Expression of HIF-1 and ubiquitin in conventional renal cell carcinoma: relationship to mutations of the von Hippel-Lindau tumor suppressor gene

Conventional clear cell renal cell carcinomas (cRCC) have mutations of the von Hippel-Lindau (VHL) tumor suppressor gene at 3p25 in approximately 50% of cases. The VHL gene normally regulates ubiquitin-mediated proteolysis of hypoxia-inducible factor 1alpha (HIF-1alpha); in cell lines, VHL inactivation blocks HIF-1alpha proteolysis, resulting in increased HIF-1 expression. This study was undertaken to investigate the relationship between VHL mutations and the expression of ubiquitin and HIF-1alpha in cRCC. Eleven cRCC were studied with microsatellite analysis for 3p deletions and with sequencing for VHL mutations. Immunohistochemistry was performed for HIF-1alpha and ubiquitin. Deletions at 3p25 were found in 10 tumors, and VHL mutations were identified in 6 of these cases. There was staining for ubiquitin and HIF-1alpha in all tumors with VHL mutations. Among the five cases without VHL mutations, staining for ubiquitin or HIF-1alpha was not present in three cases but was present in two tumors, both of which had 3p deletions. The findings support a role for VHL mutations promoting cRCC development by an impairment of HIF-1alpha proteolysis. The findings also suggest that a 3p tumor suppressor gene other than VHL may also influence HIF-1alpha degradation and that there is an additional tumorigenic pathway for cRCC that does not involve VHL or HIF-1.     

Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro- T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre- TCR, not those stimulated via c-Kit and the IL-7 receptor.      

Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism

Parathyroid hormone secretion is negatively regulated by a 7- transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.      

Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.     

Cervical carcinoma with adenoid cystic pattern: a light and electron microscopic study.

Three cases of cervical carcinoma with an adenoid cystic pattern were studied by light and electron microscopy. All were found to be compatible with the histologic picture of adenoid cystic carcinoma in other body sites. Although there was some variability in the pattern among the tumors, areas of each exhibited a cribriform appearance characterized by small cells with sparse cytoplasm arranged around cystic gland-like lumina. Only one tumor displayed cylindromatous formations similar to those described by Billroth. Two of the tumors were associated with foci of squamous cell carcinoma while the third contained areas suggestive of such a component. Electron microscopic examination showed varied morphology of the cysts, manifested by true glandlike lumina, extracellular spaces containing replicated basement membrane or enclosed stroma. In view of the observed diversity in the light and electron microscopic morphology of adenoid cystic carcinomas of the cervix, it is apparent that this tumor is not a distinct histologic entity. Accordingly, it is recommended that the terminology "cervical carcinoma with adenoid cystic pattern" be utilized.