Cardiac Sarcoidosis Birnie, David H., MD, MBChB; Nery, Pablo B., MD; Ha, Andrew C., MD ...
Journal of the American College of Cardiology,
07/2016, Volume:
68, Issue:
4
Journal Article
Peer reviewed
Open access
Abstract Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ...ventricular arrhythmias, and heart failure. An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease). In 2014, the first international guideline for the diagnosis and management of CS was published. In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis. There is controversy in published reports as to the outcome of patients with clinically silent CS. Despite a paucity of data, immunosuppression therapy (primarily with corticosteroids) has been advocated for the treatment of clinically manifest CS. Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease.
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC)
. Targeted therapies are approved for ...patients with 'classical' mutations and a small number of other mutations
. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown
. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a ...protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pah
PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake. In healthy Cynomolgus monkeys, we found that SYNB1618 inhibited increases in serum Phe after an oral Phe dietary challenge. In mice and primates, Phe was converted to trans-cinnamate by SYNB1618, quantitatively metabolized by the host to hippurate and excreted in the urine, acting as a predictive biomarker for strain activity. SYNB1618 was detectable in murine or primate feces after a single oral dose, permitting the evaluation of pharmacodynamic properties. Our results define a strategy for translation of live bacterial therapeutics to treat metabolic disorders.
The Tibetan Plateau is the highest and one of the most demanding environments ever inhabited by humans. We investigated the timing and mechanisms of its initial colonization at the Nwya Devu site, ...located nearly 4600 meters above sea level. This site, dating from 40,000 to 30,000 years ago, is the highest Paleolithic archaeological site yet identified globally. Nwya Devu has yielded an abundant blade tool assemblage, indicating hitherto-unknown capacities for the survival of modern humans who camped in this environment. This site deepens the history of the peopling of the "roof of the world" and the antiquity of human high-altitude occupations more generally.
In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition ...Examination Survey (NHANES) 1988-1994. Our goal was to determine the NAFLD prevalence in the recent 1999-2012 NHANES, risk factors for advanced fibrosis (stage 3-4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93-5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality.
The retrospective forecast skill of three coupled climate models (NCEP CFS, GFDL CM2.1, and CAWCR POAMA 1.5) and their multi-model ensemble (MME) is evaluated, focusing on the Northern Hemisphere ...(NH) summer upper-tropospheric circulation along with surface temperature and precipitation for the 25-year period of 1981–2005. The seasonal prediction skill for the NH 200-hPa geopotential height basically comes from the coupled models’ ability in predicting the first two empirical orthogonal function (EOF) modes of interannual variability, because the models cannot replicate the residual higher modes. The first two leading EOF modes of the summer 200-hPa circulation account for about 84% (35.4%) of the total variability over the NH tropics (extratropics) and offer a hint of realizable potential predictability. The MME is able to predict both spatial and temporal characteristics of the first EOF mode (EOF1) even at a 5-month lead (January initial condition) with a pattern correlation coefficient (PCC) skill of 0.96 and a temporal correlation coefficient (TCC) skill of 0.62. This long-lead predictability of the EOF1 comes mainly from the prolonged impacts of El Niño-Southern Oscillation (ENSO) as the EOF1 tends to occur during the summer after the mature phase of ENSO. The second EOF mode (EOF2), on the other hand, is related to the developing ENSO and also the interdecadal variability of the sea surface temperature over the North Pacific and North Atlantic Ocean. The MME also captures the EOF2 at a 5-month lead with a PCC skill of 0.87 and a TCC skill of 0.67, but these skills are mainly obtained from the zonally symmetric component of the EOF2, not the prominent wavelike structure, the so-called circumglobal teleconnection (CGT) pattern. In both observation and the 1-month lead MME prediction, the first two leading modes are accompanied by significant rainfall and surface air temperature anomalies in the continental regions of the NH extratropics. The MME’s success in predicting the EOF1 (EOF2) is likely to lead to a better prediction of JJA precipitation anomalies over East Asia and the North Pacific (central and southern Europe and western North America).
Dietary surveys suggest that many older, community-dwelling adults consume insufficient dietary protein, which may contribute to the age-related loss of lean mass (LM).
The objective of the study was ...to determine the association between dietary protein and changes in total LM and nonbone appendicular LM (aLM) in older, community-dwelling men and women.
Dietary protein intake was assessed by using an interviewer-administered 108-item food-frequency questionnaire in men and women aged 70–79 y who were participating in the Health, Aging, and Body Composition study (n = 2066). Changes in LM and aLM over 3 y were measured by using dual-energy X-ray absorptiometry. The association between protein intake and 3-y changes in LM and aLM was examined by using multiple linear regression analysis adjusted for potential confounders.
After adjustment for potential confounders, energy-adjusted protein intake was associated with 3-y changes in LM β (SE): 8.76 (3.00), P = 0.004 and aLM β (SE): 5.31 (1.64), P = 0.001. Participants in the highest quintile of protein intake lost ≈40% less LM and aLM than did those in the lowest quintile of protein intake (x̄ ± SE: −0.501 ± 0.106 kg compared with −0.883 ± 0.104 kg for LM; −0.400 ± 0.058 kg compared with −0.661 ± 0.057 kg for aLM; P for trend < 0.01). The associations were attenuated slightly after adjustment for change in fat mass, but the results remained significant.
Dietary protein may be a modifiable risk factor for sarcopenia in older adults and should be studied further to determine its effects on preserving LM in this population.
A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS), which produces nitric oxide ...(NO) from l‐arginine. Overexpressed or dysregulated iNOS has been implicated in numerous pathologies including sepsis, cancer, neurodegeneration, and various types of pain. Extensive knowledge has been accumulated about the roles iNOS plays in different tissues and organs. Additionally, X‐ray crystal and cryogenic electron microscopy structures have shed new insights on the structure and regulation of this enzyme. Many potent iNOS inhibitors with high selectivity over related NOS isoforms, neuronal NOS, and endothelial NOS, have been discovered, and these drugs have shown promise in animal models of endotoxemia, inflammatory and neuropathic pain, arthritis, and other disorders. A major issue in iNOS inhibitor development is that promising results in animal studies have not translated to humans; there are no iNOS inhibitors approved for human use. In addition to assay limitations, both the dual modalities of iNOS and NO in disease states (ie, protective vs harmful effects) and the different roles and localizations of NOS isoforms create challenges for therapeutic intervention. This review summarizes the structure, function, and regulation of iNOS, with focus on the development of iNOS inhibitors (historical and recent). A better understanding of iNOS’ complex functions is necessary before specific drug candidates can be identified for classical indications such as sepsis, heart failure, and pain; however, newer promising indications for iNOS inhibition, such as depression, neurodegenerative disorders, and epilepsy, have been discovered.
Enterococcus faecalis is a facultative anaerobic gram-positive commensal bacterium common in the gastrointestinal tract of animals and humans. This study aimed to investigate the protective effects ...of heat-killed E. faecalis EF-2001 (EF-2001) on acute gastric ulcer using a murine model of ethanol (EtOH)-induced acute gastric injury. EF-2001 (20, 40, and 80 mg/kg/day) was administered by oral gavage for 5 days before EtOH treatment (10 mL/kg body weight). EF-2001 effectively attenuated EtOH-induced gastric mucosal injury with reduced gastric mucosal ulcer and histological damage score. Pretreatment of EF-2001 markedly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs; ERK1/2, JNK, and p38MAPK). In addition, EF-2001 significantly inhibited phosphorylation of nuclear factor kappa B (NF-κB) and subsequently suppressed the upregulation of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor alpha, interleukin 1 beta, and interleukin 6 in gastric tissues. Taken together, these results suggest that EF-2001 exerts a gastroprotective effect against acute gastric injury, and the underlying mechanism might be associated with the suppression of MAPKs and NF-κB signaling and consequent reduction of pro-inflammatory mediators or cytokines.
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