An international matched cohort study of the contribution of metabolic impairments to subclinical atherosclerosis in United Kingdom and Jamaican African-Caribbeans

Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 (PCSK9) locus have been reported to have 15% lower low-density lipoprotein (LDL) cholesterol (C) levels and 47% lower coronary heart disease (CHD) risk. Our objective was to examine two PCSK9 single nucleotide polymorphisms (SNPs), R46L and E670G, in 5783 elderly participants in Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), of whom 43% had a history of vascular disease at baseline, and who were randomized to pravastatin or placebo with followup. In this population 3.5% were carriers of the T allele at R46L, and these subjects had significantly (p < 0.001) lower levels of LDL C (mean, −10%), no difference in LDL C lowering response to pravastatin, and a non-significant 19% unadjusted and 9% adjusted decreased risk of vascular disease at baseline, with no on trial effect. Moreover, 6.0% were carriers of the G allele at E670G with no significant relationships with baseline LDL C, response to pravastatin, or vascular disease risk being observed. Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C, but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease.     

Activation of NADPH oxidase during progression of cardiac hypertrophy to failure

Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular (LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy, NADPH-dependent O2- production in LV homogenates, measured by lucigenin (5 micro mol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by approximately 40% at the stage of LV decompensation; P<0.05). O2- production was fully inhibited by diphenyleneiodonium (100 micromol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22(phox), gp91(phox), p67(phox), and p47(phox) in the LV hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and endothelial cells. In parallel with the increase in O2- production, there was a significant increase in activation of extracellular signal-regulated kinase 1/2, extracellular signal-regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes such as the activation of redox-sensitive kinases and progression to heart failure.     

Pathophysiology of coronary thrombosis: role of plaque rupture and plaque erosion

Coronary artery disease is the leading cause of death in much of the western world. Atherosclerotic plaques in the coronary arteries contribute to luminal obstruction leading to myocardial ischemia; however, abrupt coronary artery occlusion most frequently results from superimposition of a thrombus on a disrupted plaque, leading to the most serious clinical manifestations of coronary artery disease, ie, unstable angina, acute myocardial infarction, and sudden death. Plaque that have undergone disruption and, by inference, plaques at risk for disruption (vulnerable plaques), tend to demonstrate outward vessel remodeling, contain a large lipid core, thinned out fibrous cap, reduced collagen content, and increased inflammatory cell infiltration. Plaque stabilization through change in plaque composition may be responsible for reduced frequency of acute vaso-occlusive events observed with lipid and other risk-factor modifying interventions.     

Can a Patient use an App at Home to Measure Knee Range of Motion? Utilizing a Mobile App,Curovate, to Improve Access and Adherence to Knee Range of Motion Measurements

IntroductionKnee range of motion is a critical measure of progress after knee injury and knee surgery. However, many patients do not understand the importance of knee range of motion and most do not have a way to self-monitor their knee range of motion at home. The patient being able to measure their own range of motion can provide improved access to this critical health metric, and could improve adherence with their daily knee range of motion exercises. The purpose of this technical report is to determine if a mobile app, Curovate, can provide reliable measures of knee range of motion compared to standard goniometric measurements.ProceduresThere were four positions of knee flexion and four positions of knee extension each measured twice with a standard goniometer and four different mobile devices with the app Curovate. The reliability and validity of the Curovate app was tested across mobile devices and operating systems and compare to goniometric knee range of motion measurements. A total of 80 measurements were taken. All testing was completed on a healthy 23-year-old male with no knee pathology.ResultsA strong positive correlation, Pearson’s r > = 0.9985, for all positions of knee flexion and extension across all four mobile devices as well as each mobile device compared to standard goniometric measurements.ConclusionsThis article presents a unique method for patients to measure their knee range of motion using the mobile app Curovate. Overall, the mobile app, Curovate, was found to have a strong positive correlation across four mobile devices with varying operating systems and compared to goniometric measurements.Level of evidence4     

Effects of COVID-19 Pandemic Response on Service Provision for Sexually Transmitted Infections,HIV, and Viral Hepatitis,England

Since the coronavirus disease pandemic response began in March 2020, tests, vaccinations, diagnoses, and treatment initiations for sexual health, HIV, and viral hepatitis in England have declined. The shift towards online and outreach services happened rapidly during 2020 and highlights the need to evaluate the effects of these strategies on health inequalities.     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

Upregulated phospholipase D2 expression and activity is related to the metastatic properties of melanoma

The incidence rates of melanoma have increased steadily in recent decades and nearly 25% of the patients diagnosed with early-stage melanoma will eventually develop metastasis, for which there is currently no fully effective treatment. The link between phospholipases and tumors has been studied extensively, particularly in breast and colon cancers. With the aim of finding new biomarkers and therapeutic options for melanoma, the expression of different phospholipases was assessed in 17 distinct cell lines in the present study, demonstrating that phospholipase D2 (PLD2) is upregulated in metastatic melanoma as compared to normal skin melanocytes. These results were corroborated by immunofluorescence and lipase activity assays. Upregulation of PLD2 expression and increased lipase activity were observed in metastatic melanoma relative to normal skin melanocytes. So far, the implication of PLD2 activity in melanoma malignancies has remained elusive. To the best of our knowledge, the present study was the first to demonstrate that the overexpression of PLD2 enhances lipase activity, and its effect to increase the proliferation, migration and invasion capacity of melanoma cells was assessed with XTT and Transwell assays. In addition, silencing of PLD2 in melanoma cells reduced the metastatic potential of these cells. The present study provided evidence that PLD2 is involved in melanoma malignancy and in particular, in its metastatic potential, and established a basis for future studies evaluating PLD2 blockade as a therapeutic strategy to manage this condition.     

Finite Element Analysis of the Ballistic Impact on Auxetic Sandwich Composite Human Body Armor

In this study, the ballistic impact behavior of auxetic sandwich composite human body armor was analyzed using finite element analysis. The auxetic core of the armor was composed of discrete re-entrant unit cells. The sandwich armor structure consisted of a front panel of aluminum alloy (Al 7075-T6), UHMWPE (sandwich core), and a back facet of silicon carbide (SiC) bonded together with epoxy resin. Numerical simulations were run on Explicit Dynamics/Autodyne 3-D code. Various projectile velocities with the same boundary conditions were used to predict the auxetic armor response. These results were compared with those of conventional monolithic body armor. The results showed improved indentation resistance with the auxetic armor. Deformation in auxetic armor was observed greater for each of the cases when compared to the monolithic armor, due to higher energy absorption. The elastic energy dissipation results in the lower indentation in an auxetic armor. The armor can be used safely up to 400 m/s; being used at higher velocities significantly reduced the threat level. Conversely, the conventional monolithic modal does not allow the projectile to pass through at a velocity below 300 m/s; however, the back face becomes severely damaged at 200 m/s. At a velocity of 400 m/s, the front facet of auxetic armor was destroyed; however, the back facet was completely safe, while the monolithic panel did not withstand this velocity and was completely damaged. The results are encouraging in terms of resistance offered by the newly adopted auxetic armor compared to conventional monolithic armor.