Update on ranolazine in the management of angina.

Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome)-TIMI (Thrombolysis In Myocardial Infarction) 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost-effective due to its ability to decrease angina-related hospitalizations and improve quality of life

Natural Mycosis of Rice Brown Plant Hopper (Nilaparvata lugens Stål) in Eastern India

The studies on natural mycosis of brown planthopper(BPH) in rice ecosystem of Eastern India found that Aspergillus flavus Linkk. caused maximum mortality (20 to 30%) followed by  Aspergillus niger (Teig.) (15 to 20%), Rhizopus sp. (10-20%)and Fusarium sp. (5-20%)  .  In some cases more than one fungus was found to colonise the dead insect viz. (Rhizopus + Trichoderma) - 5 to 15%, [Aspegillus flavus Linkk. + Trichoderma sp.] – 10%, [Fusarium sp. + Trichoderma sp. + Aspergillus flavus Linkk.]-5 to 10%.  Most of the fungi infected the insect solely but only  the Trichoderma sp was not found as sole coloniser of the BPH. The data  also showed that natural mycosis were most effective in I and II instars (0-25% BPH colonised) followed by III instar (0 to 20% BPH colonised), Vth instar (10 to 15% BPH colonised), IV instar (0 to 15% BPH colonised) and winged adult (5 to 10% BPH colonised).  Association of multiple fungus species with the dead insect was low in early stages (I, II and III instar) rather than IV, V and adult.  Generally incidence of Aspergillus flavus Linkk  on BPH appeared during the second week of September to third week of November with two distinct peaks on 3rd week of September and 4th week of October respectively. The correlation studies in 2 different agro- climatic zones showed that the BPH population had a significantly negative correlation with the percent infection by fungi. .  The effect  of different formulations of this natural Mycosis in laboratory showed that % mortality was highest (16%) in Talk based followed by wettable  powder of China clay (10.60%) and were significantly higher than water suspension (8.05%).  The interaction between two factors i.e. spore (A) x base (B) was also statistically significant

Parametric uncertainty analysis of pulse wave propagation in a model of a human arterial network

Accepted versio

Defected Ground Structure toward Cross Polarization Reduction of Microstrip Patch Antenna with Improved Impedance Matching

A new approach based on the incorporation of Z-shaped defected ground structure (DGS) in microstrip antenna (MSA) for improving impedance matching and cross polarization (XP) performances is proposed in this paper. Through detail analysis of the surface current densities, and input impedance, the proposed DGS is integrated into a rectangular MSA (RMSA) to realize flat relative XP reduction of 22 dB in the H-plane around broadside angular range of ±60 degrees. Further, an equivalent circuit model (ECM) for the proposed antenna is introduced by considering the mutual coupling in between the DGS and patch and the model is verified using circuit-system-EM co-simulation software, Advanced Design System (ADS). A prototype has been fabricated and tested for the validation of simulated results and it shows good agreement with each other. The antenna operates over 2.32-2.58 GHz with good far-field radiation characteristics and a peak gain of 2.8 dBi at the resonating frequency 2.4 GHz. Hence, the proposed design can be useful for the IEEE 802.11b applications

The translation of lipid profiles to nutritional biomarkers in the study of infant metabolism

$\textbf{INTRODUCTION}$: Links between early life exposures and later health outcomes may, in part, be due to $\textit{nutritional programming}$ in infancy. This hypothesis is supported by observed long-term benefits associated with breastfeeding, such as better cognitive development in childhood, and lower risks of obesity and high blood pressure in later life. However, the possible underlying mechanisms are expected to be complex and may be difficult to disentangle due to the lack of understanding of the metabolic processes that differentiate breastfed infants compared to those receiving just formula feed. $\textbf{OBJECTIVE}$: Our aim was to investigate the relationships between infant feeding and the lipid profiles and to validate specific lipids in separate datasets so that a small set of lipids can be used as nutritional biomarkers. $\textbf{METHOD}$: We utilized a direct infusion high-resolution mass spectrometry method to analyse the lipid profiles of 3.2 mm dried blood spot samples collected at age 3 months from the Cambridge Baby Growth Study (CBGS-1), which formed the discovery cohort. For validation two sample sets were profiled: Cambridge Baby Growth Study (CBGS-2) and Pregnancy Outcome Prediction Study (POPS). Lipidomic profiles were compared between infant groups who were either exclusively breastfed, exclusively formula-fed or mixed-fed at various levels. Data analysis included supervised Random Forest method with combined classification and regression mode. Selection of lipids was based on an iterative backward elimination procedure without compromising the class error in the classification mode. $\textbf{CONCLUSION}$: From this study, we were able to identify and validate three lipids: PC(35:2), SM(36:2) and SM(39:1) that can be used collectively as biomarkers for infant nutrition during early development. These biomarkers can be used to determine whether young infants (3-6 months) are breast-fed or receive formula milk.This research was funded by MRC programme award Lipid Profiling and Signalling (number UD99999906) and Biotechnology and Biological Sciences Research Council project The validation of biomarkers of metabolic efficacy in infant nutrition (ref BB/M027252/1)

Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption

Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results: We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. Conclusion: A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat

Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption.

BACKGROUND: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. RESULTS: We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. CONCLUSION: A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non‐LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long‐chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR‐α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β‐oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium‐chain carnitines which induce competitive inhibition of the acyl‐CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β‐oxidation from HCM to AS, particularly for FAO of long‐chain fatty acids, and that the PPAR‐α signaling network may be a specific metabolic therapeutic target in AS