Altered serum calcium homeostasis independently predicts mortality in patients with acute coronary syndrome: a retrospective observational cohort study

ObjectivesSerum calcium levels (sCa) were reported to be associated with risk of cardiovascular diseases. The aim of this study was to analyse the association between sCa and long-term mortality in patients with acute coronary syndrome (ACS).DesignA retrospective observational cohort study.SettingSingle-centre study with participants recruited from the local area.ParticipantsA total of consecutive 13 772 patients with ACS were included in this analysis. Patients were divided based on their sCa profile (≤2.1 mmol/L, 2.1–2.2 mmol/L, 2.2–2.3 mmol/L, 2.3–2.4 mmol/L, 2.4–2.5 mmol/L,>2.5 mmol/L) and followed up for a median of 2.96 years (IQR 1.01–4.07).Primary outcomeLong-term all-cause mortality.ResultsDuring a median follow-up period of 2.96 years, patients with sCa ≤2.1 mmol/L had the highest cumulative incidences of all-cause mortality (16.7%), whereas those with sCa 2.4–2.5 mmol/L had the lowest cumulative incidences of all-cause mortality (3.5%). After adjusting for potentially confounding variables, the Cox analysis revealed that compared with the reference group (sCa 2.4–2.5 mmol/L), all the other groups had higher mortality except for the sCa 2.3–2.4 mmol/L group (HR, 1.32, 95% CI 0.93 to 1.87). Restricted cubic splines showed that the relationship between sCa and all-cause mortality seemed to be U shaped. The optimal sCa cut-off point, 2.35 mmol/L, was determined based on the shape of restricted cubic splines.ConclusionsAltered serum calcium homeostasis at admission independently predicts all-cause mortality in patients with ACS. In addition, a U-shaped relationship between sCa and all-cause mortality exists, and maintaining sCa at approximately 2.35 mmol/L may minimise the risk of mortality.

Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively Towards Regeneration

Background: Autoimmune hepatitis (AIH) is a chronic autoimmune inflammatory disease that usually requires lifelong immunosuppression. Frequent recurrences after the discontinuation of therapy indicate that intrahepatic immune regulation is not restored by current treatments. Studies of other autoimmune diseases suggest that temporary depletion of B cells can improve disease progression in the long term. Methods: We tested a single administration of anti-CD20 antibodies to reduce B cells and the amount of IgG to induce intrahepatic immune tolerance. We used our experimental murine AIH (emAIH) model and treated the mice with anti-CD20 during the late stage of the disease. Results: After treatment, the mice showed the expected reductions in B cells and serum IgGs, but no improvements in pathology. However, all treated animals showed a highly altered serum protein expression pattern, which was a balance between inflammation and regeneration. Conclusions: In conclusion, anti-CD20 therapy did not produce clinically measurable results because it triggered inflammation, as well as regeneration, at the proteomic level. This finding suggests that anti-CD20 is ineffective as a sole treatment for AIH or emAIH.

Acute and Cumulative Effects of Repeated Exposure to Chlorpyrifos on the Liver and Kidney Function among Egyptian Adolescents

Background: There is a paucity of research that tracks changes in liver and kidney function among pesticide applicators. The aim of the current study was to investigate the role of repeated seasonal exposure to the organophosphorus pesticide, chlorpyrifos, on serum measures of liver and kidney function. Methods: Pesticide exposure was assessed by measuring the urinary concentrations of 3,5,6-trichloro-2 pyridinol (TCPy), a specific biomarker for chlorpyrifos. Chlorpyrifos exposure and 8 serum markers of liver and kidney function were measured at 15 timepoints over 3 years prior to, during, and following the end of seasonal pesticide application among adolescent applicators and non-applicators from 4 field stations in Menoufia, Egypt. Results: Urinary TCPy levels showed increases during the application cycles and recovery at the end of each application season. Altered serum markers of liver and kidney function were associated with chlorpyrifos exposure, with some markers recovering 3 months after the end of exposure each year, while other measures demonstrated progressive increase up to 300% the baseline levels at the end of 3 years. Conclusion: The study demonstrated that frequent assessment of liver and kidney function is a sound practice to evaluate cellular injury following chronic repeated occupational and environmental exposure to chlorpyrifos.

Derivation of a Human In Vivo Benchmark Dose for Perfluorooctanoic Acid From ToxCast In Vitro Concentration–Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

A computational workflow which integrates physiologically based kinetic (PBK) modeling, global sensitivity analysis (GSA), approximate Bayesian computation (ABC), and Markov Chain Monte Carlo (MCMC) simulation was developed to facilitate quantitative in vitro to in vivo extrapolation (QIVIVE). The workflow accounts for parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for perfluorooctanoic acid (PFOA) and high throughput screening (HTS) in vitro concentration–response data, determined in a human liver cell line, from the ToxCast/Tox21 database. In vivo benchmark doses (BMDs) for PFOA intake (ng/kg BW/day) and drinking water exposure concentrations (µg/L) were calculated from the in vivo dose responses and compared to intake values derived by the European Food Safety Authority (EFSA). The intake benchmark dose lower confidence limit (BMDL5) of 0.82 was similar to 0.86 ng/kg BW/day for altered serum cholesterol levels derived by EFSA, whereas the intake BMDL5 of 6.88 was six-fold higher than the value of 1.14 ng/kg BW/day for altered antibody titer also derived by the EFSA. Application of a chemical-specific adjustment factor (CSAF) of 1.4, allowing for inter-individual variability in kinetics, based on biological half-life, gave an intake BMDL5 of 0.59 for serum cholesterol and 4.91 (ng/kg BW/day), for decreased antibody titer, which were 0.69 and 4.31 the EFSA-derived values, respectively. The corresponding BMDL5 for drinking water concentrations, for estrogen receptor binding activation associated with breast cancer, pregnane X receptor binding associated with altered serum cholesterol levels, thyroid hormone receptor α binding leading to thyroid disease, and decreased antibody titer (pro-inflammation from cytokines) were 0.883, 0.139, 0.086, and 0.295 ng/ml, respectively, with application of no uncertainty factors. These concentrations are 5.7-, 36-, 58.5-, and 16.9-fold lower than the median measured drinking water level for the general US population which is approximately, 5 ng/ml.

Clinical, pathologic, and toxicologic characterization of Salvia reflexa (lance-leaf sage) poisoning in cattle fed contaminated hay

Salvia reflexa (lance-leaf sage)-contaminated alfalfa hay was fed to ~500 mixed-breed beef cattle. Within hours of exposure, nearly half of the cattle developed lethargy, anorexia, depression, and recumbency, followed by bellowing, colic, and death. Even though the uneaten contaminated hay was removed the first day, nearly 100 animals died within the first 48 h. Three of these cattle were examined postmortem, and tissues and hay samples were collected for microscopic and chemical analysis. Several days later, a smaller number of the clinically poisoned cattle developed neurologic disease with aberrant behavior, aggression, icterus, blindness, exhaustion, and death. A total of 165 cattle were fatally poisoned. Poisoned cattle had swollen, dark, mottled livers that had a prominent nutmeg-like lobular pattern on cut section. Histologically, there was severe centrilobular-to-panlobular hepatic necrosis with marked hepatocellular swelling, degeneration, and necrosis. The surviving cattle developed liver disease characterized by altered serum biochemical analyses and microscopic hepatocellular degeneration and necrosis. In subsequent biopsies and analysis, these lesions resolved within 6–7 mo. After confirming toxicity of the hay in cattle, goats, and mice, followed by a mouse bioassay–guided chemical fractionation process, Salvia reflexa was identified as the contaminant in the hay responsible for the hepatotoxicity. S. reflexa has not been reported previously to cause fatal hepatotoxicity in livestock in North America, to our knowledge.