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.     

Metabolic acidosis in children: the usefulness of 'anion gap']

Metabolic acidosis occurs frequently in small children. The most common causes are hypoxia, sepsis, gastroenteritis and hypovolaemia. Calculation of the anion gap is useful in establishing the cause. An increased anion gap represents unmeasured anions, e.g. lactate in lactic acidosis. Metabolic acidosis was diagnosed in two boys aged one year and six weeks respectively. The first patient had a normal, the second an increased anion gap in blood. By determining the pH and the anion gap in urine it is possible to distinguish between a proximal and a distal tubular disease. The first patient had distal renal tubular acidosis; he recovered after correction of the acidosis. The second patient had a defect in the mitochondrial respiratory chain; he died at the age of seven months.     

17-Hydroxyprogesterone Caproate for the Prevention of Recurrent Preterm Birth – A Systematic Review and Meta-analysis Taking into Account the PROLONG Trial

Background Prior spontaneous preterm birth is a strong risk factor for the recurrence of spontaneous preterm birth in a subsequent pregnancy and has been evaluated in prevention studies using progesterone (natural progesterone administered orally or vaginally, and 17-hydroxyprogesterone caproate [17-OHPC]) as a selection criterion. Based on the findings of a randomized, placebo-controlled study, 17-OHPC was approved for use in 2011 by the Food and Drug Administration in the USA for the prevention of recurrent preterm birth. The approval was granted with qualification that a subsequent confirmatory study would need to be carried out, the results of which have just been published (PROLONG trial). Method A systematic literature search for the period from 1970 to April 2020 using the search terms “preterm birth” and “17-OHPC” or “progesterone” was carried out. Only randomized, placebo-controlled studies of women with singleton pregnancies who received 17-OHPC to prevent recurrent preterm birth were included in the subsequent meta-analysis. The relative risk and associated 95% confidence intervals were calculated. The heterogeneity between studies was evaluated with I ² statistics. Results In addition to the original study used for the approval and the PROLONG trial, only one other study was found which met the inclusion criteria (total number of patients: 2221). With considerable heterogeneity between the studies, particularly with respect to the risk factors for preterm birth, the comparison between 17-OHPC and placebo showed no significant reduction in preterm birth rates before 37, 35 and 32 weeks of gestation and no significant differences with regard to the prevalence of miscarriage before 20 weeks of gestation or fetal deaths (antepartum or intrapartum) after 20 weeks of gestation and neonatal morbidity. Conclusion Based on the currently available data, 17-OHPC cannot be recommended for the prevention of recurrent preterm birth. Further randomized, placebo-controlled studies with clearly defined, comparable risk factors are required to identify the group of pregnant women which could benefit from the use of 17-OHPC to prevent preterm birth. Key words: preterm birth, progesterone, 17α-hydroxyprogesterone caproate, prevention     

Relationship between memory strategies and motor symptoms in Parkinson's disease

Patients with Parkinson's disease(PD) show a serious decrease in performance on tasks which lack explicit guidelines and which necessitate the subject to develop his or her own strategy. Using the California Verbal Learning Task(CVLT) we have found evidence that this phenomenon becomes also manifest in learning and memory. The goal of the present study on PD was to investigate whether or not there is an intrinsic relationship between PD-specific deviant learning characteristics and the severity of motor symptomatology. The results show, as expected, a significant correlation between the severity of bradykinetic/hypokinetic symptoms and the serial clustering gradient of the CVLT: the more bradykinetic PD patients (n = 48) were, the more they were dependent on the externally guided serial learning strategy. The findings are discussed in the context of our hypothesis that the actual deficit in patients with PD is a deficient processing of ambiguous internal cues.     

The fate of stable cemented acetabular components retained during revision of a femoral component of a total hip arthroplasty

BACKGROUND: The decision as to whether to revise or retain a well fixed cemented acetabular component during revision of a femoral component is especially difficult; the rate of loosening of cemented acetabular components is high, whereas that of porous-coated acetabular components inserted during revision is low. However, removal of a well fixed cemented acetabular component can result in increased operative morbidity and cost and in loss of acetabular bone. Data that can be used to predict the long-term survival of retained well fixed cemented acetabular components are therefore needed. METHODS: We studied the five to thirteen-year clinical and radiographic results in a group of twenty-six consecutive patients in whom a well fixed cemented acetabular component had been retained during revision of a femoral component. Typical demographic data on the patients and information about the components were recorded, and the cemented acetabular components were graded as A through F, according to the system of Ranawat et al., at the time of the femoral revision. The average duration of follow-up was 8.4 years (range, 5.0 to 12.7 years). No patient was lost to follow-up. RESULTS: Four acetabular components (15 percent) had progressive radiolucency (at forty-eight, forty-eight, fifty-nine, and seventy-five months after the femoral revision) and were considered radiographically loose despite not being associated with symptoms. All four components were graded as either E or F at the time that they were retained during the femoral revision; radiographic loosening was significantly related to these two grades (p < 0.01). No acetabular component with a grade of A, B, C, or D loosened. The components that loosened had been in vivo for a relatively shorter, as opposed to longer, duration before the femoral revision compared with the components that did not loosen (p < 0.05). CONCLUSIONS: Retention of the well fixed cemented acetabular components was associated with good clinical results but with a 15 percent rate of loosening. Revision of a cemented acetabular component solely on the basis of the duration that it was in vivo or whether a previous revision had been done does not appear to be warranted. Our findings suggest that acetabular components with a grade of A, B, C, or D at the time of a femoral revision may be retained, as these components continued to function at the time of the five to thirteen-year follow-up in the current study.     

Insidious symptomatology and misleading physical findings in popliteal artery entrapment syndrome. A case report

A patient presented with an ischemic right forefoot. She suffered rest pain but had relief on walking and on flexing her leg. Popliteal and pedal pulses were palpable. The underlying condition was popliteal artery entrapment. Compression of the popliteal artery occurred with extension of the knee and additional contraction of the gastrocnemius muscles only and was released with flexion. Distal embolizations into all three lower leg arteries had caused acute ischemia. As the emboli had travelled through both tibial vessels very distally pedal pulses were found to be normal. Treatment was operatively by resection of a tiny lateral portion of the medial gastrocnemic tendon which crossed the artery dorsally as the vessel pierced the tendon.     

Optic nerve edema as a consequence of respiratory disease

The authors describe a patient with bilateral papilledema, visual field abnormalities, poorly reactive pupils, meningeal enhancement on cranial MRI, and diffuse brain parenchymal hypervascularity. The opening pressure at the time of lumbar puncture was normal, and results of other CSF studies were normal. All abnormalities resolved with home oxygen therapy.     

Cerebral panthrombophlebitis in a paucisymptomatic patient

In most cases, extensive cerebral venous thrombosis present themselves with a severe clinical outcome and poor prognosis. We present the case of a 59-years-old patient with a slight rather unrevealing symptoms but suffering from a cerebral thrombosis impacting on both superficial and deep venous system. The etiologic assessment revealed activated protein C resistance. Clinical evolution under systemic anticoagulation was prompt, with complete repermeabilization of the various venous structures.