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.     

Trends in hotel patronage and drink driving in Hobart, Tasmania

From 1990 to 1991 in the Hobart region there was a marked fall in both hotel patronage and the proportion of patrons subsequently driving with their blood alcohol concentration above the legal limit. This was associated with smaller falls in the number of drink drivers charged and alcohol-related road accidents, which continued in the following year. It appears that the pattern of drinking and driving is changing, presumably in response to random breath testing and tougher penalties for offences.     

福建省鼠伤寒沙门氏菌病原学特征变迁趋势

目的：了解福建省鼠伤寒沙门氏菌的病原学特征变迁情况。方法：采用噬菌体分型、质粒谱分析及耐药性测定的方法,对福建省１９８０～１９９５年１５年鼠伤寒沙门氏菌的病原学特征进行动态监测。结果：福建省鼠伤寒沙门氏菌的噬菌体流行型别存在明显的变迁与更迭;质粒谱型有逐渐增多且分散趋势;菌株耐药率逐年大幅度上升,耐药谱逐年迅速增宽,多重耐药菌株逐年急剧增多,耐药现象日趋严重。结论：噬菌体分型、质粒谱分析及耐药性测定是监测福建省鼠伤寒沙门氏菌病原学特征变迁趋势的有效方法。     

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.     

Molecular cytogenetic characterization of 16p11.2 microdeletions with diverse prenatal phenotypes: Four cases report and literature review

ObjectiveChromosome 16p11.2 deletions have been recognized as a genetic disorder with well-described postnatal phenotypes. However, the prenatal manifestations are atypical for lacking of enough evidence.Case reportFour pregnant women underwent amniocentesis for cytogenetic analysis and chromosomal microarray analysis (CMA) because of various indications for prenatal diagnosis: prenatal ultrasound abnormalities (cases 1, 2 and 4) and the childbearing history of cerebral palsy child (case 3). No overlapping phenotypes were observed in cases 1, 2 and 4, which might indicate phenotypic diversities in prenatal phenotypes for 16p11.2 microdeletion. All four fetuses showed normal karyotypic results while CMA identified 0.303–0.916 Mb microdeletions of 16p11.2, encompassing BP2–BP3 and BP4–BP5 regions separately. According to the parental CMA verification, case 1 carried a maternal inherited duplication in the region of Xp22.33 and a de novo deletion in the region of Xp21.1. All parents opted for the termination of pregnancies based upon genetic counselling.ConclusionOur findings enriched the intrauterine phenotypic features of 16p11.2 microdeletions, which would be beneficial for genetic counselling in clinic. In addition, preimplantation genetic testing was recognized as a first-tier approach for such carriers if they intended to conceive again.     

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.     

Ambient bioassays for assessing water-quality conditions in receiving streams

The purpose of this paper is to show how short-term laboratory tests, conducted according to US Environmental Protection Agency (EPA) procedures, can be used effectively to assess water-quality conditions in streams or rivers that receive pollutants from industry or municipal or agricultural areas. Standardized, short-term tests with fish, aquatic invertebrates or algae are commonly used to estimate the acute or chronic toxicity of wastewaters; this is referred to as effuent testing. The methods used for testing effluents also can be used to assess water quality in receiving streams: in this application, the procedures are referred to as ambient testing. Despite similarity in methods, the major objective of effluent testing differs importantly from that of ambient testing. In effluent testing, the key objective is to determine how toxic an effluent is; in ambient testing, the main objective usually is that of determining if the water at a site is toxic. This difference is subtle but very important: it shapes the strategy for cost-effective ambient testing, and determines the framework for effective statistical analysis and interpretation of ambient toxicity test results. Specific case-study examples are provided demonstrating the kinds of information that can be extracted from ambient toxicity testing by use of different statistical methods, including analysis of variance, contingency-table analysis, and two types of multivariate procedures (principal components analysis and logistic regression). Examples also are given supporting the idea that an effective ambient testing programme should be long-term, and contain a diagnostic-testing component analogous to the toxicity identification procedures used to supplement effluent-testing programmes. Recommendations derived as lessons learned from largescale ambient toxicity testing programmes for receiving streams at Department of Energy facilities include: (1) testing more frequently with one species (preferably Ceriodaphnia) generally is more effective, in terms of information gained per dollar spent, than testing less frequently with two or more species; (2) use five or more sites per test period, plus two or more reference sites, whenever possible; (3) use four to six test periods per year; and (4) use diagnostic testing to supplement the ambient-testing programme. Various laboratory and in situ methods for environmental assessment are now under development, but these methods probably will not gain acceptance for use in regulatory situations for many years. Rapid growth in need for ecological risk assessments outstrips the rate at which new test procedures are approved for regulatory purposes. Thus, laboratory tests for estimating possible environmental impacts of toxic or disruptive pollutants are likely to be used more frequently during the next decade.     

Residual myocardial ischaemia in first non-Q versus Q wave infarction: maximal exercise testing and ambulatory ST-segment monitoring

In a prospective study of 123 consecutive survivors of a firstmyocardial infarction (43 non-Q wave, 80 Q wave), we determinedthe total residual ischaemic burden by use of pre-dischargemaximal exercise testing and post-discharge 36 h ambulatoryST-segment monitoring initiated 11 ± 5 days after theinfarction. The prevalence of exercise-induced ischae-mic manifestations in the infarct types was similar: chest pain 14%vs 16% and ST-segment depression 54% vs 54%. The ischaemic thresholddid not differ either (heart rate at 1 mm of ST-segmnent depression120 ± 27 vs 119 ± 25 beats. min^–1). Duringearly post-discharge daily activities, more patients with non-Qwave infarction demonstrated transient episodes of ST-segmentdepression: 28% vs 14% (ns). Furthermore, ischaemic episodeswere significantly longer (42.5±50.1 vs 22.0 ±20.6 min; p <0.001), and the ischaemic threshold was significantlylower in non-Q wave infarction (heart rate at onset of ST-segmentdepression 84±11 vs 88±9 beats.min^–1; p<0.05). During 3.5±0.9 years of follow-up the proportionof patients with 1 ischaemic event (non-fatal reinfarction,angina pectoris, revascularization) was significantly higherin non-Q wave infarction (51%) as compared to Q wave infarction(31%) (P<005). In both infarct types the presence of ST-segmentdepression on ambulatory recording and exercise testing significantlypredicted the development of future angina pectoris, whereaspatients at increased risk for subsequent non-fatal reinfarctionor cardiac death were not identified.     

The effect of urapidil on responses to phenylephrine,angiotensin and isoprenaline in man

Summary Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg·h^–1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 g·min^–1 before to 685 g·min^–1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has ₁-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.