International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Susceptibility of methacrylate-based root canal filling to degradation by bacteria found in endodontic infections

Objectives: To present a case of endodontic failure obturated with a methacrylate-based root filling material, Resilon/ RealSeal (RS). To determine if RS is susceptible to biodegradation by endodontically relevant microbes by a method known to show RS degradation. Method and Materials: Emulsions of RS were dispersed in agar with minimal bacterial nutrients in culture plates. Lipase PS served as a positive control. Pseudomonas aeruginosa, Fusobacterium nucleatum, Prevotella intermedia, Porphyromonas gingivalis, Porphyromonas asaccharolytica, Enterococcus faecalis, Streptococcus sanguis, Streptococcus mutans, Staphylococcus aureus, and Staphylococcus epidermidis were tested for their ability to biodegrade RS. The bacteria were inoculated in the plates and examined daily for RS degradation for 7 days. Results: Degradation of the emulsified RS manifested in the formation of clear zones around P aeruginosa, P intermedia, P asaccharolytica, S aureus, and S epidermidis. No degradation was seen with the other tested bacteria or in plates that did not contain RS emulsion. Conclusion: Endodontic pathogenic bacteria can degrade RS. These findings complement other work and suggest that the seal and integrity of root canal fillings obturated with RS may be impaired by a microbial insult

Maternal Antibiotic Exposure and the Risk of Developing Antenatal Depressive Symptoms

Background: Antenatal depression is common and has significant consequences. The literature suggests that antibiotic exposure may be associated with depression. Many individuals are exposed to antibiotics during pregnancy. Further investigation of the association between antenatal antibiotic use and the development of depression during pregnancy is needed. Methods: A national prospective observational cohort study of pregnant individuals was undertaken using an online survey, completed during the third trimester. Antenatal depressive symptoms (ADSs) were defined as having an Edinburgh Postnatal Depression Scale score of ≥13 and/or receiving a clinical diagnosis of depression. Results: One in six individuals (16.5%, n = 977) experienced ADSs during their pregnancy, of whom 37.9% received a depression diagnosis. There was no relationship between antibiotic use and the development of ADSs. Four factors were identified as significant independent predictors of ADSs: personal history of depression, severe nausea and vomiting causing an inability to eat, emotional abuse from an intimate partner within the prior 12 months, and not having a university degree. Conclusions: Antenatal antibiotic use was not associated with the development of ADSs. Given the high incidence of undiagnosed depression, new strategies and models of care that prioritise individuals with risk factors may be required to optimise antenatal care

Catalytically active alkaline molten globular enzyme: Effect of pH and temperature on the structural integrity of 5-aminolevulinate synthase

5-Aminolevulinate synthase (ALAS), a pyridoxal-5′phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in mammals. Circular dichroism (CD) and fluorescence spectroscopies were used to examine the effects of pH (1.0–3.0 and 7.5–10.5) and temperature (20 and 37 °C) on the structural integrity of ALAS. The secondary structure, as deduced from far-UV CD, is mostly resilient to pH and temperature changes. Partial unfolding was observed at pH 2.0, but further decreasing pH resulted in acid-induced refolding of the secondary structure to nearly native levels. The tertiary structure rigidity, monitored by near-UV CD, is lost under acidic and specific alkaline conditions (pH 10.5 and pH 9.5/37 °C), where ALAS populates a molten globule state. As the enzyme becomes less structured with increased alkalinity, the chiral environment of the internal aldimine is also modified, with a shift from a 420 nm to 330 nm dichroic band. Under acidic conditions, the PLP cofactor dissociates from ALAS. Reaction with 8-anilino-1-naphtalenesulfonic acid corroborates increased exposure of hydrophobic clusters in the alkaline and acidic molten globules, although the reaction is more pronounced with the latter. Furthermore, quenching the intrinsic fluorescence of ALAS with acrylamide at pH 1.0 and 9.5 yielded subtly different dynamic quenching constants. The alkaline molten globule state of ALAS is catalytically active (pH 9.5/37 °C), although the k(cat) value is significantly decreased. Finally, the binding of 5-aminolevulinate restricts conformational fluctuations in the alkaline molten globule. Overall, our findings prove how the structural plasticity of ALAS contributes to reaching a functional enzyme