Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation

YesArtemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C-8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities

Gender Bias in Diagnosis, Prevention, and Treatment of Cardiovascular Diseases: A Systematic Review

Cardiovascular disease (CVDs) has been perceived as a ‘man’s disease’, and this impacted women’s referral to CVD diagnosis and treatment. This study systematically reviewed the evidence regarding gender bias in the diagnosis, prevention, and treatment of CVDs. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. We searched CINAHL, PubMed, Medline, Web of Science, British Nursing Index, Scopus, and Google Scholar. The included studies were assessed for quality using risk bias tools. Data extracted from the included studies were exported into Statistical Product and Service Solutions (SPSS, v26; IBM SPSS Statistics for Windows, Armonk, NY), where descriptive statistics were applied. A total of 19 studies were analysed. CVDs were less reported among women who either showed milder symptoms than men or had their symptoms misdiagnosed as gastrointestinal or anxiety-related symptoms. Hence, women had their risk factors under-considered by physicians (especially by male physicians). Subsequently, women were offered fewer diagnostic tests, such as coronary angiography, ergometry, electrocardiogram (ECG), and cardiac enzymes, and were referred to less to cardiologists and/or hospitalisation. Furthermore, if hospitalised, women were less likely to receive a coronary intervention. Similarly, women were prescribed cardiovascular medicines than men, with the exception of antihypertensive and anti-anginal medicines. When it comes to the perception of CVD, women considered themselves at lower risk of CVDs than men. This systematic review showed that women were offered fewer diagnostic tests for CVDs and medicines than men and that in turn influenced their disease outcomes. This could be attributed to the inadequate knowledge regarding the differences in manifestations among both genders

A comparative study of altered hemodynamics in iliac vein compression syndrome

Introduction: Iliac vein compression syndrome (IVCS) is present in over 20% of the population and is associated with left leg pain, swelling, and thrombosis. IVCS symptoms are thought to be induced by altered pelvic hemodynamics, however, there currently exists a knowledge gap on the hemodynamic differences between IVCS and healthy patients. To elucidate those differences, we carried out a patient-specific, computational modeling comparative study.Methods: Computed tomography and ultrasound velocity and area data were used to build and validate computational models for a cohort of IVCS (N = 4, Subject group) and control (N = 4, Control group) patients. Flow, cross-sectional area, and shear rate were compared between the right common iliac vein (RCIV) and left common iliac vein (LCIV) for each group and between the Subject and Control groups for the same vessel.Results: For the IVCS patients, LCIV mean shear rate was higher than RCIV mean shear rate (550 ± 103 s−1 vs. 113 ± 48 s−1, p = 0.0009). Furthermore, LCIV mean shear rate was higher in the Subject group than in the Control group (550 ± 103 s−1 vs. 75 ± 37 s−1, p = 0.0001). Lastly, the LCIV/RCIV shear rate ratio was 4.6 times greater in the Subject group than in the Control group (6.56 ± 0.9 vs. 1.43 ± 0.6, p = 0.00008).Discussion: Our analyses revealed that IVCS patients have elevated shear rates which may explain a higher thrombosis risk and suggest that their thrombus initiation process may share aspects of arterial thrombosis. We have identified hemodynamic metrics that revealed profound differences between IVCS patients and Controls, and between RCIV and LCIV in the IVCS patients. Based on these metrics, we propose that non-invasive measurement of shear rate may aid with stratification of patients with moderate compression in which treatment is highly variable. More investigation is needed to assess the prognostic value of shear rate and shear rate ratio as clinical metrics and to understand the mechanisms of thrombus formation in IVCS patients

Rethinking justice beyond human rights. Anti-colonialism and intersectionality in the politics of the Palestinian Youth Movement

This article discusses the politics of the Palestinian Youth Movement (PYM) – a contemporary social movement operating across a number of Arab and western countries. Unlike analysis on the Arab Uprisings which focused on the national dimension of youth activism, we explore how the PYM politics fosters and upholds an explicitly transnational anti-colonial and intersectional solidarity framework, which foregrounds a radical critique of conventional notions of self-determination based on state-framed human rights discourses and international law paradigms. The struggle becomes instead framed as an issue of justice, freedom and liberation from interlocking forms and hierarchies of oppression. KEYWORDS: Palestine, transnational social movements, intersectionality, human rights, anti-colonialis

Tissue transglutaminase (TG2) enables survival of human malignant pleural mesothelioma cells in hypoxia

Malignant pleural mesothelioma (MPM) is an aggressive tumor linked to environmental/occupational exposure to asbestos, characterized by the presence of significant areas of hypoxia. In this study, we firstly explored the expression and the role of transglutaminase 2 (TG2) in MPM cell adaptation to hypoxia. We demonstrated that cells derived from biphasic MPM express the full-length TG2 variant at higher levels than cells derived from epithelioid MPM and normal mesothelium. We observed a significant induction of TG2 expression and activity when cells from biphasic MPM were grown as a monolayer in chronic hypoxia or packed in spheroids, where the presence of a hypoxic core was demonstrated. We described that the hypoxic induction of TG2 was HIF-2 dependent. Importantly, TGM2-v1 silencing caused a marked and significant reduction of MPM cell viability in hypoxic conditions when compared with normoxia. Notably, a TG2-selective irreversible inhibitor that reacts with the intracellular active form of TG2, but not a non-cell-permeable inhibitor, significantly compromised cell viability in MPM spheroids. Understanding the expression and function of TG2 in the adaptation to the hypoxic environment may provide useful information for novel promising therapeutic options for MPM treatment

Impact and cost-effectiveness of a lethal house lure against malaria transmission in central Côte d'Ivoire : a two-arm, cluster-randomised controlled trial

Background: New vector control tools are required to sustain the fight against malaria. Lethal house lures, which target mosquitoes as they attempt to enter houses to blood feed, are one approach. Here we evaluated lethal house lures consisting of In2Care (Wageningen, Netherlands) Eave Tubes, which provide point-source insecticide treatments against host-seeking mosquitoes, in combination with house screening, which aims to reduce mosquito entry. Methods: We did a two-arm, cluster-randomised controlled trial with 40 village-level clusters in central Côte d'Ivoire between Sept 26, 2016, and April 10, 2019. All households received new insecticide-treated nets at universal coverage (one bednet per two people). Suitable households within the clusters assigned to the treatment group were offered screening plus Eave Tubes, with Eave Tubes treated using a 10% wettable powder formulation of the pyrethroid β-cyfluthrin. Because of the nature of the intervention, treatment could not be masked for households and field teams, but all analyses were blinded. The primary endpoint was clinical malaria incidence recorded by active case detection over 2 years in cohorts of children aged 6 months to 10 years. This trial is registered with ISRCTN, ISRCTN18145556. Findings: 3022 houses received screening plus Eave Tubes, with an average coverage of 70% across the intervention clusters. 1300 eligible children were recruited for active case detection in the control group and 1260 in the intervention group. During the 2-year follow-up period, malaria case incidence was 2·29 per child-year (95% CI 1·97–2·61) in the control group and 1·43 per child-year (1·21–1·65) in the intervention group (hazard ratio 0·62, 95% CI 0·51–0·76; p<0·0001). Cost-effectiveness simulations suggested that screening plus Eave Tubes has a 74·0% chance of representing a cost-effective intervention, compared with existing healthcare activities in Côte d'Ivoire, and is similarly cost-effective to other core vector control interventions across sub-Saharan Africa. No serious adverse events associated with the intervention were reported during follow-up. Interpretation: Screening plus Eave Tubes can provide protection against malaria in addition to the effects of insecticide-treated nets, offering potential for a new, cost-effective strategy to supplement existing vector control tools. Additional trials are needed to confirm these initial results and further optimise Eave Tubes and the lethal house lure concept to facilitate adoption. Funding: The Bill & Melinda Gates Foundation

Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage

<p>Abstract</p> <p>Background</p> <p>The adhesion of <it>Plasmodium falciparum </it>parasitized red blood cell (PRBC) to human endothelial cells (EC) induces inflammatory processes, coagulation cascades, oxidative stress and apoptosis. These pathological processes are suspected to be responsible for the blood-brain-barrier and other organs' endothelial dysfunctions observed in fatal cases of malaria. Atorvastatin, a drug that belongs to the lowering cholesterol molecule family of statins, has been shown to ameliorate endothelial functions and is widely used in patients with cardiovascular disorders.</p> <p>Methods</p> <p>The effect of this compound on PRBC induced endothelial impairments was assessed using endothelial co-culture models.</p> <p>Results</p> <p>Atorvastatin pre-treatment of EC was found to reduce the expression of adhesion molecules and <it>P. falciparum </it>cytoadherence, to protect cells against PRBC-induced apoptosis and to enhance endothelial monolayer integrity during co-incubation with parasites.</p> <p>Conclusions</p> <p>These results might suggest a potential interest use of atorvastatin as a protective treatment to interfere with the pathophysiological cascades leading to severe malaria.</p