Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) are markedly insulin-resistant, but the molecular mechanisms of these changes and their relationship to the hyperandrogenic state remain to be clarified. Mutations have recently been identified in the insulin receptor gene of patients with extreme forms of insulin resistance associated with hyperandrogenism (eg, type A insulin resistance), and these mutations account for the insulin resistance in such patients. We performed this study to determine whether mutations in the coding portion of the insulin receptor gene were responsible for insulin resistance in PCOS. Insulin binding studies using cultured skin fibroblasts of three obese (body mass index > 27 kg/m²) women with PCOS (ie, mild hyperandrogenemia and chronic anovulation of unknown etiology) and documented insulin resistance showed no apprarent abnormalities in either the number or affinity of insulin binding sites. Direct sequencing of all 22 exons of the insulin receptor gene from two of the women with PCOS did not reveal any mutations. Furthermore, both alleles of the gene were expressed at equal levels. In a third insulin-resistant PCOS woman, there was no evidence for a mutation in the coding portion of the insulin receptor gene as determined by denaturing gradient gel electrophoresis (DGGE). We conclude that the insulin resistance in these PCOS women was caused by a defect extrinsic to the insulin receptor.     

HLA-DQA1*0101 haplotypes and disease outcome in early onset pauciarticular juvenile rheumatoid arthritis.

To further investigate a clinical impression that patients with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) who carry HLA-DQw1 have more severe arthritis, we subtyped HLA-DQw1 in American midwestern patients with EOPA-JRA. The HLA-DQA1*0101 subtype was present in 10 of 19 patients who developed persistent polyarticular erosive disease compared with 18 of 92 healthy controls (chi 2 = 9.13, p = 0.003, RR = 4.6), and occurred more frequently in this polyarticular group than in patients without polyarticular erosive disease (chi 2 = 4.11, p = 0.040, RR = 3.0). The presence of HLA-DQA1*0101 was significantly lower in patients with chronic iridocyclitis than in patients without chronic iridocyclitis (chi 2 = 7.07, p = 0.008, RR = 0.21). In HLA-DQA1*0101 positive patients, DNA sequences of the beta-1 domain of the HLA-DQ alpha and HLA-DQ beta genes (HLA-DQA1*0101, HLA-DQB1*0501 and HLA-DQB1*0503) were identical to those in controls. In this midwestern EOPA-JRA population, HLA-DQA1*0101 or genes in linkage disequilibrium with it, are associated with a cohort of patients with EOPA-JRA with distinct clinical characteristics.     

Thrombolysis and the femorofemoral bypass graft: a new technique.

Two patients with acutely thrombosed femorofemoral bypass grafts are presented. Recombinant human tissue-type plasminogen activator (rt-PA) was used successfully in thrombolysis of the occluded grafts. Utilizing a new technique the grafts were punctured directly and bolus doses of rt-PA administered.     

Dialysis efficiency in continuous ambulatory peritoneal dialysis patients treated with erythropoietin.

OBJECTIVE: To determine the effect of subcutaneous erythropoietin treatment on dialysis efficiency in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: Dialysis efficiency, platelet and white cell aggregation, and red cell deformability were measured monthly for six months in nine anaemic CAPD patients treated with erythropoietin, and on a single occasion in seven control CAPD patients with intrinsically high haemoglobin concentrations. SETTING: Renal dialysis unit. PATIENTS: Nine patients stable on CAPD for a minimum of six months and with haemoglobin concentrations less than 8.5 g/dl were treated with erythropoietin. Seven CAPD patients matched for age and renal function, with haemoglobins greater than 9.0 g/dl served as controls. RESULTS: Daily peritoneal clearances and net ultrafiltration volumes were unchanged when haematocrit increased from 25.0 +/- 2.2% to 36.5 +/- 3.5%. Spontaneous whole blood platelet aggregation was significantly increased from week twelve (pre-treatment aggregation 46 +/- 23%; 12 weeks: 67 +/- 19%, p less than 0.05; 16 weeks: 64 +/- 19%, p less than 0.01; 20 weeks: 71 +/- 16%, p less than 0.01; 24 weeks: 73 +/- 10%, p less than 0.01). CONCLUSIONS: The increase in haematocrit and platelet aggregation associated with erythropoietin treatment did not affect peritoneal clearances or ultrafiltration capacity.     

Precise and accurate measurement of proton T1 in human brain in vivo: Validation and preliminary clinical application

Precise and accurate inversion-recovery (PAIR) magnetic resonance (MR) measurements of T1 were obtained in eight brain regions and cerebrospinal fluid of 26 healthy volunteers. Accuracy of the technique was assessed by measuring T1 in small fluid volumes with the PAIR technique and with two independent spectroscopic techniques. The mean difference between T1 measured with PAIR and with the two spectroscopic techniques was 3.1% ± 1.3. The precision (reproducibility) of measurements with the PAIR technique was excellent. The coefficient of variation (CV) across 16 measurements in a head phantom was 2.0%, compared with a CV of 2.7% across 45 separate measurements in a single subject. The within-subject CV was 1.8% ± 0.6 in white matter and 1.4% ± 1.0 in basal ganglia. The between-subject CV in 26 healthy volunteers was 3.6% ± 0.6 in white matter and 4.1% ± 1.9 in basal ganglia. Comparison between a patient with an active recurrent brain tumor and an agematched patient with an inactive brain tumor showed that T1 was significantly elevated throughout the brain of the active-tumor patient, especially in white matter tracts, even though no tumor or edema was detected in the white matter on standard MR images. Comparisons between five brain tumor patients and four healthy volunteers of similar age showed that T1 was significantly and substantially elevated throughout the white matter tracts and in the caudate nucleus, putamen, and thalamus. These results are consistent with the hypothesis that white matter tracts are selectively vulnerable to edema and that T1 increases in white matter are a sensitive indicator of patient status or tumor aggressiveness.     

Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies

This article describes how genetic components of disease susceptibility can be evaluated in case-control studies, where cases and controls are sampled independently from the population at large. Subjects are assumed unrelated, in contrast to studies of familial aggregation and linkage. The logistic model can be used to test collapsibility over phenotypes or genotypes, and to estimate interactions between environmental and genetic factors. Such interactions provide an example of a context where non-hierarchical models make sense biologically. Also, if the exposure and genetic categories occur independently and the disease is rare, then analyses based only on cases are valid, and offer better precision for estimating gene-environment interactions than those based on the full data.     

Corticotropin-Releasing Factor Reduces Lipopolysaccharide-Induced Pulmonary Vascular Leak

Previous studies have suggested that corticotropin-releasing factor (CRF) has immunoregulatory effects in addition to its neuroendocrine role. We examined the ability of CRF to inhibit lipopolysaccharide (LPS)-induced pulmonary vascular leak in vivo. Female BALB/C mice were treated with either normal saline (NS) or CRF prior to injection with LPS. Pulmonary vascular leak was inhibited by CRF as assessed by measurement of lung wet-to-dry ratios. The stress-induced increase in serum corticosterone levels in mice injected with LPS alone was not further increased by treatment with CRF. This indicates that the effect of CRF was not mediated centrally by stimulation of endogenous steroid release. Histologic examination of the lungs revealed that leukocyte infiltration was significantly depressed in CRF-treated mice thus confirming the protective effect of CRF. In addition, a modest prolongation of survival was demonstrated in CRF-treated mice following challenge with LPS (p=.08). These data indicate the potential utility of CRF as a modulator of pulmonary vascular leak.     

Prevention of vascular injuries in revision total hip replacement.

Iliac-vessel injury from total hip arthroplasty is associated with hemorrhagic complications and an increased death rate. The authors identified seven patients who had severe medial displacement of the acetabular prosthesis and associated vascular injury to the iliac vessels after total hip replacement. One patient had two hip replacements. Preoperative findings included a pelvic mass (three hips), pelvic pain (eight), radiologic evidence of cement in the pelvis (three) and the acetabular prosthesis in the pelvis (eight), computed tomographic evidence of cement in the pelvis and proximity of the prosthesis to the iliac vessels (four), and arteriography showing displacement or compression of the iliac vessels (seven). Operative management in all cases involved medial exposure, mobilization and repair of the iliac vessels before revision of the hip prosthesis. Postoperative complications were deep vein thrombosis (three), in spite of prophylaxis, and occlusion of a vein interposition graft (one) requiring placement of a femoral crossover graft. There were no deaths, amputations or hemorrhagic complications. The authors advocate preoperative identification of patients who have iliac-vessel involvement by their total hip prosthesis and initial medial extraperitoneal exposure and repair of these vessels before removal of the displaced acetabular prosthesis.