An Investigation of the Mineral in Ductile and Brittle Cortical Mouse Bone

Bone is a strong and tough material composed of apatite mineral, organic matter, and water. Changes in composition and organization of these building blocks affect bone's mechanical integrity. Skeletal disorders often affect bone's mineral phase, either by variations in the collagen or directly altering mineralization. The aim of the current study was to explore the differences in the mineral of brittle and ductile cortical bone at the mineral (nm) and tissue (µm) levels using two mouse phenotypes. Osteogenesis imperfecta model, oim^‐/‐, mice have a defect in the collagen, which leads to brittle bone; PHOSPHO1 mutants, Phospho1^‐/‐, have ductile bone resulting from altered mineralization. Oim^‐/‐ and Phospho1^‐/‐ were compared with their respective wild‐type controls. Femora were defatted and ground to powder to measure average mineral crystal size using X‐ray diffraction (XRD) and to monitor the bulk mineral to matrix ratio via thermogravimetric analysis (TGA). XRD scans were run after TGA for phase identification to assess the fractions of hydroxyapatite and β‐tricalcium phosphate. Tibiae were embedded to measure elastic properties with nanoindentation and the extent of mineralization with backscattered electron microscopy (BSE SEM). Results revealed that although both pathology models had extremely different whole‐bone mechanics, they both had smaller apatite crystals, lower bulk mineral to matrix ratio, and showed more thermal conversion to β‐tricalcium phosphate than their wild types, indicating deviations from stoichiometric hydroxyapatite in the original mineral. In contrast, the degree of mineralization of bone matrix was different for each strain: brittle oim^‐/‐ were hypermineralized, whereas ductile Phospho1^‐/‐ were hypomineralized. Despite differences in the mineralization, nanoscale alterations in the mineral were associated with reduced tissue elastic moduli in both pathologies. Results indicated that alterations from normal crystal size, composition, and structure are correlated with reduced mechanical integrity of bone. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.     

Family income trajectory during childhood is associated with adolescent cigarette smoking and alcohol use

Background

Although childhood socioeconomic disadvantage has been linked with adolescent tobacco and alcohol use in cross-sectional research, less is known about the influence of changes in socioeconomic status during childhood. Upward socioeconomic mobility may attenuate the negative influence of earlier socioeconomic disadvantage on health, while downward mobility may counter the health benefits of earlier socioeconomic advantage. This study evaluated the influence of common trajectories of family income during childhood on smoking and alcohol use during adolescence.

Methods

Data utilized were part of the 15-year longitudinal Study of Early Child Care and Youth Development. A 5-class trajectory model (two stable, one downward, and two upward income trajectories) was developed previously with this sample (N = 1356). Logistic regression analyses were conducted to determine whether children of the more disadvantaged income trajectories were more likely to engage in tobacco and alcohol use at age 15 relative to those of the most advantaged trajectory.

Results

Family income trajectory was significantly associated with ever-smoking (p = .02) and past-year alcohol use at age 15 years (p = .008). Children from the less advantaged trajectories were more likely to have ever-smoked than children of the most advantaged trajectory (all p's < .05). Children of the downwardly mobile trajectory were more likely to have used alcohol within the past year than children of the most advantaged trajectories as well as the most disadvantaged trajectory (all p's < .05).

Conclusions

Findings indicate that childhood socioeconomic disadvantage influences adolescent smoking, while downward socioeconomic mobility influences adolescent alcohol use.     

Acquired aorto-pulmonary artery fistula following proximal aortic surgery

A 56-year-old man developed left heart failure secondary to left to right shunt due to acquired aorto-pulmonary artery (PA) fistula. He had previously undergone aortic root replacement for streptococcal aortic valve endocarditis. A modified strategy involving interventional radiology and surgical technique was employed to deal with this complex surgical challenge. A balloon catheter was placed in the right PA to enable fistula occlusion during cardiopulmonary bypass followed by repair using cardiopulmonary bypass and circulatory arrest.     

Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction

Purpose

To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug–drug interaction (DDI) risk using static mechanistic models.

Methods

Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of K_I and k_inact. Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI.

Results

Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The k_inact/K_I ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent–drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected.

Conclusions

13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors.     

A Role for Extracellular Vesicles in SARS-CoV-2 Therapeutics and Prevention

Extracellular vesicles (EVs) are the common designation for ectosomes, microparticles and microvesicles serving dominant roles in intercellular communication. Both viable and dying cells release EVs to the extracellular environment for transfer of cell, immune and infectious materials. Defined morphologically as lipid bi-layered structures EVs show molecular, biochemical, distribution, and entry mechanisms similar to viruses within cells and tissues. In recent years their functional capacities have been harnessed to deliver biomolecules and drugs and immunological agents to specific cells and organs of interest or disease. Interest in EVs as putative vaccines or drug delivery vehicles are substantial. The vesicles have properties of receptors nanoassembly on their surface. EVs can interact with specific immunocytes that include antigen presenting cells (dendritic cells and other mononuclear phagocytes) to elicit immune responses or affect tissue and cellular homeostasis or disease. Due to potential advantages like biocompatibility, biodegradation and efficient immune activation, EVs have gained attraction for the development of treatment or a vaccine system against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. In this review efforts to use EVs to contain SARS CoV-2 and affect the current viral pandemic are discussed. An emphasis is made on mesenchymal stem cell derived EVs’ as a vaccine candidate delivery system.

Graphical Abstract

     

Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria.

Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.