Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance.

Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.

Drug solubilization during simulated pediatric gastro-intestinal digestion.

To increase the understanding of how drugs behave following oral administration to the pediatric population, the aim of the present study was to investigate the solubilization of fluconazole and ibuprofen during simulated gastro-intestinal (GI) digestion, using an immediate transfer model mimicking pediatric GI digestion. The effects of infant formula and digestion, on the drug solubilization, were studied using simulated fasted and fed state digestion media in the presence and absence of digestive enzymes. Additionally, the effect of digestion media viscosity on the solubilization process was investigated. It was found that the solubilization of fluconazole was unaffected by all tested parameters, as the entire estimated dose equivalent was solubilized in the aqueous phase throughout all digestion studies. In contrast, the solubilization of ibuprofen was affected by all the tested parameters, i.e. in the fasted state, the solubilization of ibuprofen was limited by its solubility in the aqueous phase of the simulated GI digestion media, whereas the solubilization in the fed state was affected by drug partitioning between the lipid and the aqueous phases, and therefore by the digestion of the lipid phase. Adding Nestlé Thicken Up™, containing xanthan gum as a thickening agent, to the digestion medium increased its viscosity, which in turn resulted in a reduced initial digestion rate, increased pH fluctuations, as well as high variability in all drug solubilization data as evident in large standard deviations. Furthermore, the increased digestion medium viscosity decreased the drug recovery from the combined pellet and aqueous phase. The observed viscosity effects might translate into a more variable and lower oral bioavailability.

Molecular characterization of multidrug-resistance in Gram-negative bacteria from the Peshawar teaching hospital, Pakistan.

Extended-spectrum ß-lactamases, carbapenemases, 16S rRNA methylases conferring pan-drug aminoglycoside resistance and colistin resistance were investigated among Gram-negative bacteria recovered from clinical samples (infections) from 200 individuals hospitalized at the Khyber Teaching Hospital of Peshawar, north Pakistan, from December 2017 to March 2018. Out of 65 isolates recovered, 19% were carbapenem resistant and 16% carried a bla NDM-1 gene, confirming the widespread distribution of NDM producers in this country. The association of the NDM carbapenem-resistance determinant, together with the extended-spectrum ß-lactamase CTX-M-15 and 16S rRNA methylases, was frequent, explaining the multidrug-resistance pattern observed. All isolates remained susceptible to colistin.

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Avaliação ecocardiográfica da insuficiência mitral em pacientes com cardiomiopatia hipertrófica / Ecocardiographic evaluation of mitral insufficiency in patients with hypertrophic cardiomyopathy

A cardiomiopatia hipertrófica é uma doença de origem genética, que afeta milhares de pessoas em todo o mundo.Objetivos: Avaliar a presença de regurgitação mitral em pacientes com cardiomiopatia hipertrófica, bem como sua relação com variáveis ecodopplercardiográficas do ventrículo esquerdo. A disfunção de valva mitral encontradas nesses pacientes mostra-se um dado de extrema relevância, visto que é capaz de predizer a sobrevida e a taxa de mortalidade dos enfermos acometidos pela cardiomiopatia hipertrófica.Métodos: Foram avaliados todos os ecocardiogramas realizados no período de 2006 a 2016 no serviço de ecocardiografia do Hospital de Base de São José do Rio Preto, sendo o total de 112.930 exames. Foram selecionados aqueles com diagnóstico de cardiomiopatia hipertrófica ou espessura parietal > 15 mm, e incluídos na análise 132 pacientes.Resultados: Regurgitação valvar mitral de grau moderado e importante esteve presente em 25% e 5,3% dos pacientes, respectivamente, sendo que a regurgitação mitral esteve independentemente correlacionada com a forma obstrutiva de cardiomiopatia hipertrófica.Conclusão: A regurgitação mitral é achado frequente em pacientes com cardiomiopatia hipertrófica, no entanto, a insuficiência mitral importante é extremamente incomum e está correlacionada com a forma obstrutiva da doença

Hypertrophic Cardiomyopathy (HCM) is a genetic disease that affects thousands of people around the world.Objectives:The present study aims to evaluate the presence of mitral regurgitation in patients with HCM, as well as its relationship with left ventricular Doppler echocardiographic variables. The mitral valve failure found in these patients is an extremely important finding, since it is able to predict the survival and mortality rate of the patients affected by HCM.Materials and Methods: All echocardiograms performed from 2006 to 2016 in the echocardiographic service of Hospital de Base de São José do Rio Preto were evaluated. A total of 112,930 tests were gathered, of which those with HCM diagnosis or wall thickness >15 mm were selected and 132 patients were included in the analysis.Results: Moderate and major mitral valve regurgitation is present in 25% and 5.3% of the patients, respectively, and MRI is independently correlated with the obstructive form of HCM.Conclusion: Mitral regurgitation is a frequent finding in patients with CMP, however, significant MI is extremely uncommon and is correlated with the obstructive form of the disease

Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center.

OBJECTIVE: We evaluated patients underwent cardiac valve surgery in the presence of infective endocarditis in an attempt to identify independent predictors of 30-day mortality. METHODS: We evaluated 837 consecutive patients underwent cardiac valve surgery from January 2003 to May 2010 in a tertiary hospital in São José do Rio Preto, São Paulo (SP), Brazil. The study group comprised patients who underwent intervention in the presence of infective endocarditis and was compared to the control group (without infective endocarditis), evaluating perioperative clinical outcomes and 30-day all cause mortality. RESULTS: In our series, 64 patients (8%) underwent cardiac valve surgery in the presence of infective endocarditis, and 37.5% of them had surgical intervention in multiple valves. The study group had prolonged ICU length of stay (16%), greater need for dialysis (9%) and higher 30-day mortality (17%) compared to the control group (7%, P=0.020; 2%, P=0.002 and 9%, P=0.038; respectively). In a Cox regression analysis, age (P = 0.007), acute kidney injury (P = 0.004), dialysis (P = 0.026), redo surgery (P = 0.026), re-exploration for bleeding (P = 0.013), tracheal reintubation (P <0.001) and type I neurological injury (P <0.001) were identified as independent predictors for death. Although the manifestation of infective endocarditis influenced on mortality in univariate analysis, multivariate Cox regression analysis did not confirm such variable as an independent predictor of death. CONCLUSION: Age and perioperative complications stand out as predictors of hospital mortality in Brazilian population. Cardiac valve surgery in the presence of active infective endocarditis was not confirmed itself as an independent predictor of 30-day mortality.

Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center / Tratamento cirúrgico para endocardite infecciosa e mortalidade hospitalar em centro único brasileiro

OBJECTIVE: We evaluated patients underwent cardiac valve surgery in the presence of infective endocarditis in an attempt to identify independent predictors of 30-day mortality. METHODS: We evaluated 837 consecutive patients underwent cardiac valve surgery from January 2003 to May 2010 in a tertiary hospital in São José do Rio Preto, São Paulo (SP), Brazil. The study group comprised patients who underwent intervention in the presence of infective endocarditis and was compared to the control group (without infective endocarditis), evaluating perioperative clinical outcomes and 30-day all cause mortality. RESULTS: In our series, 64 patients (8%) underwent cardiac valve surgery in the presence of infective endocarditis, and 37.5% of them had surgical intervention in multiple valves. The study group had prolonged ICU length of stay (16%), greater need for dialysis (9%) and higher 30-day mortality (17%) compared to the control group (7%, P=0.020; 2%, P=0.002 and 9%, P=0.038; respectively). In a Cox regression analysis, age (P = 0.007), acute kidney injury (P = 0.004), dialysis (P = 0.026), redo surgery (P = 0.026), re-exploration for bleeding (P = 0.013), tracheal reintubation (P <0.001) and type I neurological injury (P <0.001) were identified as independent predictors for death. Although the manifestation of infective endocarditis influenced on mortality in univariate analysis, multivariate Cox regression analysis did not confirm such variable as an independent predictor of death. CONCLUSION: Age and perioperative complications stand out as predictors of hospital mortality in Brazilian population. Cardiac valve surgery in the presence of active infective endocarditis was not confirmed itself as an independent predictor of 30-day mortality.

OBJETIVO: Avaliamos pacientes submetidos à cirurgia valvar em vigência de endocardite infecciosa na tentativa de identificar preditores independentes de mortalidade intrahospitalar em 30 dias. MÉTODOS: Foram avaliados 837 pacientes consecutivamente submetidos à cirurgia valvar, no período de janeiro de 2003 a maio de 2010, em um hospital terciário de São José do Rio Preto, SP, Brasil. O Grupo de Estudo compreendeu indivíduos submetidos à intervenção em vigência de endocardite infecciosa e foi comparado ao Grupo Controle, considerando complicações clínicas perioperatórias e óbito por todas as causas em 30 dias. RESULTADOS: Em nossa casuística, 64 (8%) pacientes foram submetidos à cirurgia valvar em vigência de endocardite infecciosa, sendo 37,5% deles com indicação de intervenção cirúrgica em múltiplas valvas. O Grupo de Estudo apresentou maior permanência em Unidade de Terapia Intensiva (16%), necessidade de diálise (9%) e maior mortalidade em 30 dias (17%) comparado ao Grupo Controle (7%, P=0,020; 2%, P=0,002 e 9%, P=0,038; respectivamente). A análise de regressão de Cox confirmou idade (P=0,007), lesão renal aguda (P=0,004), diálise (P=0,026), reoperação (P=0,026), reintervenção por sangramento (P=0,013), reintubação orotraqueal (P<0,001) e lesão neurológica tipo I (P<0,001) como preditores independentes para óbito. Embora a manifestação de endocardite infecciosa influencie na mortalidade na análise univariada, a regressão de Cox não confirmou tal variável como preditor independente de óbito em nossa casuística. CONCLUSÃO: Idade e complicações perioperatórias destacam-se como preditores de mortalidade hospitalar em população brasileira. Cirurgia valvar em vigência de infecção ativa não se confirma como preditor independente de óbito nesta casuística.