Recent Developments on the Crosstalk Between STAT3 and Inflammation in Heart Function and Disease

The transcription factor STAT3 has a protective function in the heart. Until recently, the role of STAT3 in hypertension-induced cardiac hypertrophy was unsettled. Earlier studies revealed that global reduction of STAT3 activity reduced cardiac hypertrophy with hypertension, but caused a disruption of myofilaments and increased contractile dysfunction. However, newer studies with cardiomyocyte-specific deletion of STAT3 indicate that STAT3 does not cause cardiac hypertrophy with increased blood pressure. Rather, cardiac STAT3 is important for maintaining metabolic homeostasis, and loss of STAT3 in cardiomyocytes makes the heart more susceptible to chronic pathological insult, for example by disrupting glucose metabolism and protective signaling networks via the upregulation of certain microRNAs. This scenario has implications for understanding peripartum cardiomyopathy as well. In viral myocarditis, STAT3 opposes the initiation of the dilated phenotype by maintaining membrane integrity via the expression of dystrophin. STAT3 signaling was also found to attenuate myocarditis by polarizing macrophages to a less inflammatory phenotype. On the other hand, STAT3 contributes to immune-mediated myocarditis due to IL-6-induced complement component C3 production in the liver, as well as the differentiation of Th17 cells, which play a role in initiation and development of myocarditis. Besides canonical signaling pathways, unphosphorylated STAT3 (U-STAT3) and redox-activated STAT3 have been shown to couple to transcription in the heart. In addition, tissue signaling cytokines such as IL-22 and IL-17 have been proposed to have actions on the heart that involve STAT3, but are not fully defined. Understanding the novel and often protective aspects of STAT3 in the myocardium could lead to new therapeutic approaches to treat heart disease

Prevalence and determinants of antibiotic related adverse drug reactions in Kenya : spontaneously reported cases at the pharmcy and poisons board database

Background: Antibiotics are useful in the treatment and prevention of many infections. Despite this, they may cause adverse drug reactions (ADRs) which could further increase the morbidity, mortality and treatment costs. The national pharmacovigilance system of the Pharmacy and Poisons board in Kenya has a database in which all actual and suspected adverse drug reactions nationally from hospitals are reported and analysed. Objective: To describe the prevalence, characteristics, severity and outcome of antibiotic related adverse reactions between January 2010 and December 2015. Methods: This was a retrospective cross sectional study in which all case reports of the reported antibiotic related ADRs were reviewed. Information on the patient demographics, types of antibiotics and concomitant drugs used, adverse reaction reported, the severity and outcome was abstracted and analysed using STATA version 13. Bivariate analysis and logistic regression were conducted to determine the risk factors associated with severity and outcomes of antibiotic related ADRs. Ethical approval was obtained from the Kenyatta National Hospital/ University of Nairobi Research and Ethics Committee and the Pharmacy and Poisons board. Results: A total of 550 case reports were analysed. The majority of patients were female (62.3%, n=330), median age of 34 (IQR 22.0-45.0) years. The most commonly affected system was the integumentary system (60.9%, n=388), with skin rash as the most commonly reported ADR (39.7%,n=253). Cotrimoxazole contributed the majority of the adverse reactions (55.3%, n=304). Most of the reactions were mild to moderate (82.6%, n=440), leading to drug withdrawal for 79.1% (n=435). Sulphonamides and anti-TB drugs produced the most severe reactions (n=15.8%, n=84), while fatal reactions were only 1.5% (n=8). Older age was significantly associated with severity of the reported ADRs (p=0.003) while HIV status (p=0.011) and severity of the ADR (p=<0.001) were associated with poor outcomes. Causality assessment attributed 15.6% (n=86) of the ADRs to the suspected antibiotic while 56.5% (n=311) were probable. Conclusion: There is a high burden of antibiotic related ADRS, most of which are skin related. HIV status and severity of the ADRs are associated with poor outcomes, and the elderly experience more severe ADRs

Nanomechanical probing and strain tuning of the Curie temperature in suspended Cr2Ge2Te6-based heterostructures

Two-dimensional magnetic materials with strong magnetostriction are attractive systems for realizing strain-tuning of the magnetization in spintronic and nanomagnetic devices. This requires an understanding of the magneto-mechanical coupling in these materials. In this work, we suspend thin Cr2Ge2Te6 layers and their heterostructures, creating ferromagnetic nanomechanical membrane resonators. We probe their mechanical and magnetic properties as a function of temperature and strain by observing magneto-elastic signatures in the temperature-dependent resonance frequency near the Curie temperature, TC. We compensate for the negative thermal expansion coefficient of Cr2Ge2Te6 by fabricating heterostructures with thin layers of WSe2 and antiferromagnetic FePS3, which have positive thermal expansion coefficients. Thus we demonstrate the possibility of probing multiple magnetic phase transitions in a single heterostructure. Finally, we demonstrate a strain-induced enhancement of TC in a suspended Cr2Ge2Te6-based heterostructure by 2.5 ± 0.6 K by applying a strain of 0.026% via electrostatic force

The Russia-Ukraine crisis: Implications for global and regional food security and potential policy responses

This paper analyzes the implications of the Russian-Ukraine crisis on global and regional food security. We start with a global vulnerability analysis to identify most vulnerable regions and countries. The Middle East and North Africa (MENA) region is particularly vulnerable to trade shocks because of its high food import dependence. Thus, we provide descriptive evidence characterizing how food systems and policies impact vulnerability to the price shock in selected MENA countries: Egypt, Sudan, and Yemen. Within these countries, we show that the crisis will differentially impact poor and non-poor households as well as rural and urban households. Although the absolute level of food insecurity may still be higher in rural areas where larger numbers of poor households are located, urban poor are likely to suffer most because of the Russia-Ukraine crisis and associated hikes in food prices, especially in those countries where social protection and food subsidies are missing. On the policy side, we review lessons from previous food crises and identify actions needed to take (and to avoid) to protect most vulnerable countries and households in the short-term while also highlighting long-term policy options to diversify food, fertilizer and energy production and trade

An optical coherence tomography and endothelial shear stress study of a novel bioresorbable bypass graft

Endothelial shear stress (ESS) plays a key role in the clinical outcomes in native and stented segments; however, their implications in bypass grafts and especially in a synthetic biorestorative coronary artery bypass graft are yet unclear. This report aims to examine the interplay between ESS and the morphological alterations of a biorestorative coronary bypass graft in an animal model. Computational fluid dynamics (CFD) simulation derived from the fusion of angiography and optical coherence tomography (OCT) imaging was used to reconstruct data on the luminal anatomy of a bioresorbable coronary bypass graft with an endoluminal "flap" identified during OCT acquisition. The "flap" compromised the smooth lumen surface and considerably disturbed the local flow, leading to abnormally low ESS and high oscillatory shear stress (OSI) in the vicinity of the "flap". In the presence of the catheter, the flow is more stable (median OSI 0.02384 versus 0.02635, p < 0.0001; maximum OSI 0.4612 versus 0.4837). Conversely, OSI increased as the catheter was withdrawn which can potentially cause back-and-forth motions of the "flap", triggering tissue fatigue failure. CFD analysis in this report provided sophisticated physiological information that complements the anatomic assessment from imaging enabling a complete understanding of biorestorative graft pathophysiology

The PHIN photoinjector for the CTF3 Drive beam

A new photoinjector for the CTF3 drive beam has been designed and is now being constructed by a collaboration among LAL, CCLRC and CERN within PHIN, the second Joint Research Activity of CARE. The photoinjector will provide a train of 2332 pulses at 1.5 GHz with a complex timing structure (sub-trains of 212 pulses spaced from one another by 333 ps or 999 ps) to allow the frequency multiplication scheme, which is one of the features of CLIC, to be tested in CTF3. Each pulse of 2.33 nC will be emitted by a Cs2Te photocathode deposited by a co-evaporation process to allow high quantum efficiency in operation (>3% for a minimum of 40 h). The 3 GHz, 2 1/2 cell RF gun has a 2 port coupler to minimize emittance growth due to asymmetric fields, racetrack profile of the irises and two solenoids to keep the emittance at the output below 20 p.mm.mrad. The laser has to survive very high average powers both within the pulse train (15 kW) and overall (200 W before pulse slicing). Challenging targets are also for amplitude stability (<0.25% rms) and time jitter from pulse to pulse (<1ps rms). An offline test in a dedicated line is foreseen at CERN in 2007

Bleeding and thrombotic risk in pregnant women with Fontan physiology

Background/objectives Pregnancy may potentiate the inherent hypercoagulability of the Fontan circulation, thereby amplifying adverse events. This study sought to evaluate thrombosis and bleeding risk in pregnant women with a Fontan.  Methods We performed a retrospective observational cohort study across 13 international centres and recorded data on thrombotic and bleeding events, antithrombotic therapies and pre-pregnancy thrombotic risk factors.  Results We analysed 84 women with Fontan physiology undergoing 108 pregnancies, average gestation 33 +/- 5 weeks. The most common antithrombotic therapy in pregnancy was aspirin (ASA, 47 pregnancies (43.5%)). Heparin (unfractionated (UFH) or low molecular weight (LMWH)) was prescribed in 32 pregnancies (30%) and vitamin K antagonist (VKA) in 10 pregnancies (9%). Three pregnancies were complicated by thrombotic events (2.8%). Thirty-eight pregnancies (35%) were complicated by bleeding, of which 5 (13%) were severe. Most bleeds were obstetric, occurring antepartum (45%) and postpartum (42%). The use of therapeutic heparin (OR 15.6, 95% CI 1.88 to 129, p=0.006), VKA (OR 11.7, 95% CI 1.06 to 130, p=0.032) or any combination of anticoagulation medication (OR 13.0, 95% CI 1.13 to 150, p=0.032) were significantly associated with bleeding events, while ASA (OR 5.41, 95% CI 0.73 to 40.4, p=0.067) and prophylactic heparin were not (OR 4.68, 95% CI 0.488 to 44.9, p=0.096). Conclusions Current antithrombotic strategies appear effective at attenuating thrombotic risk in pregnant women with a Fontan. However, this comes with high (>30%) bleeding risk, of which 13% are life threatening. Achieving haemostatic balance is challenging in pregnant women with a Fontan, necessitating individualised risk-adjusted counselling and therapeutic approaches that are monitored during the course of pregnancy

Ultra-high resolution X-ray structures of two forms of human recombinant insulin at 100 K

The crystal structure of a commercially available form of human recombinant (HR) insulin, Insugen (I), used in the treatment of diabetes has been determined to 0.92 Å resolution using low temperature, 100 K, synchrotron X-ray data collected at 16,000 keV (λ = 0.77 Å). Refinement carried out with anisotropic displacement parameters, removal of main-chain stereochemical restraints, inclusion of H atoms in calculated positions, and 220 water molecules, converged to a final value of R = 0.1112 and Rfree = 0.1466. The structure includes what is thought to be an ordered propanol molecule (POL) only in chain D(4) and a solvated acetate molecule (ACT) coordinated to the Zn atom only in chain B(2). Possible origins and consequences of the propanol and acetate molecules are discussed. Three types of amino acid representation in the electron density are examined in detail: (i) sharp with very clearly resolved features; (ii) well resolved but clearly divided into two conformations which are well behaved in the refinement, both having high quality geometry; (iii) poor density and difficult or impossible to model. An example of type (ii) is observed for the intra-chain disulphide bridge in chain C(3) between Sγ6–Sγ11 which has two clear conformations with relative refined occupancies of 0.8 and 0.2, respectively. In contrast the corresponding S–S bridge in chain A(1) shows one clearly defined conformation. A molecular dynamics study has provided a rational explanation of this difference between chains A and C. More generally, differences in the electron density features between corresponding residues in chains A and C and chains B and D is a common observation in the Insugen (I) structure and these effects are discussed in detail. The crystal structure, also at 0.92 Å and 100 K, of a second commercially available form of human recombinant insulin, Intergen (II), deposited in the Protein Data Bank as 3W7Y which remains otherwise unpublished is compared here with the Insugen (I) structure. In the Intergen (II) structure there is no solvated propanol or acetate molecule. The electron density of Intergen (II), however, does also exhibit the three types of amino acid representations as in Insugen (I). These effects do not necessarily correspond between chains A and C or chains B and D in Intergen (II), or between corresponding residues in Insugen (I). The results of this comparison are reported