Effect of saroglitazar in South Indian patients with diabetic dyslipidemia uncontrolled on a moderate-intensity statin and the association of PPAR α and γ gene polymorphisms with its response

Background: Diabetic dyslipidemia is associated with atherosclerosis risk factors and cardiovascular disease. Saroglitazar is a dual PPAR α and γ agonist approved initially for diabetic dyslipidemia and later for managing non-alcoholic steatohepatitis and hyperglycemia in T2DM. This study was conducted to estimate the association of studied PPAR α and γ gene polymorphisms among patients with diabetic dyslipidemia at baseline and with triglyceride response to saroglitazar administration. Methods: A total of 54 diabetic dyslipidemia patients who are not controlled i.e., triglycerides (TG)>200 mg/dl with moderate intensity of atorvastatin (≥10 mg) were recruited to the study. All the patients were given saroglitazar 4 mg once daily for 12 weeks. PPARα single nucleotide polymorphisms (SNPs) rs1800206, rs4253778, rs135542 and those of PPARγ gene rs3856806, rs10865710, rs1805192 were genotyped by real-time PCR. Results: 54 patients (67% female) with a mean age of 48.01±6.73 years were given saroglitazar 4 mg once daily for 12 weeks. There was a significant decrease in TG (36.9%) from baseline of 292.33±83.81mg/dl (mean±SD) to 184.46±95.90 mg/dl (<0.001) and in HbA1c (0.66%) from baseline of 8.5% to 7.8% (<0.001). PPAR α and PPAR γ gene variants did not show any association with TG lowering response. Conclusions: Saroglitazar 4mg once daily effectively decreases the TG, non-HDL-C levels, and HbA1c with no major adverse events, and TG lowering response is not associated with the studied polymorphisms.

Artificial Intelligence approaches for predicting Harmful Algal Blooms (HABs)

This is the final version.Final Report to Department for Business, Energy and Industrial StrategyHABs can produce toxins, which accumulate in filter-feeding shellfish and intoxicate human consumers. The toxins are heat stable and so can't be destroyed by freezing and/or cooking. Under current regulations shellfish toxin monitoring is effectively retrospective: regulators sample, await results, and if the regulatory threshold is breached there is an investigation into the amount of shellfish harvested since the sample was taken, which might then result in a full-scale food chain product recall. By gathering high resolution field monitoring data using novel qPCR and lateral-flow (LF) techniques, we planned to refine and validate a computer model for predicting HABs caused by Dinophysis species. One of the aims of the project was to use the higher resolution data collected as part of the project to train the model towards a more accurate forecast in respect of breaches in the Dinophysis toxin threshold up to 6-8 weeks ahead. The model would then aid planning decisions for harvesting and will save costly recalls and protect human health (in this case from Diarrhetic Shellfish Poisoning - DSP). Other strands of the project consisted of use of a Novel monitoring tools, a qPCR for quantifying HAB cell abundance in seawater, and a Lateral Flow testing for quantifying Dinophysis toxins in shellfish, directly in the field. Field data from these novel methods will be validated by an accredited light microscopy technique which enables the cell densities to be quantified in water and by liquid chromatography with tandem mass spectrometry (LC-MS/MS) for validating the shellfish flesh test results from the field.Department for Environment, Food and Rural Affairs (DEFRA

B–N/B–H Transborylation: borane-catalysed nitrile hydroboration

The reduction of nitriles to primary amines is a useful transformation in organic synthesis, however, it often relies upon stoichiometric reagents or transition-metal catalysis. Herein, a borane-catalysed hydroboration of nitriles to give primary amines is reported. Good yields (48–95%) and chemoselectivity (e.g., ester, nitro, sulfone) were observed. DFT calculations and mechanistic studies support the proposal of a double B–N/B–H transborylation mechanism

Engaging with History after Macpherson

The Race Relations Amendment Act (2000) identifies a key role for education, and more specifically history, in promoting ‘race equality’ in Britain. In this article Ian Grosvenor and Kevin Myers consider the extent of young people’s current engagement with the history of ‘diversity, change and immigration’ which underpins the commitment to ‘race equality’. Finding that in many of Britain’s schools and universities a singular and exclusionary version of history continues to dominate the curriculum, they go on to consider the reasons for the neglect of multiculturalism. The authors identify the development of an aggressive national identity that depends on the past for its legitimacy and argue that this sense of the past is an important obstacle to future progress

Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia

<p>Abstract</p> <p>Background</p> <p>Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E₂and PGD₂.</p> <p>Findings</p> <p>We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE₂and PGD₂without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE₂and PGD₂. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE₂and PGD₂levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE₂in non-stimulated microglia.</p> <p>Conclusion</p> <p>Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.</p

Determinants of brain swelling in pediatric and adult cerebral malaria.

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A-EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A-EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling

Coherent lensless matched filter and an application to feature extraction in character recognition

Reduction of space variance in coherent matched filtering is considered in the context of parallel character recognition. The space variance due to vignetting apertures is eliminated by synthesizing the effect of the second lens of the Vander Lugt matched filter (MT) inside the hologram. This leads to two types of lensless matched filter (LLMF) depending on the curvature of the reference beam and the relative scale of the recorded and readout signals. For a given space-bandwidth product, two layouts of recorded and readout signals are found to minimize the space variance due to the volume of the recording medium. They are well suited for line-by-line character recognition. A study of the holographic aberrations indicates for which of these layouts the space variance of the root mean square (rms) distortion is smallest. Computer-generated plots are used to investigate the space variance of the rms astigmatism of the MF and LLMF. The condition that makes the spherical aberration and coma null is also derived. Various aspects of the LLMF are examined. The LLMF acts simultaneously as a MF and a Fresnel zone plate. Therefore, when the hologram is displaced, the LLMF behavior results from the combined displacements of its filter component and lens component. In the output plane, the correlation component only is focused by the lens component. The other diffracted output components are unfocused images. They contribute noise that affects the correlation signal. In practical cases of parallel processing, the signal-to-noise ratios of the MF and LLMF at the same reference beam angle are comparable and the resolution of available recording media places no restriction on the field of view or the signals bandwidth. Improvement of the recognition performance is another concern of the thesis. It is shown experimentally that a filter matched to character features (FEMF) discriminates better between the similar looking characters O and Q than a high-pass filter matched to their high frequency components (HPMF). Yet its sensitivity to variants is not as severe as that of the EPMF when the feature extractor is a low-pass filter. Also this low-pass filtering reduces the aberrations and allows for a detector with a coarser resolution. The increased reliability of the FEMF is achieved at the expense of a reduced diffraction efficiency and of a more critical registration of the readout signal. Experimental considerations emphasize the importance of phase accuracy in the input plane. Finally, suggestions for further research are presented.Applied Science, Faculty ofElectrical and Computer Engineering, Department ofGraduat

Using the suture/adhesive strips combination technique for skin closure in an individual with Ehlers–Danlos Syndrome

Combining sutures with adhesive strips to avoid the ‘cheese-wiring’ effect in individuals with fragile skin is a method that has been described previously. Here we demonstrate its application in an individual with Ehlers-Danlos Syndrome. Keywords: Cheese-wire effect, Sutures, Ehlers-Danlos Sydrome, Steri-Strip