Early myocardial damage and microvascular dysfunction in asymptomatic patients with systemic sclerosis: A cardiovascular magnetic resonance study with cold pressor test

Purpose: Cardiac involvement in Systemic Sclerosis (SSc) is increasingly recognized as a mayor cause of morbidity and mortality. The aim of present study is to investigate the early stages of cardiac involvement in SSc by Cardiovascular magnetic resonance (CMR), combining the non-invasive detection of myocardial inflammation and fibrosis using T2 and T1 mapping techniques and the assessment of microcirculatory impairment through perfusion response to cold pressor test (CPT). Methods: 40 SSc patients (30 females, mean age: 42.1 years) without cardiac symptoms and 10 controls underwent CMR at 1.5 T unit. CMR protocol included: native and contrast-enhanced T1 mapping, T2 mapping, T2-weighted, cineMR and late gadolinium enhancement (LGE) imaging. Microvascular function was evaluated by comparing myocardial blood flow (MBF) on perfusion imaging acquired at rest and after CPT. Native myocardial T1 and T2 relaxation times, extracellular volume fraction (ECV), T2 signal intensity ratio, biventricular volumes and LGE were assessed in each patient. Results: SSc patients had significantly higher mean myocardial T1 (1029±32ms vs. 985±18ms, p<0.01), ECV (30.1±4.3% vs. 26.7±2.4%, p<0.05) and T2 (50.1±2.8ms vs. 47±1.5ms, p<0.01) values compared with controls. No significant differences were found between absolute MBF values at rest and after CPT; whereas lower MBF variation after CPT was observed in SSc patients (+33 ± 14% vs. +44 ± 12%, p<0.01). MBF variation had inverse correlation with native T1 values (r: -0.32, p<0.05), but not with ECV. Conclusions: Myocardial involvement in SSc at preclinical stage increases native T1, T2 and ECV values, reflecting inflammation and fibrosis, and reduces vasodilatory response to CPT, as expression of microvascular dysfunction

Operations of and Future Plans for the Pierre Auger Observatory

Technical reports on operations and features of the Pierre Auger Observatory, including ongoing and planned enhancements and the status of the future northern hemisphere portion of the Observatory. Contributions to the 31st International Cosmic Ray Conference, Lodz, Poland, July 2009.Comment: Contributions to the 31st ICRC, Lodz, Poland, July 200

Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

MotivationMultiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.ResultsWe performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementationDatasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary informationSupplementary data are available at Bioinformatics online

Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis

Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia

Oxidative stress and immunologic responses following a dietary exposure to PAHs in Mya arenaria

<p>Abstract</p> <p>Background</p> <p>The aim of this research was to investigate oxidative stress and immune responses following a dietary polycyclic aromatic hydrocarbon (PAH) exposure in a marine bioindicator organism, the soft shell clam, <it>Mya arenaria</it>. Immune parameters in hemolymph (haemocyte number, efficiency of phagocytosis and haemocyte activity) and assessment of oxidative stress using catalase (CAT) activity and levels of malondialdehyde (MDA) performed on the digestive gland were estimated as biomarkers in clams fed in mesocosm with PAH contaminated phytoplankton. MDA levels and CAT activities were also measured <it>in situ </it>in organisms sampled in a control site (Metis Beach, Québec, Canada) as well as organisms sampled in a site receiving domestic effluents (Pointe-au-Père, Québec, Canada), to assess effects of abiotic variables related to seasonal variations and mixed contamination on the selected parameters.</p> <p>Results</p> <p>Results on immune parameters suggest that the PAHs may interfere with the maturation and/or differentiation processes of haemocytes. MDA results showed that lipid peroxidation did not occur following the exposure. The levels of CAT activity corresponded to weak antioxidant activity (no significant differences). Recovery was noted for all the immune endpoints at the end of the experiment.</p> <p>Conclusion</p> <p>Results suggest that immune parameters are early biomarkers that can efficiently detect a physiological change during a short term exposure to low concentrations of PAHs. The <it>in situ </it>survey (in the natural environment) suggested that clams from the Pointe-au-Père site did not show any oxidative stress as well as the clams contaminated in mesocosm, probably due to the low concentrations of PAHs used for this study. MDA levels increased however in organisms from Metis Beach, a response probably related to domestic effluents or parasitism.</p

Risk factors of one year increment of coronary calcifications and survival in hemodialysis patients

<p>Abstract</p> <p>Background</p> <p>Heart and coronary calcifications in hemodialysis patients are of very common occurrence and linked to cardiovascular events and mortality. Several studies have been published with similar results. Most of them were mainly cross-sectional and some of the prospective protocols were aimed to evaluate the results of the control of altered biochemical parameters of mineral disturbances with special regard to serum calcium, phosphate and CaxP with the use of calcium containing and calcium free phosphate chelating agents. The aim of the present study was to evaluate in hemodialysis patients classic and some non classic risk factors as predictors of calcification changes after one year and to evaluate the impact of progression on survival.</p> <p>Methods</p> <p>81 patients on hemodialysis were studied, with a wide age range and HD vintage. Several classic parameters and some less classic risk factors were studied like fetuin-A, CRP, 25-OHD and leptin. Calcifications, as Agatston scores, were evaluated with Multislice CT basally and after 12-18 months.</p> <p>Results</p> <p>Coronary artery calcifications were observed in 71 of 81 patients. Non parametric correlations between Agatston scores and Age, HD Age, PTH and CRP were significant. Delta increments of Agatston scores correlated also with serum calcium, CaxP, Fetuin-A, triglycerides and serum albumin. Logistic regression analysis showed Age, PTH and serum calcium as important predictors of Delta Agatston scores. LN transformation of the not normally distributed variables restricted the significant correlations to Age, BMI and CRP. Considering the Delta Agatston scores as dependent, significant predictors were Age, PTH and HDL. A strong association was found between basal calcification scores and Delta increment at one year. By logistic analysis, the one year increments in Agatston scores were found to be predictors of mortality. Diabetic and hypertensive patients have significantly higher Delta scores.</p> <p>Conclusions</p> <p>Progression of calcification is of common occurrence, with special regard to elevated basal scores, and is predictive of survival. Higher predictive value of survival is linked to the one year increment of calcification scores. Some classic and non classic risk factors play an important role in progression. Some of them could be controlled with appropriate management with possible improvement of mortality.</p

Temporal bacterial and metabolic development of the preterm gut reveals specific signatures in health and disease

Background - The preterm microbiome is crucial to gut health and may contribute to necrotising enterocolitis (NEC), which represents the most significant pathology affecting preterm infants. From a cohort of 318 infants, <32 weeks gestation, we selected 7 infants who developed NEC (defined rigorously) and 28 matched controls. We performed detailed temporal bacterial (n = 641) and metabolomic (n = 75) profiling of the gut microbiome throughout the disease. Results - A core community of Klebsiella, Escherichia, Staphyloccocus, and Enterococcus was present in all samples. Gut microbiota profiles grouped into six distinct clusters, termed preterm gut community types (PGCTs). Each PGCT reflected dominance by the core operational taxonomic units (OTUs), except of PGCT 6, which had high diversity and was dominant in bifidobacteria. While PGCTs 1–5 were present in infants prior to NEC diagnosis, PGCT 6 was comprised exclusively of healthy samples. NEC infants had significantly more PGCT transitions prior to diagnosis. Metabolomic profiling identified significant pathways associated with NEC onset, with metabolites involved in linoleate metabolism significantly associated with NEC diagnosis. Notably, metabolites associated with NEC were the lowest in PGCT 6. Conclusions - This is the first study to integrate sequence and metabolomic stool analysis in preterm neonates, demonstrating that NEC does not have a uniform microbial signature. However, a diverse gut microbiome with a high abundance of bifidobacteria may protect preterm infants from disease. These results may inform biomarker development and improve understanding of gut-mediated mechanisms of NEC

Perspectives of Portuguese People with Physical Disabilities Regarding Their Sexual Health: A Focus Group Study

The World Health Organization has considered sexual health as a major dimension of global health and a sexual right. However, the sexual health of people with physical disabilities is still poorly addressed by health and social care professionals, and it is very stigmatized by society. This study aimed to assess the perspectives of Portuguese people living with physical disabilities regarding issues affecting their sexual health. Nine women and 17 men with different physical disabilities participated in the study. Participants were recruited from a professional rehabilitation facility located in the North of Portugal and were assigned to four groups in one-hour sessions. Three main categories emerged from the content analysis: (1) meanings and beliefs regarding sexuality; (2) experiences of sexuality; (3) necessary changes. Despite the positive social changes towards sexuality, participants expressed that their sexual rights are still unfulfilled, as they live in a context that perpetuates their dependency. They pointed out low self-esteem, prejudice and social isolation, poor architectural accessibility and scarcity of financial support as some of the barriers to their lives and their sexual health. Finally, participants identified the main needs regarding their sexual health, such as: access to specialized information; training for health professionals. This study gives voice to people with physical disabilities and sheds light into both individual and contextual factors affecting their sexual health. Of utmost importance, this study draws attention to the need for reinforcing sexuality of people with disabilities in the social agenda and brings implications for future research and practice.This study was supported by a Grant attributed to the first author by the Portuguese Foundation for Science and Technology (SFRH/BD/112168/2015)info:eu-repo/semantics/publishedVersio