Parametric Erosion Investigation: Propellant Adiabatic Flame Temperature

The influence of quasi-independent parameters and their potential influence on erosion in guns have been investigated. Specifically, the effects of flame temperature and the effect of assuming that the Lewis number (ratio of mass-to-heat transport to the surface), Le = 1, has been examined. The adiabatic flame temperature for a propellant was reduced by the addition of a diluent from a high temperature of 3843 K (similar to that of M9) down to 3004 K, which is near the value for M30A1 propellant. Mass fractions of critical species at the surface with and without the assumption of Le = 1 are presented, demonstrating that certain species preferentially reach the surface providing varied conditions for the surface reactions. The results for gun tube bore surface regression qualitatively agree with previous studies and with current experimental data

Proteobactin and a yersiniabactin-related siderophore mediate iron acquisition in Proteus mirabilis

Proteus mirabilis causes complicated urinary tract infections (UTIs). While the urinary tract is an iron-limiting environment, iron acquisition remains poorly characterized for this uropathogen. Microarray analysis of P. mirabilis HI4320 cultured under iron limitation identified 45 significantly upregulated genes ( P  ≤  0.05) that represent 21 putative iron-regulated systems. Two gene clusters, PMI0229-0239 and PMI2596-2605, encode putative siderophore systems. PMI0229-0239 encodes a non-ribosomal peptide synthetase-independent siderophore system for producing a novel siderophore, proteobactin. PMI2596-2605 are contained within the high-pathogenicity island, originally described in Yersinia pestis , and encodes proteins with apparent homology and organization to those involved in yersiniabactin production and uptake. Cross-feeding and biochemical analysis shows that P. mirabilis is unable to utilize or produce yersiniabactin, suggesting that this yersiniabactin-related locus is functionally distinct. Only disruption of both systems resulted in an in vitro iron-chelating defect; demonstrating production and iron-chelating activity for both siderophores. These findings clearly show that proteobactin and the yersiniabactin-related siderophore function as iron acquisition systems. Despite the activity of both siderophores, only mutants lacking the yersiniabactin-related siderophore have reduced fitness in vivo . The fitness requirement for the yersiniabactin-related siderophore during UTI shows, for the first time, the importance of siderophore production in vivo for P. mirabilis .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79111/1/MMI_7317_sm_FigS1-S2_TabS1-S3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79111/2/j.1365-2958.2010.07317.x.pd

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Cardiovascular Events in Patients Received Combined Fibrate/Statin Treatment versus Statin Monotherapy: Acute Coronary Syndrome Israeli Surveys Data

The effect of combination of fibrate with statin on major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS) hospitalization is unclear. The main aim of this study was to investigate the 30-day rate of MACE in patients who participated in the nationwide ACS Israeli Surveys (ACSIS) and were treated on discharge with a fibrate (mainly bezafibrate) and statin combination vs. statin alone.The study population comprised 8,982 patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination. MACE was defined as a composite measure of death, recurrent MI, recurrent ischemia, stent thrombosis, ischemic stroke and urgent revascularization.Patients from the combination group were younger (58.1±11.9 vs. 62.9±12.6 years). However, they had significantly more co-morbidities (hypertension, diabetes), current smokers and unfavorable cardio-metabolic profiles (with respect to glucose, total cholesterol, triglyceride and HDL-cholesterol). Development of MACE was recorded in 513 (6.0%) patients from the statin monotherapy group vs. 13 (3.2%) from the combination group, p = 0.01. 30-day re-hospitalization rate was significantly lower in the combination group: 68 (15.6%) vs. 1691 (19.8%) of patients, respectively; p = 0.03. Multivariable analysis identified the fibrate/statin combination as an independent predictor of reduced risk of MACE with odds ratio of 0.54, 95% confidence interval 0.32–0.94.A significantly lower risk of 30-day MACE rate was observed in patients receiving combined fibrate/statin treatment following ACS compared with statin monotherapy. However, caution should be exercised in interpreting these findings taking into consideration baseline differences between our observational study groups

Metabolic Control in Type 1 Diabetes: Is Adjunctive Therapy the Way Forward?

Despite advances in insulin therapies, patients with type 1 diabetes (T1DM) have a shorter life span due to hyperglycaemia-induced vascular disease and hypoglycaemic complications secondary to insulin therapy. Restricting therapy for T1DM to insulin replacement is perhaps an over-simplistic approach, and we focus in this work on reviewing the role of adjuvant therapy in this population. Current data suggest that adding metformin to insulin therapy in T1DM temporarily lowers HbA1c and reduces weight and insulin requirements, but this treatment fails to show a longer-term glycaemic benefit. Agents in the sodium glucose co-transporter-2 inhibitor (SGLT-2) class demonstrate the greatest promise in correcting hyperglycaemia, but there are safety concerns in relation to the risk of diabetic ketoacidosis. Glucagon-like peptide-1 agonists (GLP-1) show a modest effect on glycaemia, if any, but significantly reduce weight, which may make them suitable for use in overweight T1DM patients. Treatment with pramlintide is not widely available worldwide, although there is evidence to indicate that this agent reduces both HbA1c and weight in T1DM. A criticism of adjuvant studies is the heavy reliance on HbA1c as the primary endpoint while generally ignoring other glycaemic parameters. Moreover, vascular risk markers and measures of insulin resistance—important considerations in individuals with a longer T1DM duration—are yet to be fully investigated following adjuvant therapies. Finally, studies to date have made the assumption that T1DM patients are a homogeneous group of individuals who respond similarly to adjuvant therapies, which is unlikely to be the case. Future longer-term adjuvant studies investigating different glycaemic parameters, surrogate vascular markers and harder clinical outcomes will refine our understanding of the roles of such therapies in various subgroups of T1DM patients

Novità dal congresso ESC 2020 per la terapia dei pazienti con scompenso cardiaco a frazione d’eiezione non ridotta: i dati del trial PARALLAX

I dati disponibili sembrano incoraggiare l\u2019utilizzo di sacubitril/valsartan nei pazienti con diagnosi di scompenso non-HFrEF al pari dei pazienti con HFrEF, col vantaggio di ridurne il rischio di ospedalizzazione per scompenso, soprattutto se pre-esiste l\u2019indicazione al trattamento con ACE-inibitori o sartanici