Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about –30 ml/min per 1.73 m²; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.     

Turned versus anodised dental implants: a meta‐analysis

The aim of this meta‐analysis was to test the null hypothesis of no difference in the implant failure rates, marginal bone loss (MBL)and post‐operative infection for patients being rehabilitated by turned versus anodised‐surface implants, against the alternative hypothesis of a difference. An electronic search without time or language restrictions was undertaken in November 2015. Eligibility criteria included clinical human studies, either randomised or not. Thirty‐eight publications were included. The results suggest a risk ratio of 2·82 (95% CI 1·95–4·06, P < 0·00001) for failure of turned implants, when compared to anodised‐surface implants. Sensitivity analyses showed similar results when only the studies inserting implants in maxillae or mandibles were pooled. There were no statistically significant effects of turned implants on the MBL (mean difference‐MD 0·02, 95%CI ?0·16–0·20; P = 0·82) in comparison to anodised implants. The results of a meta‐regression considering the follow‐up period as a covariate suggested an increase of the MD with the increase in the follow‐up time (MD increase 0·012 mm year^?1), however, without a statistical significance (P = 0·813). Due to lack of satisfactory information, meta‐analysis for the outcome ‘post‐operative infection’ was not performed. The results have to be interpreted with caution due to the presence of several confounding factors in the included studies.     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Increasing the Number of Chews before Swallowing Reduces Meal Size in Normal-Weight,Overweight, and Obese Adults

Eating slowly contributes to a lower risk of obesity, probably because it could aid appetite control. Chewing thoroughly is an effective strategy to reduce eating rate; however, insufficient data are available to demonstrate the relationship between such an eating behavior and energy intake. To investigate the effect of increasing the number of chews before swallowing on meal size, a randomized cross-over trial was conducted in 18- to 45-year-old normal-weight, overweight, and obese participants (n=45) who were recruited from the local community (Ames, IA). After assessment of baseline number of chews, participants were asked to attend three test sessions to eat pizza for lunch until comfortably full by chewing each portion of food either 100%, 150%, or 200% of their baseline number of chews before swallowing. Two-way analysis of variance was used to test the effect of treatment and body-weight status, as well as their interactions on food intake, meal duration, eating rate, and appetite at meal termination. Appetite data during 60 minutes were analyzed by repeated measures analysis of variance. Food intake in the sessions with 150% and 200% of their baseline number of chews was reduced significantly, by 9.5% and 14.8%, respectively, compared with the 100% session. Increasing the number of chews also prolonged meal duration and reduced eating rate. However, subjective appetite at meal termination or during the immediate postprandial period did not differ. These data indicate that increasing the number of chews before swallowing might be a behavioral strategy to reduce food intake and potentially aid body-weight management.     

非体外循环下冠状动脉旁路移植术患者不同抗血小板方案对乳内动脉桥血管通畅率影响的临床研究

目的:对比研究非体外循环下冠状动脉旁路移植术(OPCABG)后,分别运用单抗(阿司匹林)与双抗(阿司匹林+氯吡格雷)抗血小板治疗后,对远期乳内动脉桥血管通畅率的影响。方法:回顾性分析2005年01月至2005年12月,在安贞医院心脏外科固定手术组行OPCABG并顺利出院的230例患者的临床资料,并对其进行随访。结果:随访时间为150个月,随访期内心脏相关死亡54例(16.4%)。两组前降支通畅率分别为65.8%、66.4%(P>0.05)。结论:对于OPCABG的患者,无论给与双抗或单抗,其远期效果并无明显差异,但短期内前降支通畅率变化趋势,双抗组优于单抗组。