Recurrence of vaginal prolapse after total vaginal hysterectomy with concurrent vaginal uterosacral ligament suspension: comparison between normal-weight and overweight women

BACKGROUND: Obesity is one of the most important risk factors for the development and progression of the pelvic organ prolapse. However, data regarding whether obesity is a risk factor for recurrence after pelvic organ prolapse surgery are controversial. OBJECTIVE: The aim of this study was to estimate the risk of recurrent prolapse in any vaginal compartment after total vaginal hysterectomy with concurrent uterosacral ligament vaginal vault suspension among normal-weight women compared with either overweight or obese women. STUDY DESIGN: This is a 5-year retrospective cohort study of women who underwent total vaginal hysterectomy with concurrent vaginal uterosacral ligament suspension at one referral center for pelvic organ prolapse in Italy from January 2010 to January 2015. All women who underwent total vaginal hysterectomy with concurrent uterosacral ligament suspension were included in the analysis. Laparoscopic approach was excluded. Women were classified according to the body mass index of 2 groups: (1) normal weight (body mass index, 18.5-24.9 kg/m2) and (2) either overweight (body mass index, 25.0-29.9 kg/m2) or obese (body mass index, ≥30.0 kg/m2). The primary outcome was the incidence of recurrent prolapse in any vaginal compartment (anterior, posterior, or apical). Recurrent prolapse was defined as prolapse extending beyond the hymen with straining (pelvic organ prolapse quantification points Ba, C, Bp ≥0) or repeat treatment for prolapse with either pessary or surgery. Uterosacral ligament suspensions were performed with a vaginal approach with the use of sutures placed in the intermediate uterosacral ligament, at or above the ischial spine, and affixed to the vaginal apex. Delayed absorbable sutures were used, with 2 sutures per side. RESULTS: Three hundred sixty women who underwent total vaginal hysterectomy with concurrent uterosacral ligament suspension with at least 6 months of follow up after surgery were included in the study. The overall incidence of recurrent prolapse in any vaginal compartment was 19.7% (71/360 women). The risk of recurrent prolapse in any vaginal compartment (ie, primary outcome) was similar in the normal-weight compared with the overweight or obese group (16.7% vs 21.3%; P=.30). Women in the normal-weight group had a lower risk of recurrent anterior vaginal prolapse (10.8% vs 20.0%; adjusted odds ratio, 0.49; 95% confidence interval, 0.25-0.94) and of multiple compartment prolapse (8.3% vs 14.6%; adjusted odds ratio, 0.53; 95% confidence interval, 0.31-0.83). CONCLUSION: After total vaginal hysterectomy with concurrent uterosacral ligament suspension, the risk of recurrent vaginal prolapse was 20% based on a composite outcome definition of any anatomic prolapse beyond the hymen or pessary or repeat surgery. The most common site of recurrence was the anterior compartment. The risk of recurrent surgery was 10%. Our study showed that women with normal-weight had similar risk of recurrent prolapse compared with the overweight or obese group. In subgroup analyses, women with normal-weight had one-half the odds of recurrent anterior vaginal wall prolapse compared with those who were overweight or obese

Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4+CD25+FoxP3+ regulatory T cells activation

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear. Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses. Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs). Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance

Comprehensive genomic analysis reveals the prognostic role of LRRK2 copy-number variations in human malignancies

Genetic alterations of leucine-rich repeat kinase 2 (LRRK2), one of the most important contributors to familial Parkinson\u2019s disease (PD), have been hypothesized to play a role in cancer development due to demographical and preclinical data. Here, we sought to define the prevalence and prognostic significance of LRRK2 somatic mutations across all types of human malignancies by querying the publicly available online genomic database cBioPortal. Ninety-six different studies with 14,041 cases were included in the analysis, and 761/14,041 (5.4%) showed genetic alterations in LRRK2. Among these, 585 (76.9%) were point mutations, indels or fusions, 168 (22.1%) were copy number variations (CNVs), and 8 (1.0%) showed both types of alterations. One case showed the somatic mutation R1441C. A significant difference in terms of overall survival (OS) was noted between cases harboring somatic LRRK2 whole deletions, amplifications, and CNV-unaltered cases (median OS: 20.09, 57.40, and 106.57 months, respectively; p = 0.0008). These results suggest that both LRRK2 amplifications and whole gene deletions could play a role in cancer development, paving the way for future research in terms of potential treatment with LRRK2 small molecule inhibitors for LRRK2-amplified cases

Immunohistochemical expression of apoptotic factors, cytokeratins, and metalloproteinase-9 in periapical and epithelialized gingival lesions

The aim of the study was to assess the involvement of apoptotic factors, cytokeratins and metalloproteinase- 9 in the histogenesis of both Epithelialized Gingival Lesions (EGL) and Periapical Lesions (PAL). 55 consecutive patients, 30 with PAL and 25 with EGL, were selected for the study after clinical and radiological examinations. The PAL patients had severe periapical lesions and tooth decay with exposure of the pulp chamber. All PAL and EGL biopsies were surgically extracted, fixed in 10% buffered formalin, and processed for routine light microscopy. Ten biopsies of each category were processed for immunohistochemistry (IHC). Serial paraffin sections were stained by IHC with appropriate antibodies to detect cytokeratins (CKs) 1, 5, 8, 10 and 14, caspase-3 and -9, metalloproteinase-9, and for PCNA and TUNEL assays. Both PAL and EGL showed a high expression of the cytokeratin 1, 5 and 8 with higher expression in EGL. Moreover, CK10 was markedly less intense expressed in EGL compared to PAL, while CK14 was almost three times stronger expressed in EGL. The expression of caspase-3 and -9 was stronger in PAL compared to EGL, however, the difference was only significant for caspase-9. In PAL apoptosis detected by TUNNEL method and the expression of MMP-9 were higher than in EGL, whereas PCNA was significantly more expressed in EGL. The results clearly suggest that both lesions have exclusively an epithelial origin and that epithelial proliferation was correlated with the degree of apoptosis in both entities. PAL and EGL presented mostly similar cytokeratin expression except for CK10 and CK14, though with marked differences in the distribution and intensity of IHC reactions. Finally, the degradation of extracellular matrix in both lesions could be partially attributed to the strong presence of MMP-9. (Folia Histochemica et Cytobiologica 2012, Vol. 50, No. 4, 497\u2013503

PRENATAL DEVELOPMENT OF TEMPORO-MANDIBULAR JOINTS: STATE OF ART

The aim of this work is to analyze the state of the art of temporo-mandibular joint (MJ) to understand the varoius stage of the development of the same during embryogenesis. Various theories have been analyzed, such as the formation of apoptotic or the important role of growth factors, or the Valencia et studies in which are analyzed to numerous articular diseases in various stage of development. By the aforementioned studies show that many factors, of a different nature, are to be involved in the prenatal developlment of this important joint

Role of chronic exsposure to cigarette smoke on endoglin/CD105 expression in airway epithelium.

Dysregulation of airway epithelial cell function related to cigarette smoke exposure plays an important role in the pathophysiology of COPD and is associated to tissue damage and disease severity. CD105 is a component of the receptor complex of TGF-β, a pleiotropic cytokine involved in cellular proliferation, differentiation and migration. CD105 regulates the expression of different components of the extracellular matrix suggesting a role of CD105 in cellular transmigration and remodeling processes. The aim of the present study was to investigate the expression of endoglin/CD105 in airway epithelium of COPD patients and its involvement in tissue remodeling and progression of COPD. We evaluated the immunoreactivity for CD105 expression in bronchial biopsies isolated from COPD patients and healthy controls (HC). The analysis of metaplastic epithelium was performed in bronchial biopsies by Image Analysis software (Leica Quantimet system). Finally, we investigated the expression of CD105 protein receptor in human bronchial epithelial cells (16HBE cells) exposed to 5% Cigarette Smoke Extract (CSE) for 12 days by western blot. We found that the CD105 immunoreactivity was significantly higher in bronchial epithelium of COPD than HC. Morphometric analysis of bioptic samples of COPD showed an increase of the immunoreactivity for CD105 in the area of metaplastic than in not metaplastic epithelium. Long term exposure to CSE significantly up-regulated CD105 expression in 16HBE. Chronic inflammation due to cigarette smoke might play a critic role on the alteration of CD105 protein expression in COPD, promoting tissue remodeling, angiogenesis and dysregulation of physiological reparative mechanisms, leading to squamous metaplasia

Lack of Dystrophin Affects Bronchial Epithelium in mdx Mice

Mild exercise training may positively affect the course of Duchenne Muscular Dystrophy (DMD). Training causes mild bronchial epithelial injury in both humans and mice, but no study assessed the effects of exercise in mdx mice, a well known model of DMD. The airway epithelium was examined in mdx (C57BL/10ScSn-Dmdmdx) mice, and in wild type (WT, C57BL/10ScSc) mice either under sedentary conditions (mdx-SD, WT-SD) or during mild exercise training (mdx-EX, WT-EX). At baseline, and after 30 and 45 days of training (5 d/wk for 6 weeks), epithelial morphology and markers of regeneration, apoptosis, and cellular stress were assessed. The number of goblet cells in bronchial epithelium was much lower in mdx than in WT mice under all conditions. At 30 days, epithelial regeneration (PCNA positive cells) was higher in EX than SD animals in both groups; however, at 45 days, epithelial regeneration decreased in mdx mice irrespective of training, and the percentage of apoptotic (TUNEL positive) cells was higher in mdx-EX than in WT-EX mice. Epithelial expression of HSP60 (marker of stress) progressively decreased, and inversely correlated with epithelial apoptosis (r=-0.66, P=0.01) only in mdx mice. Lack of dystrophin in mdx mice appears associated with defective epithelial differentiation, and transient epithelial regeneration during mild exercise training. Hence, lack of dystrophin might impair repair in bronchial epithelium, with potential clinical consequences in DMD patients

From Dysbiosis to Neurodegenerative Diseases through Different Communication Pathways: An Overview

The microbiome research field has rapidly evolved over the last few decades, becoming a major topic of scientific and public interest. The gut microbiota (GM) is the microbial population living in the gut. The GM has many functions, such as maintaining gut homeostasis and host health, providing defense against enteric pathogens, and involvement in immune system development. Several studies have shown that GM is implicated in dysbiosis and is presumed to contribute to neurodegeneration. This review focuses mainly on describing the connection between the intestinal microbiome alterations (dysbiosis) and the onset of neurodegenerative diseases to explore the mechanisms that link the GM to nervous system health, such as the gut-brain axis, as well as the mitochondrial, the adaptive humoral immunity, and the microvesicular pathways. The gut-brain communication depends on a continuous bidirectional flow of molecular signals exchanged through the neural and the systemic circulation. These pathways represent a possible new therapeutic target against neuroinflammation and neurodegeneration. Progress in this context is desperately needed, considering the severity of most neurodegenerative diseases and the current lack of effective treatments

The Mechanism and Potential Therapeutic Effects of Cyclosporin, Cyclophilin, Probiotics and Syndecan-1 in an Animal Model of Inflammatory Bowel Disease

Background: Inflammatory bowel diseases (IBDs) have several treatment modalities including immunoregulators, like cyclosporine A, an immunosuppressant that interacts with cytoplasmic cyclophilin A, and probiotics. Aims: This study explored and compared the possible role of syndecan-1 in the IBD pathogenic process as well as the effectiveness of cyclophilin A, cyclosporine A, and their combination in the management of IBDs in the presence of probiotics. Methodology: IBD was induced in a total of 112 mice equally divided between syndecan-1 knock-out (KO) and Balb/c wild-type mice, using 2% dextran sulfate sodium (DSS) followed by intraperitoneal treatment with cyclosporine A, cyclophilin A, or a combination of both. In addition, a daily dose of probiotics was given in their drinking water. The animals were monitored for clinical signs and symptoms and checked for gross pathologies in the abdomen after 3 weeks. Descending and sigmoid colon biopsies were collected and fixed for routine microscopy or frozen for protein extraction and molecular testing for IL-6, CD3, CD147, and beta 1 integrins as well as pAkt expression. Results: The data showed that the induction of IBD in the syndecan-1 KO mice was more severe at the clinical, histological, and molecular levels than in the wild type. The combined CypA-CyA treatment showed no added inhibitory effect compared to single-drug treatment in both strains. Probiotics added to the combination was more effective in the wild type and, when used alone, its inhibition of IL-6 was the highest. As for the CD147 marker, there were more suppressions across the various groups in the KO mice except for the probiotics-alone group. Concerning CD3, it was significantly increased by the CypA-CyA complex, which led to more inflammation in the KO mice. Probiotics had little effect with the combination. In relation to beta 1 integrins, the CypA-CyA combination made no significant difference from CyA alone, and adding probiotics to the combination resulted in higher beta 1 integrin expression in the KO mice. As for pAkt, it was very well expressed and upregulated in both strains treated with DSS, but the effect was much larger in the KO mice. In brief, the CypA-CyA complex showed a decrease in the expression of pAkt, but there was no added effect of both drugs. Probiotics along with the complex had a similar reduction effects in both strains, with a greater effect in the wild-type mice, while probiotics alone led to a similar reduction in pAkt expressions in both strains. Conclusions: The differential effects of CyA, CypA, probiotics, and their combinations on the various inflammatory markers, as well as the histological alterations and clinical signs and symptoms, speak in favor of a clear role of syndecan-1 in reducing inflammation. However, probiotics need to be considered after more explorations into the mechanisms involved in the presence of CypA and CyA especially since pAkt is less active in their presence

Red and golden tomato administration improves fat diet-induced hepatic steatosis in rats by modulating HNF4α, Lepr, and GK expression

Introduction: Nonalcoholic fatty liver disease (NAFLD), characterized by lipid accumulation within hepatocytes exceeding 5% of liver weight, is strongly related to metabolic disorders, obesity, and diabetes and represents a health emergency worldwide. There is no standard therapy available for NAFLD. Lifestyle intervention, including phytonutrient intake, is key in preventing NAFLD development and progression. Methods: We used a rat model of NAFLD to evaluate the effect of dietary supplementation with red tomato (RT) and golden tomato (GT)—a patented mix of fruit with varying degrees of ripeness and particularly rich in naringenin and chlorogenic acid—after steatosis development. We assessed the effects on body weight, metabolic profile, and hepatic steatosis. Results and discussion: We found a correlation between the amelioration of all the parameters and the liver gene expression. Our results showed that, together with the reversion of steatosis, the consumption of RT and GT can cause a significant reduction in triglycerides, low-density lipoprotein-cholesterol, fasting glucose, and homeostasis model assessment index. Meanwhile, we observed an increase in high-density lipoprotein-cholesterol according to the amelioration of the general lipidic profile. Regarding hepatic gene expression, we found the upregulation of Gk and Hnf4α involved in metabolic homeostasis, Lepr involved in adipokine signaling, and Il6 and Tnf involved in inflammatory response. Taken together, our results suggest that dietary intake of red and golden tomatoes, as a nutraceutical approach, has potential in preventing and therapeutics of NAFLD