MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study.

BACKGROUND: Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). METHODS: We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. FINDINGS: Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. INTERPRETATION: Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. FUNDING: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

Association of hTERT Gene Polymorphism and Colorectal Cancer (CRC) Risk in the Chinese Han Population.

The catalytic subunit telomerase reverse transcriptase (hTERT) is a prerequisite for malignant transformation of human cells. Colorectal cancer (CRC) is a common malignant tumor. The genetic association of hTERT gene rs2853669 and rs2736098 polymorphisms with CRC was surveyed in the Chinese population. Two hundreds patients with CRC and 200 healthy controls were taken for blood sample collection. Sanger sequencing was applied for genotyping. Multiple logistic regression analysis was performed, and odds ratio (OR) together with confidence interval (CI) were calculated to obtain the corresponding association power. Among CRC cases (49.50%), hTERT gene rs2736098 GA genotype carriers were more prevalent compared with the control group (41.00%, P = 0.035), which increased the risk of CRC by 1.576 times (95% CI, 1.031-2.409). Distribution of the rs2736098 genotypes was significantly associated with TNM stage, tumor differentiation, tumor size and lymph node metastasis (P < 0.05). The frequencies of hTERT gene rs2853669 polymorphism were not significantly different between CRC patients and healthy controls. Logistic regression analysis indicated that both body mass index (BMI) and hTERT gene rs2736098 polymorphism remained significantly correlated with CRC susceptibility. The frequencies of hTERT gene rs2853669 polymorphism did not differ significantly between CRC patients and control group (P > 0.05). The hTERT gene rs2736098 polymorphism was correlated with CRC risk in the Chinese Han population, and the GA genotype was a risk element for the onset of CRC.

The effect of advanced paternal age on the lifespan of male offspring in an ancient Chinese genealogical data set.

BACKGROUND: Advanced paternal age has been reported to be associated with a variety of short-term outcomes in offspring, but long-term effects are rarely examined. The present study evaluated the impact of advanced paternal age on offspring's longevity. METHODS: We studied the effect of paternal reproductive age on the lifespan of male offspring using a Chinese genealogy data set that spans 226 years of the Qing Dynasty (1683-1909). Multivariable-adjusted Cox regression analyses of 1274 men with survival data were used to calculate hazard ratios (HRs) of advanced parental age at reproduction. We also evaluated whether the lifespan of brothers differed when they were born to the same parents at different ages. RESULTS: In models adjusted for maternal age, advanced paternal age was negatively associated with the lifespan of male offspring. Individuals born to fathers aged >40 years had a 32 % higher HR of a lifespan shorter than those born to fathers aged 25-29 years (adjusted HR 1.320, 95 % CI: 1.066-1.634). The adjusted HR for offspring born to fathers aged 35-39 years was 1.232 (95 % CI: 1.013-1.500). Older brothers born to fathers aged 20-34 years had a significantly lower risk of a reduced lifespan compared with their younger brothers with fathers aged ≥35 years at reproduction (P < 0.01). CONCLUSION: Advanced paternal age at reproduction is a negative factor for male offspring's life expectancy. With the sustained increase in paternal age over the past generation, further investigation is warranted into the impact on birth outcomes and public health.

VDAC1 oligomerization may enhance DDP-induced hepatocyte apoptosis by exacerbating oxidative stress and mitochondrial DNA damage.

Cisplatin (DDP)-based chemotherapy is a preferred treatment for a broad spectrum of cancers, but the precise mechanisms of its hepatotoxicity are not yet clear. Recently, the role of voltage-dependent anion channel protein 1 (VDAC1) in mitochondrial activity and cell apoptosis has attracted much attention. Our aim was to investigate the effects of mitochondrial outer membrane protein VDAC1 oligomerization in DDP-induced hepatocyte apoptosis. L-02 hepatocytes were divided into 4 groups: (a) control group, (b) 4,4'diisothiocyanate-2,2'-disulfonic acid (DIDS; 40 µm) group, (c) DDP (5 µm) group, and (d) DDP and DIDS combination group. Cell apoptosis was tested by Annexin V/FITC assay, protein expression of caspase-3, γH2AX and NDUFB6 were observed by western blot assay, reactive oxygen species (ROS), and mitochondrial superoxide anion radical (O2•- ) were detected by DCFH-DA and MitoSOX probe, and DNA damage was assessed by comet assay. Moreover, the activity of mitochondrial respiratory chain complex I was determined by the colorimetry method. Compared with the control group, apoptosis rate and activated cleaved-caspase-3 protein, ROS and O2•- generation, DNA damage marker comet tail length, and γH2AX protein level increased in the DDP treatment group (P < 0.05). Activity of mitochondrial COXI decreased after DDP treatment (P < 0.05). DIDS, as a VDAC1 oligomerization inhibitor, antagonized DDP-induced apoptosis by diminishing oxidative stress and DNA damage and protecting mitochondrial complex protein. These results show that VDAC1 oligomerization may play an important role in DDP-induced hepatocyte apoptosis by increasing ROS and mtDNA leakage from VDAC1 pores, exacerbating oxidative stress and mtDNA damage.

Severe visual loss caused by inhalational methanol poisoning in fireworks production: A report on 3 cases.

BACKGROUND: Workers in fireworks production are mainly at risk for explosion injury. However, there are few reports on the consequences of methanol poisoning in fireworks laborers. CASE PRESENTATION: We report on three patients with visual loss caused by inhalation exposure to high concentrations of methanol, who were engaged in the granulation process of the fireworks manufacturing industry. They presented with severe metabolic acidosis and visual impairments, accompanied by headache, chest tightness, shortness of breath, dizziness, and vomiting. All were diagnosed with acute methanol poisoning. One patient developed bilateral blindness and two patients improved after timely hemodialysis treatment. CONCLUSIONS: These case reports emphasize the risk of methanol poisoning in the fireworks industry or other factories using commercial alcohol with high methanol content. Early hemodialysis intervention and metabolic acidosis correction are crucial for rescuing visual impairment caused by methanol exposure. Awareness and supervision of commercial alcohol use are indispensable for similar industrial processes.

VDAC1 as a target in cisplatin anti-tumor activity through promoting mitochondria fusion.

Cisplatin is one of the most effective anti-cancer drugs, but its efficacy is limited by the development of resistance. Previous studies have shown that mitochondria play critical roles in cisplatin cytotoxicity, however, the exact mechanism of mitochondria involved in cisplatin sensitivity has not been clarified. In this study, cisplatin triggered mitochondrial oxidative stress and the decrease of mitochondria membrane potential in human cervical cancer cells. Then we screened a series of mitochondrial relevant inhibitors, including mitochondrial mPTP inhibitors DIDS and CsA, and mitochondrial respiratory complex inhibitors Rot and TTFA. Among these, only DIDS, as the inhibitor of mitochondrial outer membrane protein VDAC1, showed strong antagonism against cisplatin toxicity. DIDS mitigated cisplatin-induced MFN1-dependent mitochondrial fusion, mitochondrial dysfunction and oxidative damage. These findings demonstrated that VDAC1 may serve as a potential therapeutic target in the increase sensitivity of cisplatin, which provides an attractive pharmacological therapy to improve the effectiveness of chemotherapy.

Country performance against COVID-19: rankings for 35 countries.

OBJECTIVE: To generate rankings of 35 countries from all continents (except Africa) on performance against COVID-19. DESIGN: International time series, cross-sectional analysis. SELECTED COUNTRIES: Countries having 5500 or more cases (collectively including 85% of the world's cases) as of 16 April 2020 and that had reached 135 days into their pandemic by 30 July. MAIN OUTCOME MEASURES: The initial severity and late-pandemic performance of countries can reasonably be ranked by COVID-19 cases or deaths per million population. For guiding policy and informing public accountability during the pandemic, we propose mid-pandemic performance rankings based on doubling time in days of the total number of cases and deaths in a country. Rank orderings then follow. RESULTS: At day 25 into a country's pandemic, cross-country performance variation was modest: in most countries, cumulative deaths doubled in fewer than 5 days. By day 65, and even more so by day 135, great cross-country variation emerged. By day 135, 9 of the 10 top-performing countries on deaths were European, although they were initially hard hit by the pandemic. Thus, rankings change rapidly enough to point to the value of a dynamic indicator. Five countries-Brazil, Mexico, India, Indonesia and Israel-were among the seven poorest performers at day 135 on both cases and deaths. Doubling times for cases and for deaths are positively correlated, but differ sufficiently to point to the value of both indicators. CONCLUSIONS: Readily available data support transparently generated rankings of countries' performance against COVID-19 based on doubling times of cases and deaths. It is premature to judge the value of these rankings in practice, but the potential and early experience suggest they might help facilitate identification of good policies and inform judgements on national leadership.

Cross-sectional schooling-health associations misrepresented causal schooling effects on adult health and health-related behaviors: evidence from the Chinese Adults Twins Survey.

Adult health outcomes and health behaviors are often associated with schooling. However, such associations do not necessarily imply that schooling has causal effects on health with the signs or magnitudes found in the cross-sectional associations. Schooling may be proxying for unobserved factors related to genetics and family background that directly affect both health and schooling. Recently several studies have used within-monozygotic (MZ) twins methods to control for unobserved factors shared by identical twins. Within-MZ estimates for developed countries are generally smaller than suggested by cross-sectional associations, consistent with positive correlations between unobserved factors that determine schooling and those that determine health. This study contributes new estimates of cross-sectional associations and within-MZ causal effects using the Chinese Adults Twins Survey, the first study of its type for developing countries. The cross-sectional estimates suggest that schooling is significantly associated with adult health-related behaviors (smoking, drinking, exercising) but not with own or spouse health outcomes (general health, mental health, overweight, chronic diseases). However, within-MZ-twins estimators change the estimates for approximately half of these health indicators, in one case declining in absolute magnitudes and becoming insignificant and in the other cases increasing in absolute magnitudes. Within-MZ estimates indicate significant pro-health effects for at least one of the indicators for own health (better mental health), own health-related behaviors (less smoking) and spouse health (less overweight).