Pseudoexfoliation syndrome: in vivo confocal microscopy analysis

Pseudoexfoliation (PEX) syndrome is a common ocular disease that also affects the cornea. A case of clinical PEX syndrome, studied by in vivo corneal confocal microscopy is reported. The morphological analysis of the confocal images demonstrated hyper-reflective deposits and several dendritic cells in the basal epithelial layer. A fibrillar subepithelial structure was also found. The endothelial layer showed cell anomalies (polymegathism and pleomorphism) and hyper-reflective small endothelial deposits. Confocal microscopy is an in vivo imaging method that may provide new information on corneal alterations in PEX, and detect early corneal features.     

Optical coherence tomography versus stereoscopic fundus photography or biomicroscopy for diagnosing diabetic macular edema: a systematic review

PURPOSE: To review systematically the sensitivity and specificity of optical coherence tomography (OCT) for diagnosing macular edema attributable to diabetic retinopathy compared with well-established gold standard tests such as fundus stereophotography or contact and noncontact fundus biomicroscopy. METHODS: Medline and Embase were searched electronically and six major ophthalmic journals from 1998 to 2006 were hand searched. Two reviewers independently assessed trial searches, studied quality with the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) checklist, and extracted data. The target disease was clinically significant macular edema (CSME) according to Early Treatment of Diabetic Retinopathy Study (ETDRS) criteria. A bivariate model was used to obtain summary estimates of sensitivity and specificity and fit a summary receiver operating characteristic (ROC) curve. RESULTS: Fifteen studies were considered eligible. These studies were of good quality for most items of the QUADAS checklist, but most studies did not report masking of examiners and did not describe how withdrawals and undetermined results were treated. Seven studies included healthy control subjects, which could have artificially enhanced OCT diagnostic performance. All but one study included both eyes of the patients without taking into account the within-subject correlation in statistical analyses. Sensitivity and specificity data could be extracted from only 6 of 15 studies, because appropriate cross tabulations of index and reference tests were not reported by the others. In five of these studies, central retinal thickness cutoffs between 230 and 300 microm were adopted to define abnormal OCT results and considered the central type of CSME only, whereas in one study a complex algorithm accounting for extrafoveal CSME was used. The design of one study was case-control and was excluded from the meta-analysis. The expected operating point on the summary ROC, a pooled estimate of all studies, corresponded to a sensitivity of 0.79 (95% CI: 0.71-0.86), a specificity of 0.88 (95% CI: 0.80-0.93), a positive likelihood ratio of 6.5 (95% CI: 4.0-10.7), and a negative likelihood ratio of 0.24 (95% CI: 0.17-0.32). These values suggest a good overall performance of OCT for diagnosing CSME. CONCLUSIONS: OCT performs well compared with fundus stereophotography or biomicroscopy to diagnose diabetic macular edema. The quality of reporting of such studies should be improved, and authors should present cross tabulations of index and reference test results. Data adjusted for within-subject correlation should also be provided, although this issue represents a challenge for systematic reviewers.     

Preferential megalin-mediated transcytosis of low-hormonogenic thyroglobulin: a control mechanism for thyroid hormone release

Hormone secretion by thyrocytes occurs by fluid phase uptake and lysosomal degradation of the prohormone thyroglobulin (Tg). However, some Tg internalized by megalin bypasses lysosomes and is transcytosed across cells and released into the bloodstream. Because the hormone content of Tg is variable, we investigated whether this affects transcytosis. We found that rat Tg with a low hormone content [low-hormonogenic rat Tg (low-horm-rTg)] is transcytosed by megalin across thyroid FRTL-5 cells to a greater extent than rat Tg with a high hormone content [hormonogenic rat Tg (horm-rTg)]. In immunoprecipitation experiments, the Tg sequence Arg-2489-Lys-2503 (required for binding to megalin and heparan sulfate proteoglycans) was found to be more exposed in low-horm-rTg, which accounted for its preferential transcytosis. Thus, removal of surface heparan sulfate proteoglycans from FRTL-5 cells or blocking of 2489-2503 reduced transcytosis of low-horm-rTg to a greater extent than that of horm-rTg. Preferential transcytosis of low-horm-rTg affected hormone release. Thus, the increase in hormone release from horm-rTg in FRTL-5 cells determined by megalin blocking (due to reduced transcytosis and enhanced Tg degradation) was rescued by low-horm-rTg, suggesting that megalin is required for effective hormone release. This finding was confirmed in a small number of megalin-deficient mice, which had serological features resembling mild hypothyroidism. Reduced hormone formation within Tg in vivo, due to treatment of rats with aminotriazole or of patients with Graves' disease with methimazole, resulted in increased Tg transcytosis via megalin, in confirmation of results with FRTL-5 cells. Our study points to a major role of megalin in thyroid homeostasis with possible implications in thyroid diseases.     

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection

We studied hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics in 10 coinfected subjects in a trial of pegylated interferon-alpha2a (PEG-IFN) alone or combined with ribavirin (RBV), compared with IFN plus RBV for the treatment of HCV. Five subjects, 4 of whom were treated with PEG-IFN, achieved a sustained virological response, although it was delayed by >/=1 week in 3 subjects. The median treatment efficacy in blocking virion production was 99.7% in the PEG-IFN group and 60% with standard IFN. In 2 patients with detectable HIV loads before starting HCV study drugs, we observed a 1-log decrease in HIV RNA load. The estimated HCV virion half-life was longer in the HIV-coinfected subjects, which suggests that coinfection may contribute to a slower clearance of HCV. Although the early viral kinetics of coinfected subjects treated with PEG-IFN or IFN differ from those of singly infected subjects, the treatment response seems unaffected.     

Hormonal and psycho-relational aspects of sexual function during menopausal transition and at early menopause

Objective

The aim of the present observational, cross-sectional study was to examine the effects of hormonal and psycho-relational variables on sexual function during menopausal transition and at early postmenopause in women with hot flushes.

Study design

The sample comprised 138 women referred to a clinic for the treatment of hot flushes. They were categorised according to their stage of menopausal transition using the STRAW criteria: early menopausal transition (EMT) if their menstrual cycle was 7 or more days different from normal; late perimenopause (LMT) if they had experienced 60 days or more of amenorrhoea; and early postmenopause (EPM) if their amenorrhoea had lasted for at least 12 months but less than 4 years.

Main outcome measures

Sexual function was measured by using the Female Sexual Function Index (FSFI), while anxiety (state and trait), depression, eating disorder and marital adjustment were evaluated by validated self-report questionnaires. Levels of free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS) and estradiol (E2) were also measured.

Results

Overall sexual function varied significantly with stage of menopause, with total FSFI score less in EPM than in EMT (p = .009). A similar pattern was evident on FSFI sub-scales for sexual desire (p = .02), arousal (p = .01) orgasm (p = .01) and also pain (p = .02), but not for lubrication and satisfaction. Ratings for anxiety, depression and eating disorder did not differ across the menopausal sub-groups, and neither did ratings of marital adjustment. Both FT (p = .01) and DHEAS (p = .03) levels were slightly reduced at EPM in comparison with EMT, as were E2 levels (p = .001 EMT versus LMT; p = .0001 LMT versus EPM). In multiple regression analyses, plasma FT level was the only factor to predict FSFI full score (β = .48; p = 0.004) in women at EMT, while in women at LMT the depression score was the only factor to do so (β = −.62; p = 0.0001). The best model predicting FSFI full score at EPM included levels of DHEAS and E2 levels and state anxiety score.

Conclusions

Hormonal and some psychological variables are relevant to sexual function in symptomatic women during menopausal transition and at early menopause but their role differs with the specific stage of reproductive ageing.     

Cytogenetic and molecular genetic analyses of endometrial stromal sarcoma: nonrandom involvement of chromosome arms 6p and 7p and confirmation of JAZF1/JJAZ1 gene fusion in t(7;17)

Endometrial stromal sarcomas (ESS) are rare neoplasms with the capacity both to invade the myometrium locally and to give rise to extrauterine metastases. Cytogenetic abnormalities have been reported in 22 cases of ESS, mostly involving rearrangements of chromosomes 6, 7, and 17. The most characteristic translocation of this tumor type, t(7;17)(p15 approximately p21;q12 approximately q21), was recently shown to generate a JAZF1/JJAZ1 fusion gene. We report three additional cases of ESS with abnormal karyotypes, whose interpretation was based on the combined analysis by conventional cytogenetics and cross-species color banding FISH (RxFISH). The combination of G-banding and RxFISH in every case gave additional information beyond that obtained by either technique alone, determining the identity of even complex inter- as well as intrachromosomal rearrangements. In one of the three tumors, a t(7;17) was seen; molecular genetic studies identified the JAZF1/JJAZ1 fusion gene in this case. Two tumors had aberrations that included structural changes of chromosome arms 6p and 7p. Evidently, karyotypic, and hence pathogenetic, heterogeneity exists for tumors classified as endometrial stromal sarcomas based on their phenotypic features.     

Endothelin receptor blockade inhibits molecular effectors of Kaposi's sarcoma cell invasion and tumor growth in vivo

Endothelin-1 (ET-1) and its receptors are overexpressed in human Kaposi's sarcoma lesions. Here we show that in human KS IMM cell line ET-1 increased secretion and activation of matrix-metalloproteinase-2 (MMP-2), -3, -7, -9 and -13, as well as of membrane-type 1-MMP (MT1-MMP). ET-1 and ET-3 also enhanced the expression of tissue inhibitor of MMP-2, essential for MT1-MMP-mediated MMP-2 activation. Combined addition of both ET(B) receptor (ET(B)R) and ET(A)R antagonists completely blocked the ET-1-induced MMP activity. By immunohistochemistry, we observed that ET-1 increased MMP-2 and MT1-MMP expression and their localization at the cell surface. Treatment with both antagonists resulted also in the suppression of ET-1-induced phosphorylation of focal adhesion proteins, FAK and paxillin, which are essentials for cell motility. ET-1 induced a dose-dependent enhancement in KS IMM cell migration and MMP-dependent invasiveness that were inhibited by ET-1 receptor antagonists. The small molecule, A-182086, an orally bioavailable ET(A/B)R antagonist, completely inhibited cell proliferation and tumor growth in KS IMM xenografts. These findings demonstrate that ET-1-driven autocrine loop is crucial for enhanced invasiveness of KS IMM cells and promote tumor growth in vivo. Such activities can be blocked by the ET(A/B)R antagonists, which may be effective anti-angiogenic and anti-tumor molecules for the treatment of Kaposi's sarcoma.