High dose atorvastatin associated with increased risk of significant hepatotoxicity in comparison to simvastatin in UK GPRD cohort

Background and Aims: Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods: The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results: Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions: The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small

Neutrophil to lymphocyte ratio predicts short- and long-term mortality following revascularization therapy for ST elevation myocardial infarction

Background: Several inflammation biomarkers have been implicated in the pathogenesis and prognosis of acute coronary syndromes. However, the prognostic role of the neutrophil-lymphocyte white cell interactive response to myocardial injury in predicting short- and long-term mortality after ST elevation myocardial infarction (STEMI) remains poorly defined.Methods: We evaluated 250 consecutive STEMI patients presenting acutely for revascularization to our tertiary care center over 1 year. Patients with acute sepsis, trauma, recent surgery, autoimmune diseases, or underlying malignancy were excluded. Data gathered included demographics, clinical presentation, leukocyte markers, electrocardiograms, evaluations, therapy,major adverse cardiac events, and all-cause mortality.Results: Mean age was 62 ± 15 years, 70.4% of subjects were males while majority (49.4%) were Caucasians. Mean duration of follow-up was 571 ± 291 days (median 730 days). Univariate analysis of several inflammatory biomarkers including C-reactive protein, revealed white cell count (OR = 1.09, p < 0.001) and neutrophil to lymphocyte ratio (NLR) (OR = 1.05, p = 0.011) as predictors of short- and long-term mortality; but not mean neutrophil count (OR = 1.04, p = 0.055) or lymphocyte count alone (OR = 0.96, p = 0.551). Multivariate analysis using backward stepwise regression revealed NLR (OR = 2.64, p = 0.026), female gender (OR = 5.35, p < 0.001), cerebrovascular accident history (OR = 3.36, p = 0.023), low glomerular filtration rate (OR = 0.98, p = 0.012) and cardiac arrest on admission (OR = 17.43, p < 0.001) as robust independent predictors of long-term mortality. NLR was divided into two sub-groups based on an optimal cut off value of 7.4. This provided the best discriminatory cut off point for predicting adverse mortality outcome. Both short-term (≤ 30 days) and long-term (≤ 2 years) mortality were predicted with Kaplan-Meier survival curve separation best stratified by a NLR cut off value of 7.4.Conclusions: NLR based on an optimal cut off value of 7.4, was an excellent predictor of short- and long-term survival in patients with revascularized STEMI and warrants larger scale multi-center prospective evaluation, as a prognostic indicator. NLR offers improved prognostic capacity when combined with conventional clinical scoring systems, such as the Thrombolysis In Myocardial Infarction risk score.

A multi-bacteriocin cheese starter system comprising nisin and lacticin 3147 in Lactococcus lactis, in combination with plantaricin from Lactobacillus plantarum

Functional starter cultures demonstrating superior technological and food safety properties are advantageous to the food fermentation industry. We evaluated the efficacy of single and double bacteriocin-producing starters of Lactococcus lactis capable of producing the Class I bacteriocins, nisin A and/or lacticin 3147 in terms of starter performance. Single producers were generated by mobilising the conjugative, bacteriophage resistance plasmid pMRC01, encoding lacticin genetic determinants, or the conjugative transposon Tn5276, encoding nisin genetic determinants, to the commercial starter L. lactis CSK2775. The effect of bacteriocin co-production was examined by superimposing pMRC01 into the newly constructed nisin transconjugant. Transconjugants were improved with regard to antimicrobial activity and bacteriophage insensitivity when compared to the recipient strain and the double producer was immune to both bacteriocins. Bacteriocin production in the starter was stable, although the recipient strain proved to be a more efficient acidifier than transconjugant derivatives. Overall, combining Class I bacteriocins (the double-producer or a combination of single producers) proved as effective as individual bacteriocins for controlling Listeria innocua growth in laboratory-scale cheeses. However, using the double producer in combination with the Class II bacteriocin producer Lactobacillus plantarum, or the lacticin producer with the Class II producer, proved most effective for reducing bacterial load. As emergence of bacteriocin tolerance was reduced 10-fold in the presence of nisin and lacticin, we suggest that the double producer in conjunction with the Class II producer could serve as a protective culture providing a food-grade, multi-hurdle approach to control pathogenic growth in a variety of industrial applications. IMPORTANCE: We generated a suite of single and double-bacteriocin producing starter cultures capable of generating the Class I bacteriocins lacticin 3147 or nisin or both bacteriocins simultaneously via conjugation. The transconjugants exhibited improved bacteriophage resistance and antimicrobial activity. The single producers proved as effective as the double-bacteriocin producer at reducing Listeria numbers in laboratory-scale cheese. However, combining the double producer or the lacticin producing starter with a Class II bacteriocin producer, Lactobacillus plantarum LMG P-26358, proved most effective at reducing Listeria numbers, and was significantly better than a combination of the three bacteriocin producing strains, as the double producer is not inhibited by either of the Class I bacteriocins. Since the simultaneous use of lacticin and nisin should reduce the emergence of bacteriocin tolerant derivatives this study suggests that a protective starter system produced by bacteriocin stacking is a worthwhile multi-hurdle approach for food safety applications

Characterization of an electron conduit between bacteria and the extracellular environment

A number of species of Gram-negative bacteria can use insoluble minerals of Fe(III) and Mn(IV) as extracellular respiratory electron acceptors. In some species of Shewanella, deca-heme electron transfer proteins lie at the extracellular face of the outer membrane (OM), where they can interact with insoluble substrates. To reduce extracellular substrates, these redox proteins must be charged by the inner membrane/periplasmic electron transfer system. Here, we present a spectro-potentiometric characterization of a trans-OM icosa-heme complex, MtrCAB, and demonstrate its capacity to move electrons across a lipid bilayer after incorporation into proteoliposomes. We also show that a stable MtrAB subcomplex can assemble in the absence of MtrC; an MtrBC subcomplex is not assembled in the absence of MtrA; and MtrA is only associated to the membrane in cells when MtrB is present. We propose a model for the modular organization of the MtrCAB complex in which MtrC is an extracellular element that mediates electron transfer to extracellular substrates and MtrB is a trans-OM spanning ß-barrel protein that serves as a sheath, within which MtrA and MtrC exchange electrons. We have identified the MtrAB module in a range of bacterial phyla, suggesting that it is widely used in electron exchange with the extracellular environment

Inhibitory activity of Lactobacillus plantarum LMG P-26358 against Listeria innocua when used as an adjunct starter in the manufacture of cheese

Lactobacillus plantarum LMG P-26358 isolated from a soft French artisanal cheese produces a potent class IIa bacteriocin with 100% homology to plantaricin 423 and bacteriocidal activity against Listeria innocua and Listeria monocytogenes. The bacteriocin was found to be highly stable at temperatures as high as 100°C and pH ranges from 1-10. While this relatively narrow spectrum bacteriocin also exhibited antimicrobial activity against species of enterococci, it did not inhibit dairy starters including lactococci and lactobacilli when tested by well diffusion assay (WDA). In order to test the suitability of Lb. plantarum LMG P-26358 as an anti-listerial adjunct with nisin-producing lactococci, laboratory-scale cheeses were manufactured. Results indicated that combining Lb. plantarum LMG P-26358 (at 108 colony forming units (cfu)/ml) with a nisin producer is an effective strategy to eliminate the biological indicator strain, L. innocua. Moreover, industrial-scale cheeses also demonstrated that Lb. plantarum LMG P-26358 was much more effective than the nisin producer alone for protection against the indicator. MALDI-TOF mass spectrometry confirmed the presence of plantaricin 423 and nisin in the appropriate cheeses over an 18 week ripening period. A spray-dried fermentate of Lb. plantarum LMG P-26358 also demonstrated potent anti-listerial activity in vitro using L. innocua. Overall, the results suggest that Lb. plantarum LMG P-26358 is a suitable adjunct for use with nisin-producing cultures to improve the safety and quality of dairy products

A Cost-Effective Design for a Neutrino Factory

There have been active efforts in the U.S., Europe, and Japan on the design of a Neutrino Factory. This type of facility produces intense beams of neutrinos from the decay of muons in a high energy storage ring. In the U.S., a second detailed Feasibility Study (FS2) for a Neutrino Factory was completed in 2001. Since that report was published, new ideas in bunching, cooling and acceleration of muon beams have been developed. We have incorporated these ideas into a new facility design, which we designate as Study 2B (ST2B), that should lead to significant cost savings over the FS2 design.Comment: 46 pages, 38 figures; to be submitted to Physical Review Special Topics: Accelerators and Beam

Comparative effectiveness of dual-action versus single-action antidepressants for the treatment of depression in people living with HIV/AIDS

Background Depression is the most common psychiatric comorbidity among people living with HIV/AIDS (PLWHA). Little is known about the comparative effectiveness between different types of antidepressants used to treat depression in this population. We compared the effectiveness of dual-action and single-action antidepressants in PLWHA for achieving remission from depression. Methods We used data from the Centers for AIDS Research Network of Integrated Clinic Systems to identify 1175 new user dual-action or single-action antidepressant treatment episodes occurring from 2005 to 2014 for PLWHA diagnosed with depression. The primary outcome was remission from depression defined as a Patient Health Questionnaire-9 (PHQ-9) score <5. Mean difference in PHQ-9 depressive symptom severity was a secondary outcome. The main approach was an intent-to-treat (ITT) evaluation complemented with a per protocol (PP) sensitivity analysis. Generalized linear models were fitted to estimate treatment effects. Results In ITT analysis, 32% of the episodes ended in remission for both dual-action and single-action antidepressants. The odds ratio (OR) of remission was 1.02 (95%CI=0.63,1.67). In PP analysis, 40% of dual-action episodes ended in remission compared to 32% in single-action episodes. Dual-action episodes had 1.33 times the odds of remission (95%CI=0.55,3.21), however the result was not statistically significant. Non-significant differences were also observed for depressive symptom severity. Limitations Missing data was common but was addressed with inverse probability weights. Conclusions Results suggest that single-action and dual-action antidepressants are equally effective in PLWHA. Remission was uncommon highlighting the need to identify health service delivery strategies that aid HIV providers in achieving full remission of their patients’ depression

A longitudinal study of Sin Nombre virus prevalence in rodents, southeastern Arizona.

We determined the prevalence of Sin Nombre virus antibodies in small mammals in southeastern Arizona. Of 1,234 rodents (from 13 species) captured each month from May through December 1995, only mice in the genus Peromyscus were seropositive. Antibody prevalence was 14.3% in 21 white-footed mice (P. leucopus), 13.3% in 98 brush mice (P. boylii), 0.8% in 118 cactus mice (P. eremicus), and 0% in 2 deer mice (P. maniculatus). Most antibody-positive mice were adult male Peromyscus captured close to one another early in the study. Population dynamics of brush mice suggest a correlation between population size and hantavirus-antibody prevalence