Eph/ephrin molecules--a hub for signaling and endocytosis

The development, homeostasis, and regeneration of complex organ systems require extensive cell-cell communication to ensure that different cells proliferate, migrate, differentiate, assemble, and function in a coordinated and timely fashion. Eph receptor tyrosine kinases and their ephrin ligands are critical regulators of cell contact-dependent signaling and patterning. Eph/ephrin binding can lead to very diverse biological readouts such as adhesion versus repulsion, or increased versus decreased motility. Accordingly, depending on cell type and context, a limited and conserved set of receptor-ligand interactions is translated into a large variety of downstream signaling processes. Recent evidence indicates that the endocytosis of Eph/ephrin molecules, together with the internalization of various associated tissue-specific effectors, might be one of the key principles responsible for such highly diverse and adaptable biological roles. Here, we summarize recent insights into Eph/ephrin signaling and endocytosis in three biological systems; i.e., the brain, intestine, and vasculature.     

ESR1 and APOE gene polymorphisms, serum lipids, and hormonal replacement therapy

OBJECTIVES: The risks and benefits of hormone replacement therapy (HRT) are, at least in part, mediated by the metabolic individuality of women. Therefore, we investigated the association between polymorphisms at the estrogen receptor 1 gene (ESR1) and at the apolipoprotein E gene (APOE) with lipid and lipoprotein levels in order to verify whether these concentrations are modulated by these gene variants in women with different hormonal status. METHODS: One hundred and eighteen postmenopausal women using oral HRT with estrogen or estrogen plus progestagen (HRT+, mean age=56+/-6.7 years, 39-75 years) and 167 postmenopausal women that were not on HRT (HRT-, mean age=58+/-9.8 years, 38-85 years) participated in the study. The polymorphisms were genotyped by PCR-RFLP methods. RESULTS: No significant effect of ESR1 genotypes or haplotypes and ESR1*HRT interactions were detected on lipid levels in two-way analysis of variance. Postmenopausal women HRT nonusers carriers of the APOE*4 allele had higher T-chol and LDL-C levels than postmenopausal women HRT nonusers carriers of the APOE*3 and APOE*2 allele. T-chol and LDL-C concentrations in postmenopausal users of HRT that were APOE*4 carriers were similar to those in postmenopausal women nonusers of HRT homozygotes for APOE*3 and APOE*2 carriers. A significant APOE*4/HRT interaction was detected on T-chol and LDL-C levels by multiple regression analysis. CONCLUSION: The results from this study suggest that the HRT influence on T-chol and LDL-C levels is modulated by APOE isoforms but not by ESR1 polymorphisms.     

Neurocognitive Functioning in Patients with 22q11.2 Deletion Syndrome: A Meta-Analytic Review

The 22q11.2 deletion syndrome (22q11.2DS) is a known risk factor for development of schizophrenia and is characterized by a complex neuropsychological profile. To date, a quantitative meta-analysis examining cognitive functioning in 22q11.2DS has not been conducted. A systematic review of cross-sectional studies comparing neuropsychological performance of individuals with 22q11.2DS with age-matched healthy typically developing and sibling comparison subjects was carried out. Potential moderators were analyzed. Analyses included 43 articles (282 effects) that met inclusion criteria. Very large and heterogeneous effects were seen for global cognition (d = ? 1.21) and in specific neuropsychological domains (intellectual functioning, achievement, and executive function; d range = ? 0.51 to ? 2.43). Moderator analysis revealed a significant role for type of healthy comparison group used (typically developing or siblings), demographics (age, sex) and clinical factors (externalizing behavior). Results revealed significant differences between pediatric and adult samples, with isolated analysis within the pediatric sample yielding large effects in several neuropsychological domains (intellectual functioning, achievement, visual memory; d range = ? 0.56 to ? 2.50). Large cognitive deficits in intellectual functioning and specific neuropsychological variables in individuals with 22q11.2DS represent a robust finding, but these deficits are influenced by several factors, including type of comparison group utilized, age, sex, and clinical status. These findings highlight the clinical relevance of characterizing cognitive functioning in 22q11.2DS and the importance of considering demographic and clinical moderators in future analyses.     

No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting

Objective

About 70% of epithelial ovarian cancer patients (EOC) are diagnosed at advanced stage with a five-year survival rate of only 30%. Whilst CA125 detects peritoneally-spread disease, it has limited sensitivity for early cancers, many of which are potentially curable.

Methods

We compared the new commercially available tumor marker HE4 with CA125 individually, in combination, within the risk of malignancy index (RMI) and the newly defined risk of malignancy algorithm (ROMA). Our prospectively-collected cohort of 160 patients consisted of healthy controls, benign diseases, and borderline tumors/adenocarcinomas of ovarian, tubal, peritoneal and endometrial origin. HE4 and CA125 were measured in serum using standardized ELISA.

Results

Both markers showed similar diagnostic performance in the detection of EOC at clinically defined thresholds (CA125 35 U/ml; HE4 70 pM) but HE4 was not elevated in endometriosis. Comparison of non-malignant diagnoses (n = 71) versus early stage ovarian and tubal cancers (n = 19) revealed that HE4 and ROMA displayed the best diagnostic performance (AUC 0.86/0.87, specificity 85.9%/87.3% and sensitivity 78.9%/78.9%, respectively). Whilst RMICA125 detects peritoneal cancer better than all other models (AUC 0.99, specificity 97.2%, sensitivity 80.0%), there is no other detection benefit from RMI compared to HE4 alone or included in ROMA.

Conclusions

The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.     

Apoptotic cell capture by DCs induces unexpectedly robust autologous CD4+ T‐cell responses

Apoptotic cells represent an important source of self‐antigens and their engulfment by dendritic cells (DCs) is usually considered to be related to tolerance induction. We report here an unexpectedly high level of human CD4⁺ T‐cell proliferation induced by autologous DCs loaded with autologous apoptotic cells, due to the activation of more than 10% of naive CD4⁺ T cells. This proliferation is not due to an increase in the costimulatory capacity of DCs, but is dependent on apoptotic cell‐associated material processed through an endo‐lysosomal pathway and presented on DC MHC class II molecules. Autologous CD4⁺ T cells stimulated with apoptotic cell‐loaded DCs exhibit suppressive capacities. However, in the presence of bacterial lipopolysaccharide, apoptotic cell‐loaded DCs induce the generation of IL‐17‐producing cells. Thus, apoptotic cell engulfment by DCs may lead to increased autologous responses, initially generating CD4⁺ T cells with suppressive capacities able to differentiate into Th17 cells in the presence of a bacterial danger signal such as LPS.     

Female Sexual Function during Pregnancy and after Childbirth

IntroductionHealthy sexual function during pregnancy and after childbirth is one of the cornerstones for couples to evolve from partners to parents.AimThe aim of our review is to evaluate the available evidence and define present knowledge about female sexual function during pregnancy and after childbirth.MethodsPubMed was searched for articles on sexual function during pregnancy and after childbirth, published from 1960 up to date. The most relevant articles have been reviewed and included.Main Outcome MeasuresThe main outcome is the review of the effect of pregnancy, delivery, and postpartum on female sexuality.ResultsA total of 48 articles which specifically addressed this topic were included. Sexual function was found to have a significant global decline during pregnancy, particularly in the third trimester and this persisted for 3–6 months following delivery. The lack of adequate information about sex in pregnancy and concerns about the possible adverse obstetric outcomes are the most relevant factors responsible for the avoidance of sexual activity during pregnancy. Breast-feeding, dyspareunia, and postpartum pelvic floor dysfunction were reported as possible causes for the delay in resuming sexual intercourses after childbirth.ConclusionsCouples should be informed about the decline of libido, desire and orgasm, commonly encountered during pregnancy, particularly in the last trimester, and puerperium which may lead to reduction in sexual intercourse frequency. Serati M, Salvatore S, Siesto G, Cattoni E, Zanirato M, Khullar V, Cromi A, Ghezzi F, and Bolis P. Female sexual function during pregnancy and after childbirth.     

Randomized trial of transcutaneous tibial nerve stimulation to treat urge urinary incontinence in older women

Introduction  

The aim of this study was to examine the efficacy of transcutaneous electrical tibial nerve stimulation (TTNS) to treat urge urinary incontinence (UUI) in older women.     

Tropheryma whipplei infective endocarditis as the only manifestation of Whipple's disease

Here we describe a case of infective endocarditis caused by Tropheryma whipplei in a patient with no other symptoms of Whipple's disease. The case was diagnosed using broad-range PCR and confirmed by specific PCRs. We review the cases of infective endocarditis presenting as the only manifestation of Whipple's disease reported in the literature.