Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures

Objective

Mutations in STX1B encoding the presynaptic protein syntaxin-1B are associated with febrile seizures with or without epilepsy. It is unclear to what extent these mutations are linked to abnormalities of cortical glutamatergic or GABAergic neurotransmission. We explored this question using single- and paired-pulse transcranial magnetic stimulation (TMS) excitability markers.

Prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma: a SEER database analysis

Background: We the prognostic value of site-specific extra-hepatic disease in hepatocellular carcinoma (HCC) patients registered within the surveillance, epidemiology and end results (SEER) database.

Methods: SEER database (2010–2013) has been queried through SEER*Stat program to determine the prognosis of advanced HCC patients according to the site of extra-hepatic disease. Survival analysis has been conducted through Kaplan Meier analysis.

Results: A total of 4396 patients with stage IV HCC were identified in the period from 2010–2013 and they were included into this analysis. Patients with isolated regional lymph node involvement have better outcomes compared to patients with any other site of extra-hepatic disease (P < 0.0001 for both endpoints). Among patients with distant metastases, patients with bone metastases have better outcomes compared to patients with lung metastases (P < 0.0001 for both endpoints). Multivariate analysis revealed that younger age, normal alpha fetoprotein, single site of extra-hepatic disease, local treatment to the primary tumor and surgery to the metastatic disease were associated with better overall survival and liver cancer-specific survival.

Conclusion: Within the limits of the current SEER analysis, HCC patients with isolated lung metastases seem to have worse outcomes compared to patients with isolated bone or regional nodal metastases.?     

Biliary complications in liver transplantation: Impact of anastomotic technique and ischemic time on short- and long-term outcome

AIM: To elucidate the impact of various donor recipient and transplant factors on the development of biliary complications after liver transplantation.METHODS: We retrospectively reviewed 200 patients of our newly established liver transplantation(LT) program, who received full size liver graft. Biliary reconstruction was performed by side-to-side(SS), end-to-end(EE) anastomosis or hepeaticojejunostomy(HJ). Biliary complications(BC), anastomotic stenosis, bile leak, papillary stenosis, biliary drain complication, ischemic type biliary lesion(ITBL) were evaluated by studying patient records, corresponding radiologic imaging and reports of interventional procedures [e.g., endoscopic retrograde cholangiopancreatography(ERCP)]. Laboratory results included alanine aminotransferase(ALT), gammaglutamyltransferase and direct/indirect bilirubin with focus on the first and fifth postoperative day, six weeks after LT. The routinely employed external bile drain was examined by a routine cholangiography on the fifth postoperative day and six weeks after transplantation as a standard procedure, but also whenever clinically indicated. If necessary, interventional(e.g., ERCP) or surgical therapy was performed. In case of biliary complication, patients were selected, assigned to different complication-groups and subsequently reviewed in detail. To evaluate the patients outcome, we focussed on appearance of postoperative/post-interventional cholangitis, need for rehospitalisation, retransplantation, ITBL or death caused by BC.RESULTS: A total of 200 patients [age: 56(19-72), alcoholic cirrhosis: n = 64(32%), hepatocellular carcinoma: n = 40(20%), acute liver failure: n = 23(11.5%), cryptogenic cirrhosis: n = 22(11%), hepatitis B virus /hepatitis C virus cirrhosis: n = 13(6.5%), primary sclerosing cholangitis: n = 13(6.5%), others: n = 25(12.5%) were included. The median follow-up was 27 mo until June 2015. The overall biliary complication rate was 37.5%(n = 75) with anastomotic strictures(AS): n = 38(19%), bile leak(BL): n = 12(6%), biliary drain complication: n = 12(6%); papillary stenosis(PS): n = 7(3.5%), ITBL: n = 6(3%). Clinically relevant were only 19%(n = 38). We established a comprehensive classification for AS with four grades according to clinical relevance. The reconstruction techniques [SS: n = 164, EE: n = 18, HJ: n = 18] showed no significant impact on the development of BCs in general(all n 0.05), whereas in the HJ group significantly less AS were found(P = 0.031). The length of donor intensive care unit stay over 6 d had a significant influence on BC development(P = 0.007, HR = 2.85; 95%CI: 1.33-6.08) in the binary logistic regression model, whereas other reviewed variables had not [warm ischemic time 45 min(P = 0.543), cold ischemic time 10 h(P = 0.114), ALT init 1500 U/L(P = 0.631), bilirubin init 5 mg/d L(P = 0.595), donor age 65(P = 0.244), donor sex(P = 0.068), rescue organ(P = 0.971)]. 13%(n = 10) of BCs had no therapeutic consequences, 36%(n = 27) resulted in repeated lab control, 40%(n = 30) received ERCP and 11%(n = 8) surgical therapy. Fifteen(7.5%) patients developed cholangitis [AS(n = 6), ITBL(n = 5), PS(n = 3), biliary lesion BL(n = 1)]. One patient developed ITBL twelve months after LT and subsequently needed retransplantation. Rehospitalisation rate was 10.5 %(n = 21) [AS(n = 11), ITBL(n = 5), PS(n = 3), BL(n = 1)] with intervention or reinterventional therapy as main reasons. Retransplantation was performed in 5(2.5%) patients [ITBL(n = 1), acute liver injury(ALI) by organ rejection(n = 3), ALI by occlusion of hepatic artery(n = 1)]. In total 21(10.5%) patients died within the follow-up period. Out of these, one patient with AS developed severe fatal chologenic sepsis after ERCP.CONCLUSION: In our data biliary reconstruction technique and ischemic times seem to have little impact on the development of BCs.     

Periodontal conditions, oral Candida albicans and salivary proteins in type 2 diabetic subjects with emphasis on gender

Background  

The association between periodontal conditions, oral yeast colonisation and salivary proteins in subjects with type 2 diabetes (T2D) is not yet documented. The present study aimed to assess the relationship between these variables in type 2 diabetic subjects with reference to gender.     

The 'wise list'- a comprehensive concept to select, communicate and achieve adherence to recommendations of essential drugs in ambulatory care in Stockholm

The aim was to present and evaluate the impact of a comprehensive strategy over 10 years to select, communicate and achieve adherence to essential drug recommendations (EDR) in ambulatory care in a metropolitan healthcare region. EDRs were issued and launched as a 'Wise List' by the regional Drug and Therapeutics Committee in Stockholm. This study presents the concept by: (i) documenting the process for selecting, communicating and monitoring the impact of the 'Wise List'; (ii) analysing the variation in the number of drug substances recommended between 2000 and 2010; (iii) assessing the attitudes to the 'Wise List' among prescribers and the public; (iv) evaluating the adherence to recommendations between 2003 and 2009. The 'Wise List' consistently contained 200 drug substances for treating common diseases. The drugs were selected based on their efficacy, safety, suitability and cost-effectiveness. The 'Wise List' was known among one-third of a surveyed sample of the public in 2002 after initial marketing campaigns. All surveyed prescribers knew about the concept and 81% found the recommendations trustworthy in 2005. Adherence to recommendations increased from 69% in 1999 to 77% in 2009. In primary care, adherence increased from 83% to 87% from 2003 to 2009. The coefficient of variation (CV%) decreased from 6.1% to 3.8% for 156 healthcare centres between these years. The acceptance of the 'Wise List' in terms of trust among physicians and among the public and increased adherence may be explained by clear criteria for drug recommendations, a comprehensive communication strategy, electronic access to recommendations, continuous medical education and involvement of professional networks and patients.     

Cyclotides from an extreme habitat: characterization of cyclic peptides from Viola abyssinica of the Ethiopian highlands

As part of ongoing explorations of the structural diversity of cyclotides, the cyclotide content of a native violet of the East African highlands, Viola abyssinica (which grows at altitudes up to 3400 m), was studied. Six new cyclotides, vaby A-E (1-5) and varv E (6), were isolated and characterized by employing HPLC and MS techniques and quantitative amino acid analysis. Cyclotides 1-5 were found to have new sequences, and 1-3 have a further novel feature in their sequences, an alanine moiety in loop 2. Two of the cyclotides (1 and 4) also exhibited cytotoxic properties in a flourometric microculture cytotoxicity assay. The findings corroborate the hypothesis that investigating the cyclotide contents of violets growing in diverse environments is a promising approach for extending our knowledge of both the structural and biological diversity of cyclotides.     

Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes

The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer.