Food-grade titanium dioxide decreases hematocrit and hemoglobin and increases compulsive-like behavior in male mice

Food-grade titanium dioxide (E171) is widely used as a food additive, and it is known that after oral consumption, E171 is translocated into the bloodstream reaching the highest titanium level at 6 h. E171 is accumulated in some organs triggering toxicity, but the effects on the blood parameters after oral consumption have been less studied. Recently, evidence shows that oral exposure to E171 induces behavioral signs of anxiety and depression. The relation between blood alterations and psychiatric disorders has been previously demonstrated. However, the oral exposure to E171 effects on alterations in blood parameters and effects linked to alterations in animal behavior has not been explored. In this short communication, we aimed to investigate the effects of E171 on specific blood parameters (hematocrit, hemoglobin, number of erythrocytes, and leukocytes) and anxiety and compulsive-like behavior in males and females orally exposed to ~5 mg/kg for 4 weeks. The results showed that E171 decreased hematocrit and hemoglobin in male but not in female mice while leukocyte and erythrocyte count remained unaltered. Oral consumption of E171 decreased the levels of anxiety-like behavior in females but not in male mice, while compulsive-like behavior was increased in both male and female mice.     

Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Gray platelet syndrome: Management of perioperative bleeding in redo cardiac surgery

Gray platelet syndrome (GPS) is a rare (<1/1 000 000) and inherited platelet function disorder characterized by macrothrombocytopenia, α-granule deficiency, and hemorrhages. Bleeding intensity does not correlate with platelet count nor with functional test results. We hereby describe the perioperative bleeding prevention and management of a patient with GPS requiring multiple redo cardiac surgeries.     

Is there a diurnal pattern in the clinical symptoms of HELLP syndrome?

OBJECTIVE: To determine if there is a diurnal pattern in the clinical symptoms of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome. STUDY DESIGN: A retrospective study was performed in 134 pregnancies complicated by HELLP syndrome. The medical records were reviewed to describe each HELLP episode. Time of day was divided into three periods, day, evening, and night. The following parameters were categorized according to the time of day: onset of symptoms, consultation by the doctor, initial blood sampling, diagnosis and decrease of symptoms. Biochemical parameters at clinical presentation and consecutive changes within 24 h were recorded. RESULTS: In 65 pregnancies 77 HELLP episodes were well documented. Times of onset of symptoms and consultation by the doctor were significantly higher during the evening and night (p < 0.001), whereas times of diagnosis and decrease of symptoms occurred significantly more during the day (p < 0.001). In only 49.3% of the cases were diagnostic laboratory criteria met at clinical presentation. This was mainly due to platelet values in excess of 100 x 10(9)/l. Several hours later (median 8 h, range 2-23) the decrease in platelets occurred. CONCLUSIONS: A diurnal pattern exists in the clinical symptoms of HELLP syndrome that is characterized by an exacerbation during the night and recovery during the day. There is a considerable delay between the onset of symptoms and the fulfillment of diagnostic laboratory criteria.     

Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation

Campath-1H (alemtuzumab) induction was used for renal transplantation in combination with sirolimus as immunosuppression. We previously reported a high (28%) rate of early rejection with this regimen, and now report 3-year outcomes. Twenty-nine patients were recipients of either deceased donor or non-HLA (Human Leukocyte Antigen) identical living donor primary renal allografts. Clinical parameters including infection, malignancy, kidney function, and kidney histology were followed prospectively for 3 years. Three-year cumulative graft and patient survival were 96% and 100%, respectively. Twenty patients were maintained on steroid-free immunosuppressive regimens, and 15 patients were maintained on monotherapy for immunosuppression (12 on sirolimus). No serious infectious complications were observed and two patients developed basal cell skin cancer. The 3-year results of our initial pilot study demonstrate good graft (96%) and patient (100%) outcomes. Campath-1H induction has yielded a high proportion of patients maintained on immunosuppressive monotherapy (57%) without serious infectious- and no malignancy-related complications. The reported regimen yielded novel insights into both Campath-1H and sirolimus therapy in renal transplantation. Because of the higher incidence of early rejection, we recommend a modified strategy of immunosuppression including a brief course of a calcineurin inhibitor.     

Therapeutic Consequences of Variation in Intraarterial Pressure Measurements After Iliac Angioplasty

Purpose: To assess the accuracy of intraarterial measurement of transstenotic pressure gradients for the detection of hemodynamically suboptimal iliac angioplasty. Methods: In 14 patients, referred for diagnostic angiography, mean pressure gradients in the aorta and iliac artery were obtained twice, using a double-sensor pressure catheter. Additional iliac measurements were performed during pharmacologically induced flow augmentation. Repeatability was assessed by calculation of the mean difference plus standard deviation (MD ± SD) and repeatability coefficient (2 × SD). These results were extrapolated to 137 iliac angioplasty procedures with secondary stenting where there was a residual pressure gradient > 10 mmHg. Results: MD ± SD for repeated measurements at rest and during flow augmentation were 0 ± 2 mmHg and 1 ± 3 mmHg, respectively. Repeatability coefficients were 3 and 6 mmHg. Mean pressure gradients after hemodynamically insufficient angioplasty were 8 ± 7 mmHg at rest and 17 ± 5 mmHg following vasodilatation. Inaccurate pressure recordings may have led to inappropriate stent placement in less than 2.5%, and inappropriate denial of stent placement in less than 5% of the lesions. Conclusion: Variability of intraarterial pressure measurements has little consequence in the detection of hemodynamically significant stenosis after angioplasty. Received: 0/00/00/Accepted: 0/00/00     

Causes of Death and Risk Factors for Mortality in Patients With Severe Chronic Obstructive Pulmonary Disease

ObjectiveThe objective of this study was to assess the causes of death and risk factors for mortality in a cohort of patients with severe chronic obstructive pulmonary disease (COPD).Patients and methodsWe studied 203 patients with severe COPD (forced expiratory volume in 1 second [FEV₁] <50%), who were attended in our respiratory department day hospital (2001-2006). Clinical variables were recorded on inclusion, and clinical course and causes of death were retrospectively reviewed.ResultsThe mean (SD) age of patients was 69 (8) years and the mean FEV₁ was 30.8% (8.2%). One-hundred and nine patients died (53.7%); death was attributed to respiratory causes in 72 (80.9%), with COPD exacerbation being the most frequent specific cause within this category (48.3%). During follow-up, 18.7% required admission to the intensive care unit (ICU). Survival at 1, 3, and 5 years was 80%, 53%, and 26%, respectively. The multivariate analysis showed that mortality was associated with age, stage IV classification according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), cor pulmonale, and hospital admission during the year prior to inclusion. Need for admission to the ICU during follow-up was a factor independently associated with higher mortality.ConclusionsMortality in patients with severe COPD was high and exacerbation of the disease was one of the most frequent causes of death. Age, GOLD stage, cor pulmonale, prior admission to hospital, and need for admission to the ICU during follow-up were independent predictors of mortality.     

Monotherapy with enoxaparin for the prevention of recurrent venous thromboembolism.

This study aimed to determine whether a weight-adjusted dose of subcutaneous enoxaparin is as effective and safe as oral acenocoumarol for the secondary prophylaxis of pulmonary embolism. Three hundred and eighty consecutive noncancer outpatients hospitalized with an episode of symptomatic pulmonary embolism selected treatment with acenocoumarol or enoxaparin at a dose of 1 mg/kg once daily after being informed of the type of administration and expected frequency of laboratory monitoring for both medicinal products. Endpoints were symptomatic recurrent thromboembolic events evaluated by standard objective testing, and a composite endpoint of recurrent venous thromboembolism, major bleeding, and death from any cause. One hundred and ninety-nine patients (52%) chose acenocoumarol therapy and 181 chose enoxaparin monotherapy. Four patients in the enoxaparin group (2.2%) and six patients in the acenocoumarol group (3%) had an objective thromboembolic recurrence (hazard ratio, 1.35; 95% confidence interval, 0.38-4.79; P = 0.64). Nine patients in the enoxaparin group (5.0%) had a hemorrhagic complication compared with 11 in the acenocoumarol group (5.5%) (P = 0.81). The hospital length of stay was shorter with enoxaparin compared with acenocoumarol (11 versus 16 days, P = 0.0001). Enoxaparin is as effective and safe as acenocoumarol in the secondary prevention of recurrent thromboembolic disease and is associated with shorter hospitalization.