Trans expression of a Plasmodium falciparum histidine-rich protein II (HRPII) reveals sorting of soluble proteins in the periphery of the host erythrocyte and disrupts transport to the malarial food vacuole

The heme polymer hemozoin is produced in the food vacuole (fv) of the parasite after hemoglobin proteolysis and is the target of the drug chloroquine. A candidate heme polymerase, the histidine-rich protein II (HRPII), is proposed to be delivered to the fv by ingestion of the infected-red cell cytoplasm. Here we show that 97% of endogenous Plasmodium falciparum (Pf) HRPII (PfHRPII) is secreted as soluble protein in the periphery of the red cell and avoids endocytosis by the parasite, and 3% remains membrane-bound within the parasite. Transfected cells release 90% of a soluble transgene PfHRPIImyc into the red cell periphery and contain 10% membrane bound within the parasite. Yet these cells show a minor reduction in hemozoin production and IC(50) for chloroquine. They also show decreased transport of resident fv enzyme PfPlasmepsin I, the endoplasmic reticulum (ER) marker PfBiP, and parasite-associated HRPII to fvs. Instead, all three proteins accumulate in the ER, although there is no defect in protein export from the parasite. The data suggest that novel mechanisms of sorting (i) soluble antigens like HRPII in the red cell cytoplasm and (ii) fv-bound membrane complexes in the ER regulate parasite digestive processes.     

Alcohol as a Risk Factor for Cancer Burden: A Review

Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes in such mechanism involved are alcohol dehydrogenase, aldehyde dehydrogenase, cytochrome P450 2E1, and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver, resulting in the formation of harmful compounds (i.e., adducts) and highly reactive oxygen-containing molecules (i.e., reactive oxygen species) that can damage cell components. Approximately, worldwide 3.6 % of cancers derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, recent findings have focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Alcohol-related carcinogenesis may aggravate due to other factors such as smoking and being triggered by genetic susceptibility. Besides, the role of genetic polymorphisms of the alcohol-metabolizing enzymes could not be ruled out.     

Chromosome measurements on an XXp+ male

Summary Measurements carried out on an XX male show that there is a significant difference between the lengths of the short arm of the 2 X chromosomes of this patient and that the short arm of the longer X is also significantly different from that of the X chromosomes derived from normal individuals. The difference lies specifically in the size of the terminal band of the short arm. These results are consistent with the X-Y interchange hypothesis of Ferguson-Smith.     

Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies

Objective

To collate and evaluate the current literature reporting the prevalence and incidence of hypoglycaemia in population based studies of type 2 diabetes.

Research Design and Methods

Medline, Embase and Cochrane were searched up to February 2014 to identify population based studies reporting the proportion of people with type 2 diabetes experiencing hypoglycaemia or rate of events experienced. Two reviewers independently screened studies for eligibility and extracted data for included studies. Random effects meta-analyses were carried out to calculate the prevalence and incidence of hypoglycaemia.

Results

46 studies (n = 532,542) met the inclusion criteria. Prevalence of hypoglycaemia was 45% (95%CI 0.34,0.57) for mild/moderate and 6% (95%CI, 0.05,0.07) for severe. Incidence of hypoglycaemic episodes per person-year for mild/moderate and for severe was 19 (95%CI 0.00, 51.08) and 0.80 (95%CI 0.00,2.15), respectively. Hypoglycaemia was prevalent amongst those on insulin; for mild/moderate episodes the prevalence was 50% and incidence 23 events per person-year, and for severe episodes the prevalence was 21% and incidence 1 event per person-year. For treatment regimes that included a sulphonylurea, mild/moderate prevalence was 30% and incidence 2 events per person-year, and severe prevalence was 5% and incidence 0.01 events per person-year. A similar prevalence of 5% was found for treatment regimes that did not include sulphonylureas.

Conclusions

Current evidence shows hypoglycaemia is considerably prevalent amongst people with type 2 diabetes, particularly for those on insulin, yet still fairly common for other treatment regimens. This highlights the subsequent need for educational interventions and individualisation of therapies to reduce the risk of hypoglycaemia.     

The Effectiveness of Screening for Diabetes and Cardiovascular Disease Risk Factors in a Community Pharmacy Setting

Risk factors for cardiovascular disease including diabetes have seen a large rise in prevalence in recent years. This has prompted interest in prevention through the identifying individuals at risk of both diabetes and cardiovascular disease and has seen increased investment in screening interventions taking place in primary care. Community pharmacies have become increasingly involved in the provision of such interventions and this systematic review and meta-analysis aims to gather and analyse the existing literature assessing community pharmacy based screening for risk factors for diabetes and those with a high cardiovascular disease risk.

Methods

We conducted systematic searches of electronic databases using MeSH and free text terms from 1950 to March 2012. For our analysis two outcomes were assessed. They were the percentage of those screened who were referred for further assessment by primary care and the uptake of this referral.

Results

Sixteen studies fulfilled our inclusion criteria comprising 108,414 participants screened. There was significant heterogeneity for all included outcomes. Consequently we have not presented summary statistics and present forest plots with I² and p values to describe heterogeneity. We found that all included studies suffered from high rates of attrition between pharmacy screening and follow up. We have also identified a strong trend towards higher rates for referral in more recent studies.

Conclusions

Our results show that pharmacies are feasible sites for screening for diabetes and those at risk of cardiovascular disease. A significant number of previously unknown cases of cardiovascular disease risk factors such as hypertension, hypercholesterolemia and diabetes are identified, however a significant number of referred participants at high risk do not attend their practitioner for follow up. Research priorities should include methods of increasing uptake to follow up testing and early intervention, to maximise the efficacy of screening interventions based in community pharmacies.     

ACE/ACE2 balance might be instrumental to explain the certain comorbidities leading to severe COVID-19 cases

The outbreak of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a global catastrophe. The elderly and people with comorbidity are facing a serious complication of the disease. The entry and infection strategy of SARS-CoV-2 in a host cell is raised by an amazing way of angiotensin-converting enzyme (ACE) 2 (ACE2) receptor recognition and imbalance of ACE/ACE2 in various organs, especially in the lungs. Here it has been discussed the role of interferon and protease during the receptor recognition (begining of infection) and followed by the impact of cytokine and hypoxia in the context of the balance of ACE/ACE2. It has also very concisely delineated the biochemistry and mechanism of ACE/ACE2 balance in different stages of infection and its role in comorbidity.     

Chemically induced behavioral responses in Anopheles minimus and Anopheles harrisoni in Thailand

Behavioral responses of female mosquitoes representing two species in the Minimus Complex exposed to an operational field dose of bifenthrin or DEET (N,N-diethyl-m-toluamide) were described using an excito-repellency test system. Two test populations of An. minimus, one from the field (Tak Province, western Thailand), the other from a long-established laboratory colony, and Anopheles harrisoni collected from Kanchanaburi Province, western Thailand, were used. Results showed that all test populations rapidly escaped after direct contact with surfaces treated with either bifenthrin or DEET compared to match-paired untreated controls. Greater escape response by exposed females to bifenthrin and DEET were observed in the An. minimus colony compared to the two field populations. Field-collected An. minimus demonstrated a more rapid escape response to DEET than to bifenthrin, whereas An. harrisoni showed a converse response. Although fewer females escaped from test chambers without direct contact with treated surfaces compared to contact tests, the spatial repellency response was significantly pronounced in all test populations compared to match-paired controls (P < 0.05). DEET was found to perform as both a contact stimulant and moderate spatial repellent.     

Matrix-assisted laser desorption/ionization mass spectrometry for quantitative determination of β-blocker drugs in one-drop of human serum sample

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been applied for the quantitative determination of β-blocker drugs in one-drop of human serum samples using drop-to-drop solvent microextraction (DDSME) as a preconcentrating probe. The optimum experimental conditions for β-blocker drugs were investigated and 1.8 μL volume of toluene for 10 min extraction time with the 5% addition of NaCl under pH 11.0 was found to be the best conditions for the separation and preconcentration of drugs from 30 μL of serum sample from a patient with high blood pressure. The optimized methodologies for DDSME/MALDI-MS analyses exhibited a good linearity with intra- and inter day precision value of 8.5-10.5% and 9.4-12.6%, respectively. The proposed DDSME/MALDI-MS offers a very simple, rapid and low-cost technique for the determination of β-blocker drugs in one drop of serum sample. The reported method has been successfully applied for the determination of propranolol and nadolol in small volume of serum sample from patient suffering from high blood pressure. In future, this technique could be applied for pharmacokinetic and clinical studies.     

A Microfluidic DNA Library Preparation Platform for Next-Generation Sequencing

Next-generation sequencing (NGS) is emerging as a powerful tool for elucidating genetic information for a wide range of applications. Unfortunately, the surging popularity of NGS has not yet been accompanied by an improvement in automated techniques for preparing formatted sequencing libraries. To address this challenge, we have developed a prototype microfluidic system for preparing sequencer-ready DNA libraries for analysis by Illumina sequencing. Our system combines droplet-based digital microfluidic (DMF) sample handling with peripheral modules to create a fully-integrated, sample-in library-out platform. In this report, we use our automated system to prepare NGS libraries from samples of human and bacterial genomic DNA. E. coli libraries prepared on-device from 5 ng of total DNA yielded excellent sequence coverage over the entire bacterial genome, with >99% alignment to the reference genome, even genome coverage, and good quality scores. Furthermore, we produced a de novo assembly on a previously unsequenced multi-drug resistant Klebsiella pneumoniae strain BAA-2146 (KpnNDM). The new method described here is fast, robust, scalable, and automated. Our device for library preparation will assist in the integration of NGS technology into a wide variety of laboratories, including small research laboratories and clinical laboratories.