical situation, was performed in 52 cases. In this particular group, EE showed 87% sensitivity, which is significantly higher than the 59% recorded for conventional exercise testing (P > 0.0001). Conclusions: EE by bicycle ergometer in the supine position is a valid, noninvasive investigative technique that can be used in an outpatient situation (feasibility 95%) since it is readily available. Its value appears to be greatest in cases in which exercise ECG is not conclusive. A negative result enables the initial cardiologist to reassure the patient immediately, which has been demonstrated in the literature to have favorable prognostic value.     

MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation

The object of this study was to investigate whether exposure of pipe-layers to thermal degradation products of diphenylmethane diisocyanate (MDI) could be assessed by analysing 4,4-methylenedianiline (MDA) in hydrolysed plasma and urine, and whether the genotype for N-acetylation affected these biomarker levels. Blood and urine samples were drawn from 30-pipe-layers who had been welding polyurethane (PUR) insulated pipes during the preceding 3 months. MDA in hydrolysed plasma and urine was determined with a gas chromatography-mass spectrometry technique, and genotype for N-acetylation was analysed with a polymerase chain reaction technique. MDA in plasma was detected in 18 of the 30 pipe-layers. Their plasma concentrations of MDA varied from 0.05 to 8.48 g/1. There was a significant negative correlation between time since last welding of PUR-insulated pipes and P-MDA (r _s = 0.50, P = 0.005). There was also a significant positive correlation between the estimated number of welded PUR-insulated pipes during the preceding 3 months and P-MDA (r _s = 0.68, P = < 0.001). No significant association between genotype of N-acetylation and P-MDA was observed in a multiple regression analysis when adjustment was made for the estimated cumulative exposure to thermal degradation products of MDI. MDA in urine was detected in only four of the 30 pipe-layers. These four subjects had been welding PUR pipes on the same day as the sampling, or on the day before. The present results indicate the spot plasma samples analysed for MDA may give a rather good estimate of exposure to MDI during the preceding months. P-MDA, but not U-MDA, therefore seems to be a useful biomarker of long-term exposure to MDI. The individual N-acetylation capacity did not affect the plasma levels of MDA.     

Diffusion of information about genetic risk within families

Recent developments in genetics are likely to exacerbate the ethical issues in clinical practice, especially with regard to privacy and disclosure of genetic information. To evaluate the behaviour of patients with respect to transmitting carrier information, we undertook a survey of 283 families with a balanced chromosomal rearrangement as a model. In these families, 1816 relatives were considered at risk and 806 of them were karyotyped (44.4%). The percentage of karyotypes performed is significantly related to the number of living children of the index couple, the reason for referral, the nature of the anomaly, the training of the counsellor and the age of the index case. This study shows the limits of the screening of at risk individuals within families, based on the willingness of the patients, and addresses practical and ethical issues around family disclosure in medical genetics.     

A genetic analysis of the hyperthermic response to d-amphetamine in two inbred strains of mice

A genetic analysis of amphetamine-induced hyperthermia was conducted in inbred mice of the strains Balb/c and C₃H and in their F₁F₂ and backcross generations. The results of biometric analysis indicate that the effect of amphetamine on body temperature is genetically determined. The mode of inheritance characterized by a partial dominance (Balb/C over C₃H strain). However, a possible matermal effect of C₃H can overcome the dominant effect in male progenies and inhibit amphetamine hyperthermic effect.     

The clinical utility of provocative radionuclide oesophageal transit in the evaluation of non-cardiac chest pain

We combined edrophonium provocative testing with the technique of radionuclide oesophageal transit (RET) in 30 consecutive patients with non-cardiac chest pain (NCCP) and 12 controls. The oesophageal transit time of aqueous technetium-99m sulfur colloid was determined before and after intravenous infusion of 80 g/kg edrophonium chloride (ED). Patient symptoms during provocative RET (P-RET) were recorded. Thirteen (43%) of the patients had abnormal study results, whereas all control subjects had normal results. Three groups considered abnormal were observed: (a) in two patients (6%), the pain was reproduced and transit pre- and post-ED administration was prolonged (>15 s); (b) in six patients (20%), the pain was reproduced, but transit was normal pre- and post-ED; (c) in five patients (17%), transit pre- and post-ED was prolonged, but no pain was reproduced. In five patients (17%), ED prolonged the transit time > 15 s without pain, but the baseline transit was normal. Transit time was measurable in 23 patients. Mean pre-ED transit time was 10.2 ± 7.4 s (mean ± SD) and post-ED, 12.4 ± 8.0 s (P=0.3). We conclude that ED has no significant effect on transit time, and the pain induced by ED rarely correlates with an abnormal transit; P-RET provides additional information to baseline RET, increasing sensitivity, and may be a useful screening method in the evaluation of patients with NCCP.     

Retropublic colpourethropexy with transabdominal anterior and/or posterior repair for the treatment of genuine stress urinary incontinence and genital prolapse

A new operative technique combining retropublic colpourethropexy with transabdominal internal anterior and/or internal posterior repair for the treatment of genuine stress incontinence (GSI) and genital prolapse is described in 75 cases. The overall success rate in correcting GSI was 92.0%, with a 94.8% success rate in the primary surgical group (n=58) and an 82.4% in the secondary group (n=17). Average follow-up has been 1.31 years (range 6 weeks–6 years). There was a 3.4% incidence of residual prolapse. Nine patients also underwent concomitant colpourethropexy. Overall surgical complications include febrile morbidity 4/75 (5.3%), wound infection 1/75 (1.3%), deep vein thrombosis 1/75 (1.3%) and partial ureteric obstruction 1/75 (1.3%). There were no statistically significant changes in multichannel urodynamic studies preoperatively and at 1 year following surgery. Onethird (2/6) of the GSI failures had low MUCP (<20 cm H₂O) prior to surgery and continued so at 1 year follow-up.EDITORIAL COMMENT: Genital prolapse is often present in patients who have GSI. If an operation is performed to correct the GSI, and those areas of weakness in the pelvic support system that are contributing to the genital prolapse are not treated, the genital prolapse will become more severe. In the operation which has been described, the colpopexy sutures will correct any cystourethrocele, and the removal of the wedge of tissue from the anterior superior vaginal wall will correct the cystocele. The removal of the wedge of tissue from the posterior superior vaginal wall will reduce the redundancy of the posterior vaginal fornix, but a culdeplasty of the Moschcowitz or Halban type is recommended to treat or prevent an enterocele and to place the vaginal apex in the hollow of the sacrum. Any coexistent rectocele must always be treated vaginally. If it is not treated, it will appear to be more advanced following elevation of the anterior vaginal wall by retropubic urethropexy and the anterior repair which has been recommended.Genital prolapse is best treated by a vaginal approach. When one must une an abdominal approach, ancillary procedures such as the authors have described should be considered. A bulbous upper vagina is ideal for childbearing but if the apical support system and vaginal wall is weakened it is predisposed to prolapse. If the surgeon, in operating for genital prolapse, which involves the upper vagina, will taper the vaginal apex and support it by obliteration of the cul-desac and shortening and reattachment of the uterosacralcardinal complex, postoperative prolapse will be less likely to recur.     

Predictive testing for BRCA1 and 2 mutations: a male contribution.

BACKGROUND: Management strategies for women carrying BRCA1 and 2 mutations are becoming clearer and predictive testing for a known family mutation is commonly undertaken. Implications for men are not as clear and they participate less frequently. PATIENTS AND METHODS: Twenty-six men from 10 extended families underwent predictive testing. Their motivation, reaction and outcome were studied. Subjects had appropriate pre- and post-test counselling. Informed consent was obtained before predictive testing for known deleterious mutations. DNA analysis followed standard procedures. RESULTS: Eighteen tested positive and eight negative. Four had adverse psychological reactions and three reneged on their commitments to impart results. The spouse of another man had an adverse psychological reaction to the disclosure of his positive result. Two, already suffering from prostate cancer, were phenocopies and paternal lineage transmission was unexpectedly determined in another. Risk was removed from 33 offspring and confirmed for 56. CONCLUSIONS: Complex themes associated with genetic testing are confirmed and the spectrum extended. Men appear to understand the importance of participating in this process. Methods of avoiding adverse reactions merit further study along with other aspects of the process.     

Physical performance in long-term survivors of acute leukaemia in childhood

The aim of this study was to assess the physical performance in long-term survivors of acute leukaemia in childhood and to evaluate the effects of anthracycline therapy. Electrocardiography, echocardiography and spiroergometry were carried out on 56 patients aged 9–28 years, of whom 44 patients had been treated with 15–483 mg/m² doxorubicin (or equivalent). Acute leukaemia had been diagnosed 1.5–16 years earlier. Of the patients 75% reached normal maximal oxygen uptake, 69% normal oxygen uptake at the anaerobic threshold and 95% normal maximal work rate. Of the patients 75% achieved adequate values for maximal heart rate and 78% normal blood lactate concentration. No difference was seen between patients treated with and without anthracyclines. Conclusion The results of this study provide little evidence for cardiopulmonary impairment in long-term survivors of ALL. Both the cardiac function, as evaluated by ECG and echocardiography, and the physical performance in spiroergometry are normal in a large number of these patients. Anthracycline treatment does not appear to have a negative effect on these parameters. Received: 30 October 1996 / Accepted in revised form: 7 October 1997