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Chagas cardiomyopathy is caused by Trypanosoma cruzi ( Tc ). We identified two candidate antigens (TcG2 and TcG4) that elicit antibodies and T cell responses in naturally infected diverse hosts. In this study, we cloned TcG2 and TcG4 in a nanovector and evaluated whether nano-immunotherapy (referred as nano2/4) offers resistance to chronic Chagas disease. For this, C57BL/6 mice were infected with Tc and given nano2/4 at 21 and 42 days post-infection (pi). Non-infected, infected, and infected mice treated with pcDNA3.1 expression plasmid encoding TcG2/TcG4 (referred as p2/4) were used as controls. All mice responded to Tc infection with expansion and functional activation of splenic lymphocytes. Flow cytometry showed that frequency of splenic, poly-functional CD4 + and CD8 + T cells expressing interferon-γ, perforin, and granzyme B were increased by immunotherapy ( Tc. nano2/4 > Tc. p2/4) and associated with 88%-99.7% decline in cardiac and skeletal (SK) tissue levels of parasite burden ( Tc. nano2/4 > Tc. p2/4) in Chagas mice. Subsequently, Tc. nano2/4 mice exhibited a significant decline in peripheral and tissues levels of oxidative stress (e.g., 4-hydroxynonenal, protein carbonyls) and inflammatory infiltrate that otherwise were pronounced in Chagas mice. Further, nano2/4 therapy was effective in controlling the tissue infiltration of pro-fibrotic macrophages and established a balanced environment controlling the expression of collagens, metalloproteinases, and other markers of cardiomyopathy and improving the expression of Myh7 (encodes β myosin heavy chain) and Gsk3b (encodes glycogen synthase kinase 3) required for maintaining cardiac contractility in Chagas heart. We conclude that nano2/4 enhances the systemic T cell immunity that improves the host's ability to control chronic parasite persistence and Chagas cardiomyopathy.

The effect of hemodynamic optimization in critically ill patients has been challenged in recent years. The aim of the meta-analysis was to evaluate if a protocolized intervention based on the result of hemodynamic monitoring reduces mortality in critically ill patients. We performed a systematic review and meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions. The study was registered in the PROSPERO database (CRD42015019539). Randomized controlled trials published in English, reporting studies on adult patients treated in an intensive care unit, emergency department or equivalent level of care were included. Interventions had to be protocolized and based on results from hemodynamic measurements, defined as cardiac output, stroke volume, stroke volume variation, oxygen delivery, and central venous-or mixed venous oxygenation. The control group had to be treated without any structured intervention based on the parameters mentioned above, however, monitoring by central venous pressure measurements was allowed. Out of 998 screened papers, thirteen met the inclusion criteria. A total of 3323 patients were enrolled in the six trials with low risk of bias (ROB). The mortality was 22.4% (374/1671 patients) in the intervention group and 22.9% (378/1652 patients) in the control group, OR 0.94 with a 95% CI of 0.73-1.22. We found no statistically significant reduction in mortality from hemodynamic optimization using hemodynamic monitoring in combination with a structured algorithm. The number of high quality trials evaluating the effect of protocolized hemodynamic management directed towards a meaningful treatment goal in critically ill patients in comparison to standard of care treatment is too low to prove or exclude a reduction in mortality.

Much is known about the prevalence and correlates of dating violence, especially the perpetration of physical dating violence, among older adolescents. However, relatively little is known about the prevalence and correlates of the perpetration of cyber dating abuse, particularly among early adolescents. In this study, using a predominantly ethnic-minority sample of sixth graders who reported ever having had a boyfriend/girlfriend (n = 424, 44.2 % female), almost 15 % reported perpetrating cyber dating abuse at least once during their lifetime. Furthermore, using a cross-sectional design, across multiple levels of the socio-ecological model, the individual-level factors of (a) norms for violence for boys against girls, (b) having a current boyfriend/girlfriend, and (c) participation in bullying perpetration were correlates of the perpetration of cyber dating abuse. Collectively, the findings suggest that dating violence interventions targeting these particular correlates in early adolescents are warranted. Future studies are needed to establish causation and to further investigate the relative importance of correlates of the perpetration of cyber dating abuse among early adolescents that have been reported among older adolescents.

Purpose: Obesity is characterised by chronic, low-grade systemic inflammation. Elevated FeNO levels reflect airway inflammation in various lung diseases including asthma., Methods: This is a cross-sectional analysis of data from NHANES 2007-2010. Participants younger than 20 years old with history of cough/cold symptoms in the past 7 days, smoking, exercise in the previous hour, consumption of nitric oxide rich meats/vegetables, or use of inhaled corticosteroids during the previous 2 days were excluded. BMI (in kg/m 2 ) was divided in to 4 categories: underweight (UW) (0-18.5), Normal (N) (≥18.5 to <25), Overweight (OW) (≥25 and <30) and Obese (O) ≥30., Results: There were a total of 149,629,652 weighted participants: UW (22,235,218), N (45,021,536), OW (5,1670,522) and O (50,199,974); 50.36% were men and 49.63% were women. The mean age increased with BMI category [p<.0001]. Mean FeNO levels (in ppb) increased with increasing BMI category: UW (12.52±1.05) N (16.25±0.64), OW (16.62±0.34), and O (16.78±0.39) [p=0.0035]. FEV1/FVC (%) decreased with increasing BMI category: UW (80.68) compared to N (78.51), OW (77.67) and O (78.72) [p=0.0014]. There is a weak yet statistically significant correlation between FeNO levels and both age, BMI. Multivariate analysis predicting FeNO based on BMI category, adjusting for age, gender, race and airway obstruction found age less than 60 years, male gender, certain races and UW BMI category were associated with statistically significantly lower FeNO levels., Conclusions: Older age and male gender are associated with increased FeNO levels. Controlling for age, gender, and race, obese individuals have a statistically significantly higher FENO than underweight individuals., (Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Glucocorticoids (GC) are a frontline therapy for numerous acute and chronic diseases because of their demonstrated efficacy at reducing systemic inflammation. An unintended side effect of GC therapy is the stimulation of skeletal muscle atrophy. Pathophysiological mechanisms responsible for GC-induced skeletal muscle atrophy have been extensively investigated, and the ability to treat patients with GC without unintended muscle atrophy has yet to be realized. We have reported that a single, standard-of-care dose of Methylprednisolone increases in vivo expression of NF-κB-inducing kinase (NIK), an important upstream regulatory kinase controlling NF-κB activation, along with other key muscle catabolic regulators such as Atrogin-1 and MuRF1 that induce skeletal muscle proteolysis. Here, we provide experimental evidence that overexpressing NIK by intramuscular injection of recombinant human NIK via adenoviral vector in mouse tibialis anterior muscle induces a 30% decrease in the average fiber cross-sectional area that is associated with increases in mRNA expression of skeletal muscle atrophy biomarkers MuRF1, Atrogin-1, myostatin and Gadd45. A single injection of GC induced NIK mRNA and protein within 2 h, with the increased NIK localized to nuclear and sarcolemmal locations within muscle fibers. Daily GC injections induced skeletal muscle fore limb weakness as early as 3 days with similar atrophy of muscle fibers as observed with NIK overexpression. NIK overexpression in primary human skeletal muscle myotubes increased skeletal muscle atrophy biomarkers, while NIK knockdown significantly attenuated GC-induced increases in NIK and Atrogin-1. These results suggest that NIK may be a novel, previously unrecognized mediator of GC-induced skeletal muscle atrophy., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Unlabelled: Bacterial type IV coupling proteins (T4CPs) bind and mediate the delivery of DNA substrates through associated type IV secretion systems (T4SSs). T4CPs consist of a transmembrane domain, a conserved nucleotide-binding domain (NBD), and a sequence-variable helical bundle called the all-alpha domain (AAD). In the T4CP structural prototype, plasmid R388-encoded TrwB, the NBD assembles as a homohexamer resembling RecA and DNA ring helicases, and the AAD, which sits at the channel entrance of the homohexamer, is structurally similar to N-terminal domain 1 of recombinase XerD. Here, we defined the contributions of AADs from the Agrobacterium tumefaciens VirD4 and Enterococcus faecalis PcfC T4CPs to DNA substrate binding. AAD deletions abolished DNA transfer, whereas production of the AAD in otherwise wild-type donor strains diminished the transfer of cognate but not heterologous substrates. Reciprocal swaps of AADs between PcfC and VirD4 abolished the transfer of cognate DNA substrates, although strikingly, the VirD4-AADPcfC chimera (VirD4 with the PcfC AAD) supported the transfer of a mobilizable plasmid. Purified AADs from both T4CPs bound DNA substrates without sequence preference but specifically bound cognate processing proteins required for cleavage at origin-of-transfer sequences. The soluble domains of VirD4 and PcfC lacking their AADs neither exerted negative dominance in vivo nor specifically bound cognate processing proteins in vitro. Our findings support a model in which the T4CP AADs contribute to DNA substrate selection through binding of associated processing proteins. Furthermore, MOBQ plasmids have evolved a docking mechanism that bypasses the AAD substrate discrimination checkpoint, which might account for their capacity to promiscuously transfer through many different T4SSs., Importance: For conjugative transfer of mobile DNA elements, members of the VirD4/TraG/TrwB receptor superfamily bind cognate DNA substrates through mechanisms that are largely undefined. Here, we supply genetic and biochemical evidence that a helical bundle, designated the all-alpha domain (AAD), of T4SS receptors functions as a substrate specificity determinant. We show that AADs from two substrate receptors, Agrobacterium tumefaciens VirD4 and Enterococcus faecalis PcfC, bind DNA without sequence or strand preference but specifically bind the cognate relaxases responsible for nicking and piloting the transferred strand through the T4SS. We propose that interactions of receptor AADs with DNA-processing factors constitute a basis for selective coupling of mobile DNA elements with type IV secretion channels., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Malignant brain tumors are among the most lethal of human tumors, with limited treatment options currently available. A complex array of recurrent genetic and epigenetic changes has been observed in gliomas that collectively result in derangements of common cell signaling pathways controlling cell survival, proliferation, and invasion. One important determinant of gene expression is DNA methylation status, and emerging studies have revealed the importance of a recently identified demethylation pathway involving 5-hydroxymethylcytosine (5hmC). Diminished levels of the modified base 5hmC is a uniform finding in glioma cell lines and patient samples, suggesting a common defect in epigenetic reprogramming. Within the tumor microenvironment, infiltrating immune cells increase oxidative DNA damage, likely promoting both genetic and epigenetic changes that occur during glioma evolution. In this environment, glioma cells are selected that utilize multiple metabolic changes, including changes in the metabolism of the amino acids glutamate, tryptophan, and arginine. Whereas altered metabolism can promote the destruction of normal tissues, glioma cells exploit these changes to promote tumor cell survival and to suppress adaptive immune responses. Further understanding of these metabolic changes could reveal new strategies that would selectively disadvantage tumor cells and redirect host antitumor responses toward eradication of these lethal tumors.

Gouty arthritis is an inflammatory condition associated with debilitating clinical symptoms, functional impairments, and a substantial impact on quality of life. This condition is initially triggered by the deposition of monosodium urate crystals into the joint space. This causes an inflammatory cascade resulting in the secretion of several proinflammatory cytokines and neutrophil recruitment into the joint. While generally effective, currently available agents are associated with a number of adverse events and contraindications that complicate their use. Based on our increased understanding of the inflammatory pathogenesis of gouty arthritis, several new agents are under development that may provide increased efficacy and reduced toxicity.

Objective: The objective of this study was to determine if the continued use of vitamin A in a nursery utilizing early surfactant and nasal continuous positive airway pressure (CPAP) was warranted., Study Design: A retrospective, cohort study of appropriately sized, preterm neonates weighing ≤1000 g at birth was conducted. Two time periods were compared: Pre-Vitamin A was composed of extremely low birth weight who were routinely cared for with early nasal CPAP (n = 76); and Post-Vitamin A (n = 102) consisted of ELBWs who were cared for similar to Pre-Vitamin A, but with the addition of vitamin A. Outcome variables included the incidence of BPD and other pulmonary and major neonatal morbidities., Results: Between Pre-Vitamin A and Post-Vitamin A the incidence of moderate to severe BPD decreased by 11%, from 33% to 22% (p = 0.2). No difference was found in the number of ventilator days or in the incidence of any other neonatal morbidity or mortality, including intraventricular hemorrhage, necrotizing enterocolitis, or patent ductus arteriosus requiring surgical ligation., Conclusion: In a neonatal unit utilizing early surfactant followed by nasal CPAP at delivery, supplementing extremely premature neonates with vitamin A demonstrated a trend towards a decrease in the incidence of moderate to severe BPD; however, this change requires a larger sample to verify in the future.

Differentiation of chronic pancreatitis and pancreatic carcinoma can be a clinical and radiologic dilemma. Several patients with chronic pancreatitis can undergo unnecessary major abdominal surgery for benign lesions. This pictorial review illustrates the computed tomographic findings and histopathologic features of lesions mimicking pancreatic neoplasm in patients with chronic pancreatitis. Several benign lesions can simulate pancreatic malignancy in patients with chronic pancreatitis. Knowledge of the computed tomographic appearance of these benign entities is important to prevent unnecessary surgeries.

Diffuse alveolar damage (DAD) is the histologic correlate of most patients with adult respiratory distress syndrome (ARDS). It is a relatively straight forward diagnosis and the main differential diagnosis clinically is acute pneumonia and histologically is bronchiolitis obliterans and organizing pneumonia (BOOP). The histologic progression of DAD includes 3 phases (exudative, proliferative, and fibrotic) that correlate with the time rather than its specific cause. The factors that govern which patients will do well and which will develop a fulminant course is not known.

Purpose: Both ATV and SL reduce myocardial infarct size (IS) by enhancing expression and activity of NOS isoforms. We investigated whether atorvastatin (ATV) and sildenafil (SL) have synergistic effects on myocardial infarct size (IS) reduction and enhancing nitric oxide synthase (NOS) expression., Method: Rats were randomized to nine groups: ATV-1 (1 mg/kg/d); ATV-10 (10 mg/kg/d); SL-0.7 (0.7 mg/kg); SL-1 (1 mg/kg); ATV-1 + SL-0.7; water alone (controls); 1400W (iNOS inhibitor; 1 mg/kg); ATV-10 + 1400W; and ATV-1 + SL-0.7 + 1400W. ATV was administered orally for 3 days. SL was administered intraperitoneally 18 h before surgery and 1400W intravenously 15 min before surgery. Rats either underwent 30 min ischemia-4 h reperfusion or the hearts were explanted for immunoblotting and enzyme activity tests without being exposed to ischemia., Results: IS (% risk area, mean +/- SEM) was smaller in the ATV-10 (13 +/- 1%), SL-1 (11 +/- 2%), SL-0.7 (18 +/- 2%) and ATV-1 + SL-0.7 (9 +/- 1%) groups as compared with controls (34 +/- 3%; P < 0.001), whereas ATV-1 had no effect (29 +/- 2%). ATV-1 + SL-0.7 (9 +/- 1%) reduced IS more than SL-0.7 alone (p = 0.012). 1400W abrogated the protective effect of ATV-10 (35 +/- 3%) and ATV-1 + SL-0.7 (34 +/- 1%). SL-0.7 and ATV-10 increased phosphorylated endothelial (P-eNOS; 210 +/- 2.5% and 220 +/- 8%) and inducible (iNOS; 151 +/- 1% and 154 +/- 1%) NOS expression, whereas ATV-1 did not. These changes were significantly enhanced by ATV-1 + SL-0.7 (P-eNOS, 256 +/- 2%, iNOS 195 +/- 1%). SL-1 increased P-eNOS (311 +/- 22%) and iNOS (185 +/- 1%) concentrations., Conclusions: Combining low-dose ATV with SL augments the IS limiting effects through enhanced P-eNOS and iNOS expression.

Erectile dysfunction (ED) is increasingly considered as one manifestation of systemic vascular disease. Accordingly, ED and coronary artery disease share mutual risk factors and frequently coexist. Sexual health is an important aspect of our patients' lives, and ED is a common concern of the cardiovascular patient. Despite this, sexual function is under-addressed in the cardiac patient. Even when this topic is broached by the primary care physician or urologist, ED frequently remains untreated due to safety concerns involving cardiac disease and other comorbidities. This article describes our experience with this unique patient population, as well as our approach to building a multidisciplinary clinic designed to specifically address the important issue of ED in the cardiac patient.

Chronic heart failure (HF) is an increasingly common cardiovascular disorder. The goal of health-care providers is to optimize quality of life in this population, including sexual health. Up to 75% of patients with HF report erectile dysfunction (ED). As HF is a condition with distinct physiologic sequelae, some unique organic and psychological factors contributing to ED in this patient population have been identified, along with risk factors common to the development of coronary artery disease, HF and ED. This review describes contributing factors to ED in the setting of HF and highlights treatment considerations for this distinct patient population.

Erectile dysfunction (ED) is a highly prevalent and increasingly common, mainly vascular disorder. Most patients with chronic cardiovascular diseases experience decreased libido and frequency of sexual activity, as well as ED. Some unique organic and psychological factors contributing to ED have been identified in patients with underlying cardiovascular problems. Certain risk factors are common to the development of coronary artery disease, heart failure and ED, including diabetes mellitus, hypertension, smoking and dyslipidemia. Additionally, the use of medications such as beta blockers, digoxin and thiazide diuretics might eventually cause but more likely worsen sexual dysfunction. These unintended consequences can lead to medical noncompliance in misguided efforts to retain satisfactory sexual activity, and thereby worsen cardiovascular problems. Accordingly, it is important for physicians dealing with patients with cardiovascular diseases to address sexual concerns in their patients. After careful evaluation, most patients with stable cardiac disorders can resume sexual activity and/or can be treated for ED.

This study describes gene expression in the fetus hearts obtained from mouse model for phenylketonuria. These hearts have cardiovascular disease (CVD). Therefore genes involved in CVD were examined. Several genes associated with heart development and inflammation were found to be altered. In order to investigate whether the abnormal gene expression alters transcription and translation, the levels of troponin mRNA and protein were determined. One step real time RT-PCR showed a reduction in cardiac troponin I, troponin T2 and ryanodine receptor 2. Determination of troponin I and T protein levels showed reduced levels of these proteins. Our results suggest that altered gene expression affects protein production. These changes are likely involved in the cardiovascular defects seen in the mouse.

Background: Phaeohyphomycosis refers to infections caused by phaeoid fungi that can have an aggressive course in normal hosts. Involvement of the central nervous system may occur with a generally poor outcome. Clinical report and literature review: We report a case of Bipolaris sp. brain abscess in an immunologically competent host. We also review all previous cases of cerebral phaeohyphomycosis in normal hosts reported in the literature to date., Conclusions: Central nervous system phaeohyphomycosis remains an unusual disease; however, its incidence has been increasing in recent years. The prognosis of this condition is still poor, despite medical and surgical interventions. Aggressive diagnostic approaches and careful interpretation of cultures might modify the natural history of this disease.