Design of a New α-1-C-Alkyl-DAB Derivative Acting as a Pharmacological Chaperone for ß-Glucocerebrosidase Using Ligand Docking and Molecular Dynamics Simulation.

Some point mutations in ß-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of α-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for ß-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein⁻ligand docking and molecular dynamics simulations. We found that the activity cliff between α-1-C-heptyl-DAB and α-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.

Biological Activities of Lactose-Derived Prebiotics and Symbiotic with Probiotics on Gastrointestinal System.

Lactose-derived prebiotics provide wide ranges of gastrointestinal comforts. In this review article, the probable biochemical mechanisms through which lactose-derived prebiotics offer positive gastrointestinal health are reported along with the up-to-date results of clinical investigations; this might be the first review article of its kind, to the best of our knowledge. Lactose-derived prebiotics have unique biological and functional values, and they are confirmed as 'safe' by the Food and Drug Administration federal agency. Medical practitioners frequently recommend them as therapeutics as a pure form or combined with dairy-based products (yoghurt, milk and infant formulas) or fruit juices. The biological activities of lactose-derived prebiotics are expressed in the presence of gut microflora, mainly probiotics (Lactobacillus spp. in the small intestine and Bifidobacterium spp. in the large intestine). Clinical investigations reveal that galacto-oligosaccharide reduces the risks of several types of diarrhea (traveler's diarrhea, osmotic diarrhea and Clostridium difficile associated relapsing diarrhea). Lactulose and lactosucrose prevent inflammatory bowel diseases (Crohn's disease and ulcerative colitis). Lactulose and lactitol reduce the risk of hepatic encephalopathy. Furthermore, lactulose, galacto-oligosaccharide and lactitol prevent constipation in individuals of all ages. It is expected that the present review article will receive great attention from medical practitioners and food technologists.

The caries preventive effect of 1-year use of low-dose xylitol chewing gum. A randomized placebo-controlled clinical trial in high-caries-risk adults.

OBJECTIVES: The caries preventive effect of long-term use (1 year) of low-dosage (2.5 g/die) of xylitol chewing gum in a high-caries-risk adult population was evaluated. MATERIALS AND METHODS: In this randomized clinical trial, 179 high-caries-risk adults were assigned to two experimental groups, xylitol and polyols. Caries status, salivary mutans streptococci (MS), and plaque pH were re-evaluated after 2 years from baseline in 66 xylitol and 64 polyol subjects. Outcomes (the net caries increment for initial, moderate, and extensive caries lesions and for the caries experience) were evaluated using the nonparametric Mann-Whitney U test. RESULTS: The total caries experience increment was 1.25 ± 1.26 in the xylitol group and 1.80 ± 2.33 in the polyol group (p = 0.01). Subjects treated with xylitol chewing gums had a reduction of risk rate at tooth level of 23% with respect to those treated with polyols with a number needed to treat of 55 teeth. The area under the curve at pH 5.7 was statistically significantly lower (p = 0.02) during the experimental period in the xylitol group. A decrease of the concentration of salivary MS was noted in the xylitol group (p < 0.01). CONCLUSIONS: Subjects using the low-dose xylitol chewing gum showed a significantly lower increment of initial and extensive caries lesions and overall a lower increment of caries experience. CLINICAL RELEVANCE: One-year use of chewing gums provides an effective means for the prevention of caries disease. TRIAL REGISTRATION NUMBER: NCT02310308.

Maltitol inhibits small intestinal glucose absorption and increases insulin mediated muscle glucose uptake ex vivo but not in normal and type 2 diabetic rats.

This study investigated the effects of maltitol on intestinal glucose absorption and muscle glucose uptake using ex vivo and in vivo experimental models. The ex vivo experiment was conducted in isolated jejunum and psoas muscle from normal rats. The in vivo study investigated the effects of a single bolus dose of maltitol on gastric emptying, intestinal glucose absorption and digesta transit in normal and type 2 diabetic rats. Maltitol inhibited glucose absorption in isolated rat jejunum and increased glucose uptake in isolated rat psoas muscle in the presence of insulin but not in the absence of insulin. In contrast, maltitol did not significantly (p > 0.05) alter small intestinal glucose absorption or blood glucose levels as well as gastric emptying and digesta transit in normal or type 2 diabetic rats. The results suggest that maltitol may not be a suitable dietary supplement for anti-diabetic food and food products to improve glycemic control.

Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.

BACKGROUND: Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol. OBJECTIVES: To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy. SEARCH METHODS: We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA: We included RCTs, irrespective of publication status, language, or blinding. DATA COLLECTION AND ANALYSIS: Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses. MAIN RESULTS: We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence). AUTHORS' CONCLUSIONS: This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.

Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis.

BACKGROUND: Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol. OBJECTIVES: To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy. SEARCH METHODS: We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies. SELECTION CRITERIA: We included RCTs, irrespective of publication status, language, or blinding. DATA COLLECTION AND ANALYSIS: Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses. MAIN RESULTS: We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence). AUTHORS' CONCLUSIONS: This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.

Current state of knowledge of hepatic encephalopathy (part III): non-absorbable disaccharides.

Nonabsorbable disaccharides have been the mainstay of treatment for hepatic encephalopathy since introduced into clinical practice in 1966. Their beneficial effects reflect their ability to reduce the intestinal production/absorption of ammonia. A recent Cochrane review confirmed the efficacy and safety of nonabsorbable disaccharides for the treatment and prevention of hepatic encephalopathy in patients with cirrhosis. The findings were robust and support the use of nonabsorbable disaccharides as a first line treatment for hepatic encephalopathy, in this patient population, and for its prevention.

Effects of sugar-free chewing gum sweetened with xylitol or maltitol on the development of gingivitis and plaque: a randomized clinical trial.

OBJECTIVE: The objective of this study was to test the effect of sugar-free chewing gum sweetened with xylitol or maltitol compared to the use of a gum base or no gum on gingivitis and plaque scores under both brushing and non-brushing circumstances. METHODS: The design of the study was a four-group, double-blinded, randomized controlled study with a 3-week duration. In each group, the participants did not brush the teeth in the lower jaw designated to develop experimental gingivitis, while maintaining normal oral hygiene procedures in the upper jaw. After professional dental prophylaxis, the participants were allocated into one of four groups (xylitol, maltitol, gum base or no gum). Chewing gum was used five times a day for 10 min. RESULTS: 220 participants completed the study and provided evaluable data. The increase in bleeding on marginal probing (BOMP) and plaque scores (PS) in the non-brushed (lower) jaw with experimental gingivitis was significant in all groups (P < 0.001). As compared to the gum base, the increase in BOMP in the xylitol and maltitol group was significantly lower. In the brushed upper jaw, no significant changes for BOMP were observed from the baseline to the end point of the study, and there were no significant differences in BOMP and PS between the groups. CONCLUSION: In circumstances where regular brushing is performed, no effect of chewing gum was observed on bleeding and plaque scores. In the absence of brushing, chewing xylitol or maltitol gum provided a significant inhibitory effect on gingivitis scores compared to chewing gum base. The difference when compared to the group not using gum was not significant.

Disaccharides in the treatment of hepatic encephalopathy.

Management of hepatic encephalopathy (HE) primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as nonabsorbable disaccharides and antimicrobial agents like rifaximin. The nonabsorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and minimal hepatic encephalopathy (MHE). Lactulose significantly improves cognitive function and health-related quality of life in patients with MHE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Lactulose has also shown to be effective in primary and secondary prophylaxis of HE. Disaccharides were found to be comparable to rifaximin in recent systemic reviews in the treatment of HE however conclusion was based on inclusion of some poor quality trials. Combination therapy of disaccharides either with rifaximin, L-ornithine L-aspartate,probiotics for the treatment of HE needs further validation in large studies.

Effects of maltitol and xylitol chewing-gums on parameters involved in dental caries development.

AIM: The effects on plaque parameters of sugar free chewing-gums (CG) sweetened with either maltitol or xylitol were assessed to better understand the role polyols can play in dental caries prevention. MATERIALS AND METHODS: A double-blind, parallel, randomised, controlled study was conducted in China. Subjects (N = 258, age = 13 to 15 years-old) were divided into 4 groups: 2 receiving polyols CG, containing respectively maltitol or xylitol, a group receiving gum base (placebo) and a negative control group not receiving any gum. CG were chewed for 30 days. This corresponds to a 10 g consumption of polyol per day. Plaque parameters (growth, pH, bacteria and insoluble glucans) were evaluated throughout the experimental period. RESULTS: All parameters studied were significantly modified with gum base compared to no-gum: plaque pH increased; plaque growth, bacteria (S. mutans, S. sobrinus, A. viscosus and Lactobacillus) and insoluble glucans decreased. Maltitol and xylitol CG led similarly to a higher plaque pH (AUC, p⋜0.05) on short (at baseline after the first CG consumption) and long term (after 4 weeks of daily CG consumption), with or without saliva stimulation compared to both control and placebo groups. They led to a decrease in plaque growth (p=0.02) over the experimental period compared to controls. Moreover, they significantly reduced the concentration of 4 cariogenic bacteria species (p⋜0.05) in dental plaque compared to gum base. CONCLUSION: Sugar free CG sweetened with either maltitol or xylitol can similarly reduce plaque acidogenicity compared to gum base through a decrease in oral bacteria presence. The use of a gum base placebo allowed to isolate effects on parameters involved in dental caries development specific to maltitol and xylitol, and to show these effects were similar.

Osmotic and stimulant laxatives for the management of childhood constipation.

BACKGROUND: Constipation within childhood is an extremely common problem. Despite the widespread use of osmotic and stimulant laxatives by health professionals to manage constipation in children, there has been a long standing paucity of high quality evidence to support this practice. OBJECTIVES: We set out to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation. SEARCH METHODS: The search (inception to May 7, 2012) was standardised and not limited by language and included electronic searching (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register), reference searching of all included studies, personal contacts and drug companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared osmotic or stimulant laxatives with either placebo or another intervention, with patients aged 0 to 18 years old were considered for inclusion. The primary outcome was frequency of defecation. Secondary endpoints included faecal incontinence, disimpaction, need for additional therapies and adverse events. DATA COLLECTION AND ANALYSIS: Relevant papers were identified and the authors independently assessed the eligibility of trials. Methodological quality was assessed using the Cochrane risk of bias tool.The Cochrane RevMan software was used for analyses. Patients with final missing outcomes were assumed to have relapsed. For continuous outcomes we calculated a mean difference (MD) and 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes we calculated an odds ratio (OR) and 95% confidence intervals (95% CI) using a fixed-effect model. The chi square and I(2) statistics were used to assess statistical heterogeneity. A random-effects model was used in situations of unexplained heterogeneity MAIN RESULTS: Eighteen RCTs (1643 patients) were included in the review. Nine studies were judged to be at high risk of bias due to lack of blinding, incomplete outcome data and selective reporting. Meta-analysis of two studies (101 patients) comparing polyethylene glycol (PEG) with placebo showed a significantly increased number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08). Common adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea, diarrhoea and headache. Meta-analysis of 4 studies with 338 participants comparing PEG with lactulose showed significantly greater stools per week with PEG (MD 0.95 stools per week, 95% CI 0.46 to 1.44), although follow up was short. Patients who received PEG were significantly less likely to require additional laxative therapies. Eighteen per cent of PEG patients required additional therapies compared to 30% of lactulose patients (OR 0.49, 95% CI 0.27 to 0.89). No serious adverse events were reported with either agent. Common adverse events in these studies included diarrhoea, abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants comparing PEG with milk of magnesia showed that the stools/wk was significantly greater with PEG (MD 0.69 stools per week, 95% CI 0.48 to 0.89). However, the magnitude of this difference is quite small and may not be clinically significant. One child was noted to be allergic to PEG, but there were no other serious adverse events reported. Meta-analysis of 2 studies with 287 patients comparing liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in the number of stools per week favouring paraffin (MD 4.94 stools per week, 95% CI 4.28 to 5.61). No serious adverse events were reported. Adverse events included abdominal pain, distention and watery stools. No statistically significant differences in the number of stools per week were found between PEG and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1 study, 125 patients, P = 0.481), senna and lactulose (1 study, 21 patients, P > 0.05), lactitol and lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63 to 1.03), and PEG and liquid paraffin (1 study, 158 patients, MD 0.70, 95% CI -0.38 to 1.78). AUTHORS' CONCLUSIONS: The pooled analyses suggest that PEG preparations may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE analyses indicated that the overall quality of the evidence for the primary outcome (number of stools per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias in the studies in the pooled analyses. Thus, the results of the pooled analyses should be interpreted with caution because of quality and methodological concerns, as well as clinical heterogeneity, and short follow up. However, PEG appears safe and well tolerated. There is also evidence suggesting the efficacy of liquid paraffin (mineral oil), which was also well tolerated.There is no evidence to demonstrate the superiority of lactulose when compared to the other agents studied, although there is a lack of placebo controlled studies. Further research is needed to investigate the long term use of PEG for childhood constipation, as well as the role of liquid paraffin.

The caries-preventive effect of xylitol/maltitol and erythritol/maltitol lozenges: results of a double-blinded, cluster-randomized clinical trial in an area of natural fluoridation.

OBJECTIVE: Xylitol studies suggest caries reductions in the order of 50%. Based on animal/microbial studies, erythritol potentially has caries-preventive properties. However, clinical studies are required to confirm this. The aim of the study was to investigate the additional caries-preventive effect of xylitol/maltitol and erythritol/maltitol lozenges delivered at school, relative to controls receiving comprehensive prevention, in a low-caries prevalence population. METHODS: A 4-year, cluster-randomized, double-blinded clinical trial. Five hundred and seventy-nine 10-year-old consenting subjects from 21 schools were randomly assigned to one of five groups. Four groups used the lozenges on school days, in three teacher-supervised sessions daily, over 1 or 2 years. The daily amount was 4.7 g/4.6 g for xylitol/maltitol and 4.5 g/4.2 g for erythritol/maltitol. The groups received free examinations and care in the public health centre. Four hundred and ninety-six children were analysed. The main outcome measure was dentin caries increment based on a clinical examination at 4 years since the start. The groups were compared in relation to the increment using hierarchical logistic regression to adjust for potential clustering. RESULTS: Use of xylitol/maltitol or erythritol/maltitol lozenges did not result in caries reduction. A strong relationship between baseline caries prevalence and the 4-year increment was observed (OR = 7.38; 95% CI: 3.78-14.41). CONCLUSIONS: The results suggest that in relatively low-caries conditions the school-based use of xylitol/maltitol or erythritol/maltitol lozenges would not have additional caries-preventive effect when compared with comprehensive prevention.

[Hepatic encephalopathy and liver transplantation]. / Hepaticus encephalopathia és májátültetés.

About 6500-7000 people/year die in Hungary due to liver cirrhosis which is often complicated with hepatic encephalopathy (HE). While conventional interpretation is that hepatic encephalopathy is a consequence of high blood ammonia level, recent data indicate that the degree of encephalopathy is related to systemic inflammatory response during decompensation. In this review the authors overview and analyze the latest treatment modalities of hepatic encephalopathy based on most recent findings. They found that frequently used evidence based treatment which apply metronidazole, neomycine or disaccharides was only partially effective in clinical studies. Use of rifaximine only is supported by grade I evidence, however it is quite a costly drug. The authors could not identify a generally accepted guideline for the treatment of HE with a systematic literature review, although it has significant effect on survival after liver transplantation. Therefore, the authors urge to develop a consensus guideline for the treatment of HE.

Nonfluoride caries-preventive agents: new guidelines.

UNLABELLED: Nonfluoride caries-prevention agents have been developed and promoted to the dental profession in the recent past. The oral healthcare professional is encouraged to use evidence-based information when making clinical decisions. Recently, a systematic review was completed by a panel of experts convened by the American Dental Association Council on Scientific Affairs and recommendations were developed to address efficacy of nonfluoride agents in reducing the incidence of caries and arresting or reversing the progression of caries. The panel found that all nonfluoride agents should be used as adjuncts, following initial use of primary caries prevention strategies (fluoride, sealants, anticaries diet). This paper discusses the levels of certainty for evidence statements and clinical applications of these recommendations. CLINICAL SIGNIFICANCE: The panel concluded that certain nonfluoride agents may provide some benefits as adjunctive therapies in children and adults at higher risk of developing caries.

Astrocyte-neuron lactate transport in the ACC contributes to the occurrence of long-lasting inflammatory pain in male mice.

Lactate transport is an important means of communication between astrocytes and neurons and is implicated in a variety of neurobiological processes. However, the connection between astrocyte-neuron lactate transport and nociceptive modulation has not been well established. Here, we found that Complete Freund's adjuvant (CFA)-induced inflammation pain leads to a significant increase in extracellular lactate levels in the anterior cingulate cortex (ACC). Inhibition of glycogenolysis and lactate release in the ACC disrupted the persistent, but not acute, inflammation pain induced by CFA, and this effect was reversed by exogenous L-lactate administration. Knocking down the expression of lactate transporters (MCT1, MCT4, or MCT2) also disrupted the long lasting inflammation pain induced by CFA. Moreover, glycogenolysis in the ACC is critical for the induction of molecular changes related to neuronal plasticity, including the induction of phospho- (p-) ERK, p-CREB, and Fos. Taken together, our findings indicate that astrocyte-neuron lactate transport in the ACC is critical for the occurrence of persistent inflammation pain, suggesting a novel mechanism underlying chronic pain.

Fluorous iminoalditols: a new family of glycosidase inhibitors and pharmacological chaperones.

A collection of new reversible glycosidase inhibitors of the iminoalditol type featuring N-substituents containing perfluorinated regions has been prepared for evaluation of physicochemical, biochemical and diagnostic properties. The vast variety of feasible oligofluoro moieties allows for modular approaches to customised structures according to the intended applications, which are influenced by the fluorine content as well as the distance of the fluorous moiety from the ring nitrogen. The first examples, in particular in the D-galacto series, exhibited excellent inhibitory activities. A preliminary screen with two human cell lines showed that, at subinhibitory concentrations, they are powerful pharmacological chaperones enhancing the activities of the catalytically handicapped lysosomal D-galactosidase mutants associated with GM1 gangliosidosis and Morquio B disease.

2,5-Dideoxy-2,5-imino-d-altritol as a new class of pharmacological chaperone for Fabry disease.

Chromatographic separation of the extract from roots of Adenophora triphylla resulted in the isolation of two pyrrolidines, six piperidines, and two piperidine glycosides. The structures of new iminosugars were elucidated by spectroscopic methods as 2,5-dideoxy-2,5-imino-d-altritol (DIA) (2), beta-1-C-butenyl-1-deoxygalactonojirimycin (8), 2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (9), and 6-O-beta-d-glucopyranosyl-2,3-dideoxy-beta-1-C-ethyl-1-deoxygalactonojirimycin (10). beta-1-C-Butyl-1-deoxygalactonojirimycin (7) and compound 8 were found to be better inhibitors of alpha-galactosidase than N-butyl-1-deoxygalactonojirimycin. The present work elucidated that DIA was a powerful competitive inhibitor of human lysosome alpha-galactosidase A (alpha-Gal A) with a K(i) value of 0.5muM. Furthermore, DIA improved the thermostability of alpha-Gal A in vitro and increased intracellular alpha-Gal A activity by 9.6-fold in Fabry R301Q lymphoblasts after incubation for 3days. These experimental results suggested that DIA would act as a specific pharmacological chaperone to promote the smooth escape from the endoplasmic reticulum (ER) quality control system and to accelerate transport and maturation of the mutant enzyme.

Improved metabolic control after 12-week dietary intervention with low glycaemic isomalt in patients with type 2 diabetes mellitus.

The polyol isomalt (Palatinit) is a very low glycaemic sugar replacer. The effect of food supplemented with isomalt instead of higher glycaemic ingredients like sucrose and/or starch hydrolysates on metabolic control in patients with type 2 diabetes was examined in this open study. Thirty-three patients with type 2 diabetes received a diet with foods containing 30 g/d isomalt instead of higher-glycaemic carbohydrates for 12 weeks. Metformin and/or thiazolidindiones were the only concomitant oral antidiabetics allowed during the study. Otherwise, the participants maintained their usual diet during the test phase, but were instructed to refrain from additional sweetened foods. Before start, after 6 weeks and 12 weeks (completion of the study), blood samples were taken and analysed for clinical routine parameters, metabolic, and risk markers. Thirty-one patients completed the study. The test diet was well accepted and tolerated. After 12 weeks, significant reductions were observed for: glycosylated haemoglobin, fructosamine, fasting blood glucose, insulin, proinsulin, C-peptide, insulin resistance (HOMA-IR), and oxidised LDL (an atherosclerosis risk factor). In addition, significant lower nonesterified fatty acid concentrations were found in female participants. Routine blood measurements and blood lipids remained unchanged. The substitution of glycaemic ingredients by isomalt and the consequent on reduction of the glycaemic load within otherwise unchanged diet was accompanied by significant improvement in the metabolic control of diabetes. The present study is in agreement with findings of previous reported studies in human subjects demonstrating beneficial effects of low glycaemic diets on glucose metabolism in patients with diabetes mellitus type 2.

Hypothesis: hexitols in chewing gum may play a role in reducing postoperative ileus.

Gum-chewing has been suggested as a method to stimulate bowel motility and shorten postoperative ileus after colorectal surgery. Patients chewing gum pass flatus, and have bowel movement, earlier than those having ordinary postoperative treatment, and have a lower incidence of postoperative complications. The mechanisms suggested in order to explain this phenomena are all centered in the action of chewing, that may act on cephalic-vagal stimulation of digestion, producing hormones associated with bowel motility, or as sham feeding, stimulating the motility of the duodenum, stomach, and rectum, or by stimulation of secretion of saliva, and pancreatic juices. Interestingly, no suggestions are made about the possible effects of the ingredients of these gums. Sorbitol and other hexitols are key ingredients in most 'sugar-free' chewing gums and candies. Ingestion of relatively small amounts of sorbitol causes gastrointestinal symptoms like gas, bloating, and abdominal cramps in a dose dependent manner. Therefore, the hypothesis suggested herein is that the content of maxitols in 'sugar-free' chewing gums may play a role in the amelioration of ileus after surgery, and should be added to the list of probable mechanisms involved in the observed phenomena.

[Elderly hereditary hemorrhagic telangiectasia female with portosystemic encephalopathy].

We present a 71-year-old woman with hereditary hemorrhagic telangiectasia (HHT) who at age 69, had undergone total gastrectomy because of repeated upper gastrointestinal bleeding. A day prior to admission she began to demonstrate abnormal behavior. Examination showed she was restless and had higher brain dysfunction. Triphasic waves were seen on EEG, and a high signal in the globus pallidus on T1-weighted MRI. Plasma NH3 level was increased after a meal. Abdominal CT scan showed vascular anomalies including a portohepatic vein shunt. She was diagnosed with portosystemic encephalopathy. After treatment with a low-protein diet, lactitol, and branched chain-amino acids, her clinical condition, plasma NH3 level after a meal, and EEG returned to normal. Because portosystemic shunt is rare in HHT, there have been few reports of portosystemic encephalopathy with this condition. However, with aging, the possibility of portosystemic encephalopathy increases because of age-related increases in portosystemic shunt volume.