GH20 and GH84 β-N-acetylglucosaminidases with different linkage specificities underpin mucin O-glycan breakdown capability of Bifidobacterium bifidum

Intestinal mucous layers mediate symbiosis and dysbiosis of host–microbe interactions. These interactions are influenced by the mucin O-glycan degrading ability of several gut microbes. The identities and prevalence of many glycoside hydrolases (GHs) involved in microbial mucin O-glycan breakdown have been previously reported; however, the exact mechanisms and extent to which these GHs are dedicated to mucin O-glycan degradation pathways warrant further research. Here, using Bifidobacterium bifidum as a model mucinolytic bacterium, we revealed that two β-N-acetylglucosaminidases belonging to the GH20 (BbhI) and GH84 (BbhIV) families play important roles in mucin O-glycan degradation. Using substrate specificity analysis of natural oligosaccharides and O-glycomic analysis of porcine gastric mucin (PGM) incubated with purified enzymes or B. bifidum carrying bbhI and/or bbhIV mutations, we showed that BbhI and BbhIV are highly specific for β-(1→3)- and β-(1→6)-GlcNAc linkages of mucin core structures, respectively. Interestingly, we found that efficient hydrolysis of the β-(1→3)-linkage by BbhI of the mucin core 4 structure [GlcNAcβ1-3(GlcNAcβ1-6)GalNAcα-O-Thr] required prior removal of the β-(1→6)-GlcNAc linkage by BbhIV. Consistent with this, inactivation of bbhIV markedly decreased the ability of B. bifidum to release GlcNAc from PGM. When combined with a bbhI mutation, we observed that the growth of the strain on PGM was reduced. Finally, phylogenetic analysis suggests that GH84 members may have gained diversified functions through microbe–microbe and host–microbe horizontal gene transfer events. Taken together, these data strongly suggest the involvement of GH84 family members in host glycan breakdown

Improvement of the human intestinal flora by ingestion of the probiotic strain Lactobacillus johnsoniiLa1

To exert beneficial effects for the host, for example, improving the intestinal microflora, a probiotic must reach the intestine as a viable strain. These properties must be demonstrated by in vitro as well as in vivo methods. However, only a few well-designed human clinical studies have shown these properties. Lactobacillus johnsonii La1 has been shown to give many beneficial effects for the host, but it is unclear whether a viable strain of L. johnsonii La1 has the effect of improving host intestinal microflora. In the present study, a randomised double-blind placebo-controlled cross-over trial was conducted to elucidate the effect of L. johnsonii La1 on human intestinal microflora. Twenty-two young healthy Japanese women were randomly divided into two groups, and either received fermented milk with L. johnsonii La1 or a fermented milk without L. johnsonii La1 (placebo) daily for 21d. Consumption of the fermented milk: (a) increased total Bifidobacterium and Lactobacillus, and decreased lecithinase-positive Clostridium in the faeces; (b) increased the faecal lactic acid concentrations; (c) decreased the faecal pH; (d) increased the defecation frequency. These changes were stronger than those observed with the placebo. L. johnsonii La1 was identified in all subjects only after the consumption of the fermented milk. These results suggest that L. johnsonii La1 can contribute to improve intestinal microflora with probiotic propertie

An efficient and generic reversible debugger using the virtual machine based approach

The reverse execution of programs is a function where pro-grams are executed backward in time. A reversible debugger is a debugger that provides such a functionality. In this pa-per, we propose a novel reversible debugger that enables reverse execution of programs written in the C language. Our approach takes the virtual machine based approach. In this approach, the target program is executed on a special virtual machine. Our contribution in this paper is two-fold. First, we propose an approach that can address problems of (1) compatibility and (2) efficiency that exist in previous works. By compatibility, we mean that previous debuggers are not generic, i.e., they support only a special language or special intermediate code. Second, our approach provides two execution modes: the native mode, where the debuggee is directly executed on a real CPU, and the virtual ma-chine mode, where the debuggee is executed on a virtual machine. Currently, our debugger provides four types of trade-off settings (designated by unit and optimization) to consider trade-offs between granularity, accuracy, overhead and memory requirement. The user can choose the appro-priate setting flexibly during debugging without finishing and restarting the debuggee

The role of digital rectal examination for diagnosis of acute appendicitis: A systematic review and meta-analysis

Background: Digital rectal examination (DRE) has been traditionally recommendedto evaluate acute appendicitis, although several reports indicate its lack of utility for this diagnosis. No metaanalysis has examined DRE for diagnosis of acute appendicitis. Objectives: To assess the role of DRE for diagnosis of acute appendicitis. Data Sources: Cochrane Library, PubMed, and SCOPUS from the earliest available date of indexing through November 23, 2014, with no language restrictions. Study Selection: Clinical studies assessing DRE as an index test for diagnosis of acute appendicitis. Data Extraction and Synthesis: Two independent reviewers extracted study data and assessed the quality, using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Bivariate random-effects models were used for the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) as point estimates with 95% confidence intervals (CI). Main Outcomes and Measures: The main outcome measure was the diagnostic performance of DRE for diagnosis of acute appendicitis. Results: We identified 19 studies with a total of 7511 patients. The pooled sensitivity and specificity were 0.49 (95% CI 0.42-0.56) and 0.61 (95% CI 0.53-0.67), respectively. The positive and negative likelihood ratios were 1.24 (95% CI 0.97-1.58) and 0.85 (95% CI 0.70-1.02), respectively. The DOR was 1.46 (0.95-2.26). Conclusion and Relevance: Acute appendicitis cannot be ruled in or out through the result of DRE. Reconsideration is needed for the traditional teaching that rectal examination should be performed routinely in all patients with suspected appendicitis

Prognostic models for radiation-induced complications after radiotherapy in head and neck cancer patients

Objectives: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows:. Primary objective The review question is “Which prognostic models are available to predict the risk of radiation-induced side effects after radiation exposure to patients with head and neck cancer, what is their quality, and what is their predictive performance?”. Investigation of sources of heterogeneity between studies We will assess sources of heterogeneity among the prognostic models developed in the eligible studies. The potential sources are study population (e.g. site/stage of cancer, the use of other treatment [surgery and chemotherapy]), predictors, definition and incidence of the predicted outcomes, and prediction horizons. If there are multiple validation studies for the same model, the same sources of between-study heterogeneity will be investigated

Five-year follow-up of Japanese patients with Paget's disease of the bone after treatment with low-dose oral alendronate: a case series

<p>Abstract</p> <p>Introduction</p> <p>Paget's disease of the bone is characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton. Although this disease is rare in Japan, it is common in western and southern Europe, and among British migrants in Australia and New Zealand. Bisphosphonates have been widely used for the treatment of Paget's disease of the bone and are considered to be the treatment of choice. However, there have been few reports on the long-term follow-up examination of patients after their treatment with bisphosphonates.</p> <p>Case presentation</p> <p>We report the treatment with a low dose of oral alendronate (5 mg per day) which was effective in reducing bone turnover and pain over the five-year follow-up period in two Japanese patients, a 66-year-old man and a 68-year-old woman, with Paget's disease of the bone. Furthermore, in one patient, no clinical symptoms, such as bone pain or increases in serum total alkaline phosphatase and urinary N-terminal telopeptide of type I collagen as markers of bone turnover, were observed over the patient's five-year follow-up period.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the first report of a long-term follow-up of patients with Paget's disease of the bone after a six-month treatment with low-dose oral alendronate (5 mg per day).</p

What are Effective Strategies to Reduce Low-Value Care? An Analysis of 121 Randomized Deimplementation Studies

Background: Low-value care is healthcare leading to no or little clinical benefit for the patient. The best (combinations of) interventions to reduce low-value care are unclear. Purpose: To provide an overview of randomized controlled trials (RCTs) evaluating deimplementation strategies, to quantify the effectiveness and describe different combinations of strategies. Methods: Analysis of 121 RCTs (1990-2019) evaluating a strategy to reduce low-value care, identified by a systematic review. Deimplementation strategies were described and associations between strategy characteristics and effectiveness explored. Results: Of 109 trials comparing deimplementation to usual care, 75 (69%) reported a significant reduction of low-value healthcare practices. Seventy-three trials included in a quantitative analysis showed a median relative reduction of 17% (IQR 7%-42%). The effectiveness of deimplementation strategies was not associated with the number and types of interventions applied. Conclusions and Implications: Most deimplementation strategies achieved a considerable reduction of low-value care. We found no signs that a particular type or number of interventions works best for deimplementation. Future deimplementation studies should map relevant contextual factors, such as the workplace culture or economic factors. Interventions should be tailored to these factors and provide details regarding sustainability of the effect.</p