Absence of association between Pfnfs1 mutation and in vitro susceptibility to lumefantrine in Plasmodium falciparum.

Artemether-lumefantrine (AL) is the most widely used antimalarial drug for treating uncomplicated falciparum malaria. This study evaluated whether the K65Q mutation in the Plasmodium falciparum cysteine desulfurase IscS (Pfnfs1) gene was associated with alternated susceptibility to lumefantrine using clinical parasite samples from Ghana and the China-Myanmar border area. Parasite isolates from the China-Myanmar border had significantly higher IC50 values to lumefantrine than parasites from Ghana. In addition, the K65 allele was significantly more prevalent in the Ghanaian parasites (34.5%) than in the China-Myanmar border samples (6.8%). However, no difference was observed in the lumefantrine IC50 value between the Pfnfs1 reference K65 allele and the non reference 65Q allele in parasites from the two regions. These data suggest that the Pfnfs1 K65Q mutation may not be a reliable marker for reduced susceptibility to lumefantrine.

Neutrophil elastase: From mechanisms to therapeutic potential.

Neutrophil elastase (NE), a major protease in the primary granules of neutrophils, is involved in microbicidal activity. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process. NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling. However, NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction. Additionally, it plays a complex role in various physiological processes and mediates several diseases. Sivelestat, a specific NE inhibitor, has strong potential for clinical application, particularly in the treatment of coronavirus disease 2019 (COVID-19). This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.

In Vitro Susceptibility of Plasmodium falciparum Isolates from the China-Myanmar Border Area to Piperaquine and Association with Candidate Markers.

Plasmodium falciparum from the Greater Mekong subregion has evolved resistance to the artemisinin-based combination therapy dihydroartemisinin and the partner drug piperaquine. To monitor the potential westward spread or independent evolution of piperaquine resistance, we evaluated the in vitro susceptibility of 120 P. falciparum isolates collected at the China-Myanmar border during 2007-2016. The parasite isolates displayed a relatively wide range of piperaquine susceptibility estimates. While 56.7% of the parasites showed bimodal drug response curves, all but five generated area-under-the-curve (AUC) estimates consistent with a susceptible phenotype. Using the piperaquine survival assay (PSA), 5.6% parasites showed reduced susceptibility. Of note, parasites from 2014-2016 showed the highest AUC value and the highest proportion with a bimodal curve, suggesting falling effectiveness in these later years. Unsupervised K-mean analysis of the combined data assigned parasites into three clusters and identified significant correlations between IC50, IC90, and AUC values. No parasites carried the E415G mutation in a putative exo-nuclease, new mutations in PfCRT, or amplification of the plasmepsin 2/3 genes, suggesting mechanisms of reduced piperaquine susceptibility that differ from those described in other countries of the region. The association of increased AUC, IC50, and IC90 values with major PfK13 mutations (F446I and G533S) suggests that piperaquine resistance may evolve in these PfK13 genetic backgrounds. Additionally, the Pfmdr1 F1226Y mutation was associated with significantly higher PSA values. Further elucidation of piperaquine resistance mechanisms and continuous surveillance are warranted.

Associations of county-level cumulative environmental quality with mortality of chronic obstructive pulmonary disease and mortality of tracheal, bronchus and lung cancers.

Chronic obstructive pulmonary disease (COPD) and tracheal, bronchus, and lung (TBL) cancers are among the leading causes of mortality worldwide. Many environmental factors have been linked to COPD and TBL cancers. This study examined the associations of cumulative environmental quality indices with COPD mortality and TBL cancers mortality, respectively. Environmental Quality Index (EQI) was constructed to represent cumulative environmental quality for the overall environment and 5 major environmental domains (e.g., air, water, built). Associations of each EQI indices with COPD mortality and TBL cancers mortality, across 3109 counties in the 48 contiguous states of the US, were examined using simultaneous autoregressive (SAR) models. Stratified analyses were conducted in females versus males and according to rural-urban continuum codes (RUCC) to assess the heterogeneity across the overall population. Overall poor environmental quality was associated with a percent difference (PD) of 0.75 [95% confidence intervals (95% CI), 0.46, 1.05] in COPD mortality and an PD of 1.22 (95% CI, 0.97, 1.46) in TBL cancers mortality. PDs were higher in females than in males for both COPD and TBL cancers. The built domain had the largest effect on COPD mortality (PD, 0.85; 95% CI, 0.58, 1.12) while the air domain had the largest effect on TBL cancers mortality (PD, 1.54; 95% CI, 1.31, 1.76). The EQI-mortality associations varied among different RUCCs, but no consistent trend was found. This result suggests that poor environmental quality, particularly poor air quality and built environment quality may increase the mortality risk for COPD and that for TBL cancers. Females appear to be more susceptible to the effect of cumulative environmental quality. Our findings highlight the importance of improving overall and domain-specific cumulative environmental quality in reducing COPD and TBL cancer mortalities in the United States.

Morphological and molecular characteristics of Sarcocystis bertrami from horses and donkeys in China.

While Sarcocystis parasites from the muscles of donkey and horse have been characterized as different species, similarities between the parasites in these host raises questions about this assignment (Levine and Tadros, 1980; Matuschka, 1983; Odening et al., 1995b). To resolve this, we examined the tissue cysts of Sarcocystis collected from donkeys and horses were studied by morphological and molecular methods. Morphological studies performed by light microscopy (LM) revealed that each of two types of cysts were present in samples from each host type. Under LM, villar protrusions (VP) were sometimes observed on the larger (Type I) and smaller (Type II) of these cyst types; when present, these were sometimes short and sometimes long. By electron microscopy (EM), VPs from both horse and donkey cysts were found to share similar structures, appearing to be typical of 'type 11a' VPs found on the Sarcocystis wall of Sarcocystis fayeri as described by Dubey et al., 1977. The VP of cysts in both horses and donkeys contained microtubules extending from the villar tips to the ground substance (GS). Ovoid, osmiophilic bodies (OB) were found along the length of the microtubules within the villi, but this feature was not found in all VP. To understand the phylogeny of the parasites, a portion of the coxI gene was sequenced from 22 isolated cysts (9 from donkeys and 13 from horses). Phylogenetic relationships were reconstructed from these sequences and the closest homologues available in GenBank, revealing that all of the samples, regardless of host origin or morphological appearance under LM, grouped in one clade. Ours is the first attempt to combine morphological measurements with coxI sequences in assessing such equine parasites; the results confirm a close relationship of the parasites from horse and donkey with S. fayeri. Further, the data suggest that the cysts in each host likely belong to the same species. As the first named species was Sarcocystis bertrami, we propose S. bertrami (syn. Sarcocystis fayeri) as the descriptor for this parasite of both horses and donkeys. Ultimately, this finding will only be validated by cross-transmission infection experiments that score the ability of parasite isolates from one Equus to infect the other.

Air Pollution and Mortality in China.

Ambient air pollution has been an important environmental issue in most areas of China. This chapter summarized the mortality effects of short-term and long-term exposures to various air pollutants among Chinese population. The literature review identified sufficient information to support significant short-term mortality effects of various air pollutants from time series analyses and case-crossover studies, such as PM10, PM2.5, SO2, NO2, and O3. On the other hand, though the literature review suggested a positive effect of long-term exposure to air pollution on mortality and lung cancer risk, the evidence has been limited among Chinese population, indicating that more studies, especially cohort studies, are warranted.

Ambient PM2.5 and Stroke: Effect Modifiers and Population Attributable Risk in Six Low- and Middle-Income Countries.

BACKGROUND AND PURPOSE: Short-term exposure to ambient fine particulate pollution (PM2.5) has been linked to increased stroke. Few studies, however, have examined the effects of long-term exposure. METHODS: A total of 45 625 participants were interviewed and included in this study, the participants came from the Study on Global Ageing and Adult Health, a prospective cohort in 6 low- and middle-income countries. Ambient PM2.5 levels were estimated for participants' communities using satellite data. A multilevel logistic regression model was used to examine the association between long-term PM2.5 exposure and stroke. Potential effect modification by physical activity and consumption of fruit and vegetables was assessed. RESULTS: The odds of stroke were 1.13 (95% confidence interval, 1.04-1.22) for each 10 µg/m3 increase in PM2.5. This effect remained after adjustment for confounding factors including age, sex, smoking, and indoor air pollution (adjusted odds ratio=1.12; 95% confidence interval, 1.04-1.21). Further stratified analyses suggested that participants with higher levels of physical activity had greater odds of stroke, whereas those with higher consumption of fruit and vegetables had lower odds of stroke. These effects remained robust in sensitivity analyses. We further estimated that 6.55% (95% confidence interval, 1.97%-12.01%) of the stroke cases could be attributable to ambient PM2.5 in the study population. CONCLUSIONS: This study suggests that ambient PM2.5 may increase the risk of stroke and may be responsible for the astounding stroke burden in low- and middle-income countries. In addition, greater physical activity may enhance, whereas greater consumption of fruit and vegetables may mitigate the effect.

Disease Burden from Hepatitis B Virus Infection in Guangdong Province, China.

OBJECTIVE: To estimate the disease burden and financial burden attributed to hepatitis B virus (HBV) infection in Guangdong Province. METHODS: Based on the data of incidence, mortality and healthcare cost of HBV-related diseases and other socio-economic data in Guangdong Province, we estimated deaths, disability-adjusted life-years (DALYs) and economic cost for the three HBV-related diseases-hepatitis B, liver cirrhosis and liver cancer-in Guangdong following the procedures developed for the global burden of disease study. Then disease burden and economic cost attributed to HBV infection was estimated. RESULTS: HBV infection was estimated to have caused 33,600 (95% confidence interval (CI): 29,300-37,800) premature deaths and the loss of 583,200 (95% CI: 495,200-671,100) DALYs in Guangdong in 2005. The greatest loss of deaths and DALYs were from liver cancer. The 45-59 years age group had the greatest burden attributable to HBV infection. The estimated total annual cost of HBV-related diseases in Guangdong was RMB 10.8 (95% CI: 8.7-13.0) billion, the direct and indirect cost were RMB 2.6 (95% CI: 2.1-3.2) and 8.2 (95% CI: 6.6-9.8) billion. CONCLUSIONS: HBV infection is a great medical challenge as well as a significant economic burden to Guangdong Province. The results suggest that substantial health benefits could be gained by extending effective public health and clinical interventions to reduce HBV infection in Guangdong Province.