Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines.

OBJECTIVE: Little is known about the interaction of gliadin with intestinal epithelial cells and the mechanism(s) through which gliadin crosses the intestinal epithelial barrier. We investigated whether gliadin has any immediate effect on zonulin release and signaling. MATERIAL AND METHODS: Both ex vivo human small intestines and intestinal cell monolayers were exposed to gliadin, and zonulin release and changes in paracellular permeability were monitored in the presence and absence of zonulin antagonism. Zonulin binding, cytoskeletal rearrangement, and zonula occludens-1 (ZO-1) redistribution were evaluated by immunofluorescence microscopy. Tight junction occludin and ZO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR). RESULTS: When exposed to gliadin, zonulin receptor-positive IEC6 and Caco2 cells released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein-protein interaction, and increased monolayer permeability. Pretreatment with the zonulin antagonist FZI/0 blocked these changes without affecting zonulin release. When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. CONCLUSIONS: Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules

Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression

Purpose: To evaluate the effect of delayed start of combination therapy (CT) with dutasteride 0.5 mg and tamsulosin 0.4 mg on the risk of acute urinary retention or benign prostatic hyperplasia (BPH)-related surgery (AUR/S) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) at risk of disease progression. Methods: Using a time-to-event model based on pooled data from 10,238 patients from Phase III/IV dutasteride trials, clinical trial simulations (CTS) were performed to assess the risk of AUR/S up to 48 months in moderate-to-severe LUTS/BPH patients following immediate and delayed start of CT for those not responding to tamsulosin monotherapy. Simulation scenarios (1300 subjects/arm) were investigated, including immediate start (reference) and alternative delayed start (six scenarios 1–24 months). AUR/S incidence was described by Kaplan–Meier survival curves and analysed using log-rank test. The cumulative incidence of events as well as the relative and attributable risks were summarised stratified by treatment. Results: Survival curves for patients starting CT at month 1 and 3 did not differ from those who initiated CT immediately. By contrast, significant differences (p < 0.001) were observed when switch to CT occurs ≥ 6 months from the initial treatment. At month 48, AUR/S incidence was 4.6% vs 9.5%, 11.0% and 11.3% in patients receiving immediate CT vs. switchers after 6, 12 and 24 months, respectively. Conclusions: Start of CT before month 6 appears to significantly reduce the risk of AUR/S compared with delayed start by ≥ 6 months. This has implications for the treatment algorithm for men with LUTS/BPH at risk of disease progression

Changes in Motor, Cognitive, and Behavioral Symptoms in Parkinson's Disease and Mild Cognitive Impairment During the COVID-19 Lockdown

Objective: The effects of the COVID-19 lockdown on subjects with prodromal phases of dementia are unknown. The aim of this study was to evaluate the motor, cognitive, and behavioral changes during the COVID-19 lockdown in Italy in patients with Parkinson's disease (PD) with and without mild cognitive impairment (PD-MCI and PD-NC) and in patients with MCI not associated with PD (MCInoPD). Methods: A total of 34 patients with PD-NC, 31 PD-MCI, and 31 MCInoPD and their caregivers were interviewed 10 weeks after the COVID-19 lockdown in Italy, and changes in cognitive, behavioral, and motor symptoms were examined. Modified standardized scales, including the Neuropsychiatric Inventory (NPI) and the Movement Disorder Society, Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I and II, were administered. Multivariate logistic regression was used to evaluate associated covariates by comparing PD-NC vs. PD-MCI and MCInoPD vs. PD-MCI. Results: All groups showed a worsening of cognitive (39.6%), pre-existing (37.5%), and new (26%) behavioral symptoms, and motor symptoms (35.4%) during the COVID-19 lockdown, resulting in an increased caregiver burden in 26% of cases. After multivariate analysis, PD-MCI was significantly and positively associated with the IADL lost during quarantine (OR 3.9, CI 1.61–9.58), when compared to PD-NC. In the analysis of MCInoPD vs. PD-MCI, the latter showed a statistically significant worsening of motor symptoms than MCInoPD (OR 7.4, CI 1.09–45.44). Regarding NPI items, nighttime behaviors statistically differed in MCInoPD vs. PD-MCI (16.1% vs. 48.4%, p = 0.007). MDS-UPDRS parts I and II revealed that PD-MCI showed a significantly higher frequency of cognitive impairment (p = 0.034), fatigue (p = 0.036), and speech (p = 0.013) than PD-NC. On the contrary, PD-MCI showed significantly higher frequencies in several MDS-UPDRS items compared to MCInoPD, particularly regarding pain (p = 0.001), turning in bed (p = 0.006), getting out of bed (p = 0.001), and walking and balance (p = 0.003). Conclusion: The COVID-19 quarantine is associated with the worsening of cognitive, behavioral, and motor symptoms in subjects with PD and MCI, particularly in PD-MCI. There is a need to implement specific strategies to contain the effects of quarantine in patients with PD and cognitive impairment and their caregivers

Impact of disease progression on individual IPSS trajectories and consequences of immediate versus delayed start of treatment in patients with moderate or severe LUTS associated with BPH

PURPOSE: Despite superiority of tamsulosin-dutasteride combination therapy versus monotherapy for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH), patients at risk of disease progression are often initiated on α-blockers. This study evaluated the impact of initiating tamsulosin monotherapy prior to switching to tamsulosin-dutasteride combination therapy versus immediate combination therapy using a longitudinal model describing International Prostate Symptom Score (IPSS) trajectories in moderate/severe LUTS/BPH patients at risk of disease progression. METHODS: Clinical trial simulations (CTS) were performed using data from 10,238 patients from Phase III/IV dutasteride trials. The effect of varying disease progression rates was explored by comparing profiles on- and off-treatment. CTS scenarios were investigated, including a reference (immediate combination therapy) and six alternative virtual treatment arms (delayed combination therapy of 1-24 months). Clinical response (≥ 25% IPSS reduction relative to baseline) was analysed using log-rank test. Differences in IPSS relative to baseline at various on-treatment time points were assessed by t tests. RESULTS: Delayed combination therapy initiation led to significant (p < 0.01) decreases in clinical response. At month 48, clinical response rate was 79.7% versus 74.1%, 70.3% and 71.0% and IPSS was 6.3 versus 7.6, 8.1 and 8.0 (switchers from tamsulosin monotherapy after 6, 12 and 24 months, respectively) with immediate combination therapy. More patients transitioned from severe/moderate to mild severity scores by month 48. CONCLUSIONS: CTS allows systematic evaluation of immediate versus delayed combination therapy. Immediate response to α-blockers is not predictive of long-term symptom improvement. Observed IPSS differences between immediate and delayed combination therapy (6-24 months) are statistically significant

Non-stoichiometric molybdenum oxides as cathodes for lithium cells: Part II. Secondary batteries

Mo4O11, Mo8O23 and Mo9O26 have been examined as cathodes for secondary lithium cells. These oxides can form ternary phases from which Li+ can be almost quantitatively recovered on charge, for limited e/Mo values (e.g. 0.8 for Mo8O23). Higher values of e/Mo make the reduction process irreversible due to the destruction of the original lattices. Cyclic voltammetry experiments have shown that these oxides can maintain their reversible behaviour for many cycles, provided the cathodic scanning is limited. Cycling of prismatic Li/Mo8O23 cells has confirmed that this oxide can behave reversibly with good voltage retention even at discharge depths near the limiting valu

Risk of recurrence after nephrectomy: Comparison of predictive ability of validated risk models

Objective: To assess accuracy of University of California Los Angeles Integrated Staging System (UISS), Stage, Size, Grade and Necrosis (SSIGN) score, Leibovich score and GRade, Age, Nodes and Tumor (GRANT) score, the ASSURE (Adjuvant Sunitinib or Sorafenib vs. placebo in resected Unfavorable REnal cell carcinoma) score models and seventh American Joint Committee on Cancer (AJCC)/TNM staging system in predicting recurrence-free survival (RFS) in surgically-treated non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Materials and methods: Kaplan-Meier curves and the log-rank test tested RFS according to risk groups among the UISS, SSIGN, Leibovich and GRANT models and the AJCC/TNM system. The Heagerty's C-index for survival tested for discrimination of each model at different time points after nephrectomy. Results: Three hundred and fifty-eight M0 ccRCC patients were included. RFS significantly differed among each risk category for all models (P < 0.001). SSIGN showed the highest c-index over time (from 0.89 at 6-month to 0.82 at 60-month), followed by Leibovich (from 0.89–0.82), AJCC/TNM stage (from 0.82–0.77), ASSURE (from 0.81 to 0.76), GRANT (from 0.83–0.73) and UISS (from 0.76–0.72). For all models, peak discriminatory ability was reached before 12 months. The most prominent decline occurred within 24 months and reaches the lowest discriminatory ability at 60 months. Conclusions: Predictive models, with preference for SSIGN and Leibovich scores, are reliable to predict recurrence after nephrectomy and should be recommended to tailor postoperative surveillance protocols

Model-based meta-analysis of individual IPSS trajectories in patients with benign prostatic hyperplasia with moderate or severe symptoms

Aims: International Prostate Symptom Score (IPSS) is a marker of lower urinary tract symptoms (LUTS) deterioration or improvement in benign prostate hyperplasia (BPH). Whereas changes in IPSS relative to baseline have been used as endpoints in clinical trials, little attention has been given to the time course of symptoms. The current investigation aimed to develop a drug‐disease model to describe individual IPSS trajectories in moderate and severe BPH patients. Methods: A model‐based meta‐analytical approach was used including data from 10 238 patients enrolled into Phase III and IV studies receiving placebo, tamsulosin, dutasteride or combination therapy over a period of up to 4 years. Model predictive performance was assessed using statistical and graphical criteria. Subsequently, simulations were performed to illustrate the implications of treatment with drugs showing symptomatic and disease‐modifying properties in patients with varying disease progression rates. Results: Improvement and worsening of IPSS could be characterized by a model including a sigmoid function which disentangles drug effects from placebo and varying disease progression rates on IPSS. Mean estimate (95% confidence intervals) for the disease progression rate was 0.319 (0.271–0.411) month−1. Treatment effect on IPSS (DELTA) was found to be 0.0605, 0.0139 and 0.0310 month−1 for placebo, tamsulosin and combination therapy, respectively. In addition, it appears that individual trajectories can be clustered together into different phenotypes describing the underlying disease progression rate (i.e. slow, moderate and fast progressors). Conclusions: The availability of a drug‐disease model enables the evaluation of interindividual differences in disease progression rate, deterioration of symptoms and treatment effects on LUTS/BPH