Multistage antiplasmodial activity of hydroxyethylamine compounds,in vitro and in vivo evaluations

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species. New therapeutics acting against the pathogenic asexual and sexual stages, including liver-stage malarial infection, have now attained more attention in achieving malaria eradication efforts. In this paper, two previously identified potent antiplasmodial hydroxyethylamine (HEA) compounds were investigated for their activity against the malaria parasite''s multiple life stages. The compounds exhibited notable activity against the artemisinin-resistant strain of P. falciparum blood-stage culture with 50% inhibitory concentrations (IC₅₀) in the low micromolar range. The compounds'' cytotoxicity on HEK293, HepG2 and Huh-7 cells exhibited selective killing activity with IC₅₀ values > 170 μM. The in vivo efficacy was studied in mice infected with P. berghei NK65, which showed a significant reduction in the blood parasite load. Notably, the compounds were active against liver-stage infection, mainly compound 1 with an IC₅₀ value of 1.89 μM. Mice infected with P. berghei sporozoites treated with compound 1 at 50 mg kg⁻¹ dose had markedly reduced liver stage infection. Moreover, both compounds prevented ookinete maturation and affected the developmental progression of gametocytes. Further, systematic in silico studies suggested both the compounds have a high affinity towards plasmepsin II with favorable pharmacological properties. Overall, the findings demonstrated that HEA and piperidine possessing compounds have immense potential in treating malarial infection by acting as multistage inhibitors.

Malaria, a global threat to the human population, remains a challenge partly due to the fast-growing drug-resistant strains of Plasmodium species.     

Online selling of wildlife part with spurious name: a serious challenge for wildlife crime enforcement

International Journal of Legal Medicine - We examined an online sold product “Hatha Jodi” synonym of “paired arm” for the confirmation of its biological source. It was...     

Nonhuman primates as models for the discovery and development of radiation countermeasures

Introduction: Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans.

Area covered: The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys.

Expert opinion: The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes for NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.     

Fibroblast growth factor 23 concentrations in humoral hypercalcemia of malignancy and hyperparathyroidism

OBJECTIVE: To determine whether fibroblast growth factor 23 (FGF 23) concentrations are increased in the serum of patients with humoral hypercalcemia of malignancy and in those with hyperparathyroidism. PATIENTS AND METHODS: Serum samples from patients with hypercalcemia and documented elevations of parathyroid hormone-related protein or parathyroid hormone levels were examined for FGF 23 concentrations. Specimens from healthy age-matched controls were evaluated to establish a reference range for FGF 23. RESULTS: Mean +/- SEM concentrations of FGF 23 were elevated in the 7 patients with humoral hypercalcemia of malignancy (385 +/- 134 relative unit [RU]/mL) compared with 11 healthy controls (43.9 +/- 5.8 RU/mL; P = .005). In the 11 patients with hyperparathyroidism, FGF 23 concentrations were increased (mean +/- SEM 86.6 +/- 228 RU/mL), but the increases were not statistically significant. The increases in FGF 23 in these disorders did not correlate with changes in serum phosphate or 1alpha,25-dihydroxyvitamin D levels. CONCLUSION: Levels of FGF 23 are elevated in patients with tumors associated with humoral hypercalcemia of malignancy. The precise cause of such elevations requires further investigation.     

The phenomenon of drop in output at larger field sizes for telecobalt units

It is known that the output factors (OPFs) for external-beam radiotherapy units increase with field size due to increased scattered radiation from the collimator system. Saturation in the OPF value is generally reported beyond approximately 30 × 30 cm². For the first time, to the best of our knowledge, we report on a drop in OPF values, although marginal, measured for a telecobalt machine beyond the 38 × 38 cm² field size. We believe that reporting and explaining the results will lead to a better understanding of the scatter composition of the radiation from telecobalt machines. This also has the potential to impact the estimation of low dose regions in patients, in addition to being a purely scientific inquiry. We used Monte Carlo (MC) simulations to validate the measured values. The MC data showed that the decrease in OPF was due to decreased scatter from the machine head.     

Association between joint hypermobility and pelvic organ prolapse in women: a systematic review and meta-analysis

Introduction and hypothesis

Abnormalities of common collagen proteins have been noted in individuals affected by POP and JHM, suggesting a common aetiology. We assessed strength, consistency and potential for bias in pooled associations of the relationship between JHM and POP.

Methods

We searched MEDLINE, EMBASE and CINAHL, as well as International Continence Society (ICS) and International Urogynaecologic Association (IUGA) annual meeting abstracts, including reference lists, without language restrictions. We included case–control and cohort studies and applied strict criteria for choosing eligible studies. Methodologically trained reviewers independently screened abstracts and full texts to confirm eligibility. We extracted data on study and patient characteristics, clinical assessment tools, and methodology. We assessed comparability and representativeness of source populations, confidence in the assessment of JHM and POP and adjustment for confounding and missing data. Meta-analysis was performed using a random effects model.

Results

We retrieved 39 full texts, of which 14 were used in the meta-analysis. Overall pooled odds ratio (OR) was 2.37 [95 % confidence interval (CI) 1.54–3.64, I²?=?77.0 %]. We identified no significant factors in meta-regression, and there was no evidence of publication bias; six studies were at high risk of bias with frequent differences in sampling frames, limited validity for clinical assessments and failure to match for important prognostic variables.

Conclusions

We found a strong association between POP and JHM, with an effect size that is clinically relevant. Our findings are limited by high heterogeneity and the potential for residual confounding factors. JHM is an important early indicator for POP risk, and future longitudinal studies should explore the shared aetiology.