Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

It is poorly understood why there is greater cardiovascular disease risk associated with the apolipoprotein E4 (apoE) allele vs. apoE3, and also greater risk with the LRP8/apolipoprotein E receptor 2 (ApoER2) variant ApoER2-R952Q. Little is known about the function of the apoE–ApoER2 tandem outside of the central nervous system. We now report that in endothelial cells apoE3 binding to ApoER2 stimulates endothelial NO synthase (eNOS) and endothelial cell migration, and it also attenuates monocyte–endothelial cell adhesion. However, apoE4 does not stimulate eNOS or endothelial cell migration or dampen cell adhesion, and alternatively it selectively antagonizes apoE3/ApoER2 actions. The contrasting endothelial actions of apoE4 vs. apoE3 require the N-terminal to C-terminal interaction in apoE4 that distinguishes it structurally from apoE3. Reconstitution experiments further reveal that ApoER2-R952Q is a loss-of-function variant of the receptor in endothelium. Carotid artery reendothelialization is decreased in ApoER2^−/− mice, and whereas adenoviral-driven apoE3 expression in wild-type mice has no effect, apoE4 impairs reendothelialization. Moreover, in a model of neointima formation invoked by carotid artery endothelial denudation, ApoER2^−/− mice display exaggerated neointima development. Thus, the apoE3/ApoER2 tandem promotes endothelial NO production, endothelial repair, and endothelial anti-inflammatory properties, and it prevents neointima formation. In contrast, apoE4 and ApoER2-R952Q display dominant-negative action and loss of function, respectively. Thus, genetic variants of apoE and ApoER2 impact cardiovascular health by differentially modulating endothelial function.Cardiovascular disease risk is modified by common genetic variants of apolipoprotein E (apoE) and its receptor apolipoprotein E receptor 2 (ApoER2), which is a member of the LDL receptor family. Compared with the most common allele apoE3, individuals with the apoE4 allele have an increased risk of atherosclerosis and coronary heart disease (1, 2). The LRP8 gene, which encodes ApoER2, is a major gene locus for premature atherosclerosis and acute myocardial infarction identified in four independent human populations. In particular, homozygous carriers of the ApoER2-R952Q variant have a twofold increased risk of these conditions (3–5). ApoER2-R952Q also has an additive effect with apoE4, with the combined genotype QQ/E4 showing a 3.9-fold greater susceptibility to cardiovascular disease (5). ApoER2 polymorphism-associated risk is independent of cholesterol levels (3–5), and although apoE4 may impact LDL abundance (2), there is also evidence that apoE4-associated risk goes well beyond changes in lipoprotein status (6–9). Whereas there is considerable understanding of the biology of the apoE–ApoER2 tandem in the central nervous system and in Alzheimer’s disease (10), the basis for the cardiovascular impact of the receptor and apoE variants remains unclear.Our prior work demonstrated that ApoER2 is expressed in endothelial cells, where it plays a critical role in the pathogenesis of the antiphospholipid syndrome (APS) (11). The receptor is enriched in caveolae/lipid rafts in which signaling molecules regulating endothelial NOS (eNOS) are compartmentalized (12, 13). We now know that in APS, antiphospholipid antibody recognition of the cell surface protein β2-GPI on endothelial cells promotes β2-GPI dimerization and interaction with the extracellular domain of ApoER2, causing the activation of PP2A and eNOS antagonism. The resulting decrease in bioavailable NO underlies APS-related thrombosis (11). However, the normal function of the receptor in endothelium, and whether and how it modulates apoE actions on endothelium, are unknown.In addition to regulating thrombogenesis, eNOS-derived NO plays a major role in cardiovascular protection via promotion of the integrity of the endothelial cell monolayer and attenuation of endothelial cell–leukocyte adhesion (13). Recognizing that eNOS enzymatic activity is both positively and negatively modulated by signaling molecules in endothelial caveolae/lipid rafts (14), to better understand the biology of ApoER2 in endothelium we hypothesized that apoE3 binding to the receptor activates eNOS. Experiments were performed in cell culture and in mice to test this hypothesis and to determine whether genetic variants in apoE or ApoER2 disrupt this process and thereby adversely impact endothelial function.     

Correction: A clinical and computational study on anti-obesity effects of hydroxycitric acid

Correction for ‘A clinical and computational study on anti-obesity effects of hydroxycitric acid’ by Manu Tomar et al., RSC Adv., 2019, 9, 18578–18588.

The authors regret that the name of one of the authors (Raghavendra Pralhada Rao) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Epidemiology,clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.     

A multi-institutional comparison of mitoxantrone,etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.     

Emergency endoscopic variceal band ligation in a COVID-19 patient presented with hematemesis while on mechanical ventilation

COVID-19, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), is now a global pandemic with serious health consequences. Currently, many strict control measures are applied in health care settings, including endoscopy units, in order to limit virus spread. Several recommendations called to limit endoscopic procedures to emergent endoscopies; however, several uncertainties still exist concerning patient safety, protective measures, and infection control methods in emergency endoscopic settings. In this case report, we present a case of successful endoscopic band ligation for bleeding esophageal varices in man with COVID-19 disease who presented with an acute attack of hematemesis while on mechanical ventilation (MV). Esophago-gastroduodenoscopy was performed in the ICU room after preparing the setting, and revealed large, risky esophageal varices. Endoscopic band ligation was done with successful control of bleeding. Third-level measures of medical protection were applied for the participating medical personnel, and patient monitoring was maintained all through the procedure. After the procedure, the bleeding stopped, and the patient was vitally stable and conscious. We conclude that emergency endoscopic interventions could be performed safely with appropriate arrangements in patients with confirmed COVID-19 on MV.     

Sustained release and enhanced oral bioavailability of rivaroxaban by PLGA nanoparticles with no food effect

Journal of Thrombosis and Thrombolysis - The purpose of the currents study was to enhance bioavailability of rivaroxaban (RXB) and reduce the food effect. RXB loaded PLGA nanoparticles...     

Perspectives of physicians practicing in low and middle income countries towards generic medicines: A narrative review

Objectives

This review was conducted to document published literature related to physicians’ knowledge, attitudes, and perceptions of generic medicines in low- and middle-income countries (LMICs) and to compare the findings with high-income countries.

Methods

A systematic search of articles published in peer-reviewed journals from January 2001 to February 2013 was performed. The search comprised nine electronic databases. The search strategy involved using Boolean operators for combinations of the following terms: generic medicines, generic medications, generic drugs, generic, generic substitution, generic prescribing, international non-proprietary, prescribers, doctors, general practitioners, physicians, and specialists.

Results

Sixteen articles were included in this review. The majority (n = 11) were from high income countries and five from LMICs. The main difference between high income countries and LMICs is that physicians from high income countries generally have positive views whereas those from LMICs tend to have mixed views regarding generic medicines. Few similarities were identified among different country income groups namely low level of physicians’ knowledge of the basis of bioequivalence testing, cost of generic medicines as an encouraging factor for generic medicine prescribing, physicians’ concerns towards safety and quality of generic medicines and effect of pharmaceutical sales representative on generic medicine prescribing.

Conclusion

The present literature review revealed that physicians from LMICs tend to have mixed views regarding generic medicines. This may be due to differences in the health care system and pharmaceutical funding system, medicine policies, the level of educational interventions, and drug information sources in countries of different income levels.     

Langzeitresultate nach arthroskopischem SLAP-Repair

Introduction

The increasing number of surgically treated superior labrum anterior to posterior (SLAP) lesions in the past decade calls for an investigation of the long-term clinical results and assessment of possible predictive factors that could have an influence on the postoperative outcome.

Patients and methods

Out of 77 patients 60 were treated surgically with arthroscopic SLAP repair. Of these 78?% of the patients were available at final follow-up and the mean duration of follow-up was 57.7 months (range 26?94 months). All patients were followed up clinically by evaluation of the Constant-Murley (CMS), Rowe (RS) and the subjective shoulder value (SSV) scores. Patients were subdivided according to age at time of surgery, concomitant rotator cuff pathology, existing isolated SLAP lesions, existing accompanying injury, etiology of injury and pre-existing cartilage lesion at the time of surgery.

Results

The median age and gender-adjusted CMS was 89?% (range 38–106?%). The average functionality of the operated shoulder in SSV was 90?% and 87?% of patients were very satisfied or satisfied with the clinical outcome. Both the age and generally accompanying lesions and in particular partial lesions of the rotator cuff had no effect on the postoperative outcome. Pre-existing cartilage lesions resulted in significantly lower functionality of the shoulder as part of the SSV (p?=?0.0221).Both absolute and age and gender-related CMS (p?=?0.0104) and SSV (p?=?0.0418) were significantly higher in the posttraumatic group than the group with degenerative etiology.

Discussion

Clinical results after arthroscopic repair of SLAP lesions are stable in an average long-term of approximately 5 years. The degenerative and recurrent microtraumatic etiology and pre-existing cartilage damage can be predictive factors for a worse postoperative outcome.     

Management of high-energy tibial plateau fractures by Ilizarov external fixator

Background

Despite the evolution of surgical techniques and implants, high energy tibial plateau fractures remain a challenging problem. The goals of treatment are to obtain a well-aligned stable joint with a painless functional range of motion and prevention of posttraumatic arthritis. Indirect reduction techniques and other soft tissue preservation methods safeguard the vascularity and emphasize restoring both joint congruity and the mechanical axis of the limb. The aim of this study was to evaluate the clinical outcome of using Ilizarov external fixator in the treatment of Schatzker type V–VI tibial plateau fracture.

Methods

This study was done during the period 2009–2011 for the treatment of 30 patients with high energy tibial plateau fractures (Schatzker type V in 17 and type VI in 13 patients) by Ilizarov external fixator. The mean age was 36 years .There were 23 males. The right limb was affected in 17 patients. There were 10 open fractures and other associated injuries in 9 patients.

Results

The mean of follow up period was 18 months. All the fractures were united in an average time of 15 weeks. There were pin track infection in 20 patients and other few complications in 8 patients. According to knee society score, there was an excellent result in 16.7 %, good in 60 %, fair in 20 %, and poor in 3.3 %.

Conclusion

Ilizarov external fixation is a safe and effective treatment option for high energy tibial plateau fractures with good functional results.