Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial

Aim: We assessed the management and outcomes of non-ST segment elevation myocardial infarction (NSTEMI) patients randomly assigned to fractional flow reserve (FFR)-guided management or angiography-guided standard care. Methods and results: We conducted a prospective, multicentre, parallel group, 1 : 1 randomized, controlled trial in 350 NSTEMI patients with ≥ coronary stenosis ≥30% of the lumen diameter assessed visually (threshold for FFR measurement) (NCT01764334). Enrolment took place in six UK hospitals from October 2011 to May 2013. Fractional flow reserve was disclosed to the operator in the FFR-guided group (n = 176). Fractional flow reserve was measured but not disclosed in the angiography-guided group (n = 174). Fractional flow reserve ≤0.80 was an indication for revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The median (IQR) time from the index episode of myocardial ischaemia to angiography was 3 (2, 5) days. For the primary outcome, the proportion of patients treated initially by medical therapy was higher in the FFR-guided group than in the angiography-guided group [40 (22.7%) vs. 23 (13.2%), difference 95% (95% CI: 1.4%, 17.7%), P = 0.022]. Fractional flow reserve disclosure resulted in a change in treatment between medical therapy, PCI or CABG in 38 (21.6%) patients. At 12 months, revascularization remained lower in the FFR-guided group [79.0 vs. 86.8%, difference 7.8% (−0.2%, 15.8%), P = 0.054]. There were no statistically significant differences in health outcomes and quality of life between the groups. Conclusion: In NSTEMI patients, angiography-guided management was associated with higher rates of coronary revascularization compared with FFR-guided management. A larger trial is necessary to assess health outcomes and cost-effectiveness

Genome-wide transcriptome and physiological analyses provide new insights into peanut drought response mechanisms

Drought is one of the main constraints in peanut production in West Texas and eastern New Mexico regions due to the depletion of groundwater. A multi-seasonal phenotypic analysis of 10 peanut genotypes revealed C76-16 (C-76) and Valencia-C (Val-C) as the best and poor performers under deficit irrigation (DI) in West Texas, respectively. In order to decipher transcriptome changes under DI, RNAseq was performed in C-76 and Val-C. Approximately 369 million raw reads were generated from 12 different libraries of two genotypes subjected to fully irrigated (FI) and DI conditions, of which ~329 million (90.2%) filtered reads were mapped to the diploid ancestors of peanut. The transcriptome analysis detected 4,508 differentially expressed genes (DEGs), 1554 genes encoding transcription factors (TFs) and a total of 514 single nucleotide polymorphisms (SNPs) among the identified DEGs. The comparative analysis between the two genotypes revealed higher and integral tolerance in C-76 through activation of key genes involved in ABA and sucrose metabolic pathways. Interestingly, one SNP from the gene coding F-box protein (Araip.3WN1Q) and another SNP from gene coding for the lipid transfer protein (Aradu.03ENG) showed polymorphism in selected contrasting genotypes. These SNPs after further validation may be useful for performing early generation selection for selecting drought responsive genotypes

Inhomogeneous magnetism in single crystalline Sr3_3CuIrO6+δ_{6+\delta}: Implications to phase-separation concepts

The single crystalline form of an insulator, Sr$_3$CuIrO$_{6+\delta}$, is shown to exhibit unexpectedly more than one magnetic transition (at 5 and 19 K) with spin-glass-like magnetic susceptibility behaviour. On the basis of this finding, viz., inhomogeneous magnetism in a chemically homogeneous material, we propose that the idea of "phase- separation" described for manganites [1] is more widespread in different ways. The observed experimental features enable us to make a comparison with the predictions of a recent toy model [2] on {\it magnetic} phase separation in an insulating environment.Comment: 4 pages, 4 figure

Toll-Like Receptors 2 and 4 Regulate the Frequency of IFNγ-Producing CD4+ T-Cells during Pulmonary Infection with Chlamydia pneumoniae

TLR2 and TLR4 are crucial for recognition of Chlamydia pneumoniae in vivo, since infected TLR2/4 double-deficient mice are unable to control the infection as evidenced by severe loss of body weight and progressive lethal pneumonia. Unexpectedly, these mice display higher pulmonary levels of the protective cytokine IFNγ than wild type mice. We show here, that antigen-specific CD4+ T-cells are responsible for the observed IFNγ-secretion in vivo and their frequency is higher in TLR2/4 double-deficient than in wild type mice. The capacity of TLR2/4 double-deficient dendritic cells to re-stimulate CD4+ T-cells did not differ from wild type dendritic cells. However, the frequency of CD4+CD25+Foxp3+ T-cells was considerably higher in wild type compared to TLR2/4 double-deficient mice and was inversely related to the number of IFNγ-secreting CD4+ effector T-cells. Despite increased IFNγ-levels, at least one IFNγ-mediated response, protective NO-secretion, could not be induced in the absence of TLR2 and 4. In summary, CD4+CD25+Foxp3+ regulatory T-cells fail to expand in the absence of TLR2 and TLR4 during pulmonary infection with C. pneumoniae, which in turn enhances the frequency of CD4+IFNγ+ effector T-cells. Failure of IFNγ to induce NO in TLR2/4 double-deficient cells represents one possible mechanism why TLR2/4 double-deficient mice are unable to control pneumonia caused by C. pneumoniae and succumb to the infection

Genome-wide transcriptome and physiological analyses provide new insights into peanut drought response mechanisms

Drought is one of the main constraints in peanut production in West Texas and eastern New Mexico regions due to the depletion of groundwater. A multi-seasonal phenotypic analysis of 10 peanut genotypes revealed C76-16 (C-76) and Valencia-C (Val-C) as the best and poor performers under deficit irrigation (DI) in West Texas, respectively. In order to decipher transcriptome changes under DI, RNAseq was performed in C-76 and Val-C. Approximately 369 million raw reads were generated from 12 different libraries of two genotypes subjected to fully irrigated (FI) and DI conditions, of which ~329 million (90.2%) filtered reads were mapped to the diploid ancestors of peanut. The transcriptome analysis detected 4,508 differentially expressed genes (DEGs), 1554 genes encoding transcription factors (TFs) and a total of 514 single nucleotide polymorphisms (SNPs) among the identified DEGs. The comparative analysis between the two genotypes revealed higher and integral tolerance in C-76 through activation of key genes involved in ABA and sucrose metabolic pathways. Interestingly, one SNP from the gene coding F-box protein (Araip.3WN1Q) and another SNP from gene coding for the lipid transfer protein (Aradu.03ENG) showed polymorphism in selected contrasting genotypes. These SNPs after further validation may be useful for performing early generation selection for selecting drought-responsive genotypes

Multivariable regression analysis in Schistosoma mansoni-infected individuals in the Sudan reveals unique immunoepidemiological profiles in uninfected, egg+ and non-egg+ infected individuals

Background: In the Sudan, Schistosoma mansoni infections are a major cause of morbidity in schoolaged children and infection rates are associated with available clean water sources. During infection, immune responses pass through a Th1 followed by Th2 and Treg phases and patterns can relate to different stages of infection or immunity. Methodology: This retrospective study evaluated immunoepidemiological aspects in 234 individuals(range 4–85 years old) from Kassala and Khartoum states in 2011. Systemic immune profiles(cytokines and immunoglobulins) and epidemiological parameters were surveyed in n = 110 persons presenting patent S. mansoni infections (egg+), n = 63 individuals positive for S. mansoni via PCR in sera but egg negative (SmPCR+) and n = 61 people who were infection-free (Sm uninf). Immunoepidemiological findings were further investigated using two binary multivariable regression analysis. Principal Findings: Nearly all egg+ individuals had no access to latrines and over 90% obtained water via the canal stemming from the Atbara River. With regards to age, infection and an egg+ status was linked to young and adolescent groups. In terms of immunology, S. mansoni infection per se was strongly associated with increased SEA-specific IgG4 but not IgE levels. IL-6, IL-13 and IL-10 were significantly elevated in patently-infected individuals and positively correlated with egg load. In contrast, IL-2 and IL-1β were significantly lower in SmPCR+ individuals when compared to Sm uninf and egg+ groups which was further confirmed during multivariate regression analysis. Conclusions/Significance: Schistosomiasis remains an important public health problem in the Sudan with a high number of patent individuals. In addition, SmPCR diagnostics revealed another cohort of infected individuals with a unique immunological profile and provides an avenue for future studies on non-patent infection states. Future studies should investigate the downstream signalling pathways/mechanisms of IL-2 and IL-1β as potential diagnostic markers in order to distinguish patent from non-patent individuals

Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown</p> <p>Methods</p> <p>To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-β.</p> <p>Results</p> <p>The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-β and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. <it>In vitro</it>, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25^hiCD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-β to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation.</p> <p>Conclusion</p> <p>In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.</p

Regulatory and Activated T Cells in Human Schistosoma haematobium Infections

Acquired immunity against helminths is characterised by a complex interplay between the effector Th1 and Th2 immune responses and it slowly manifests with age as a result of cumulative exposure to parasite antigens. Data from experimental models suggest that immunity is also influenced by regulatory T cells (Treg), but as yet studies on Treg in human schistosome infections are limited