Assessment of potential cardiotoxic side effects of mitoxantrone in patients with multiple sclerosis

Previous studies showed that mitoxantrone can reduce disability progression in patients with multiple sclerosis (MS). There is, however, concern that it may cause irreversible cardiomyopathy with reduced left ventricular (LV) ejection fraction (EF) and congestive heart failure. The aim of this prospective study was to investigate cardiac side effects of mitoxantrone by repetitive cardiac monitoring in MS patients. The treatment protocol called for ten courses of a combined mitoxantrone (10 mg/m(2) body surface) and methylprednisolone therapy. Before each course, a transthoracic echocardiogram was performed to determine the LV end-diastolic diameter, the end-systolic diameter and the fractional shortening; the LV-EF was calculated. Seventy-three patients participated (32 males; age 48 +/- 12 years, range 20-75 years; 25 with primary progressive, 47 with secondary progressive and 1 with relapsing-remitting MS) who received at least four courses of mitoxantrone. Three of the 73 patients were excluded during the study (2 patients discontinued therapy; 1 patient with a previous history of ischemic heart disease developed atrial fibrillation after the second course of mitoxantrone). The mean cumulative dose of mitoxantrone was 114.0 +/- 33.8 mg. The mean follow-up time was 23.4 months (range 10-57 months). So far, there has been no significant change in any of the determined parameters (end-diastolic diameter, end-systolic diameter, fractional shortening, EF) over time during all follow-up investigations. Mitoxantrone did not cause signs of congestive heart failure in any of the patients. Further cardiac monitoring is, however, needed to determine the safety of mitoxantrone after longer follow-up times and at higher cumulative doses. Copyright (C) 2005 S. Karger AG, Basel

Cardiovascular Events in Patients With Fabry Disease Natural History Data From the Fabry Registry

ObjectivesThese analyses were designed to determine the incidence of major cardiovascular (CV) events and the natural history of CV complications in patients with Fabry disease.BackgroundFabry disease, a genetic disorder caused by deficiency of alpha-galactosidase A activity, is associated with CV dysfunction.MethodsMajor CV events (myocardial infarction, heart failure, or cardiac-related death) were analyzed in 2,869 Fabry Registry patients during the natural history period (i.e., before enzyme replacement therapy or among patients who never received therapy). Multivariate logistic regression analyses were performed to identify significant predictors of CV events.ResultsEighty-three of 1,424 men (5.8%) and 54 of 1,445 women (3.7%) experienced CV events at mean ages of 45 and 54 years, respectively. Heart failure was the most common first CV event, reported by 50 men (3.5%) and 33 women (2.3%). Hypertension and left ventricular hypertrophy were the risk factors most strongly associated with CV events. When these parameters were used as covariates in logistic regression analyses, the odds ratio (OR) for hypertension in men was 7.8 (95% confidence interval [CI]: 2.1 to 28.6, p = 0.0019), and the OR for hypertension in women was 4.5 (95% CI: 1.6 to 12.3, p = 0.0037). The OR for left ventricular hypertrophy was 4.8 in men (95% CI: 1.03 to 22.2, p = 0.0463) and 8.2 in women (95% CI: 2.6 to 26.0, p = 0.0003).ConclusionsMajor CV events occurred in approximately 5% of Fabry Registry patients during the natural history period. All patients with Fabry disease should be monitored for possible CV risk factors, particularly hypertension and left ventricular hypertrophy

Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82

G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments

Sustainable Human Development: Corporate Challenges and Potentials the Case of Bayer CropScience's Cotton Seed Production in Rural Karnataka (India)

This paper aims to explore concepts, methods and empirical results of potential impacts of Transnational Corporations (TNC) on Sustainable Human Development (SHD) in emerging market countries. In doing so, a further major goal is to explain, illustrate and discuss how the theoretical CA framework used in the GeNECA project2 can be applied to corporate SHD impacts. Our findings are based on the case of Bayer CropScience’s Model Village Project in rural Karnataka, India. To achieve our goals, we first establish a theoretical framework for assessing corporate impacts on SHD to capture SHD effects. Thereafter, we introduce the case of Bayer CropScience’s seed production in rural India, for which a “Model Village Project (MVP)” has been established to explore ways, potentials and challenges of promoting SHD of the villagers and corporate goals in a win-win-strategy. Afterwards, we explain methodological requirements, our representative database for the quantitative analyses, and the qualitative methods that we use for project evaluation. Based on findings of the authors’ external evaluation of the MVP, we discuss the baseline situation in the model villages with respect to corporate potentials, challenges and limitations to foster SHD impacts. Methodologically, we find the combination of quantitative representative methods and qualitative assessments to be most effective to capture corporate potentials and risks. Furthermore it turns out to be promising to extend the analyses beyond standardized benchmarks like the MDGs. We show that major determinants of SHD established in the paper result in a portfolio of corporate opportunities and risks. For instance, the reality of underemployment in the model villages provides specific corporate opportunities like an abundant pool of labor supply. However, it also produces corporate risks, e.g. lack of capital available for necessary investment by suppliers who frequently suffer from poverty, risk of over-indebtedness and a resulting inability to accumulate enough capital and to raise productivity. In the comprehensive opportunity and riskportfolio of this Bayer CropScience case, we find abundant potential business cases which we discuss further in the text. We conclude that corporate potentials as well as risks of corporate neglect and violations of people-centered SHD also depend on how much the villagers are enabled and empowered to make most of their agency as individuals and as groups. Furthermore, it depends on trust building as a prerequisite of awareness raising of the villagers themselves, so that they are willing and able to participate successfully in the undertaken procedures

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Die erleichterte Befristung älterer Arbeitnehmer/innen – Eine Evaluation mit Daten des Mikrozensus

Kausalanalyse, Differenz-von-Differenzen, Beschäftigung Älterer , Causal effect, Difference-in-differences, Employment of elderly ,

Glucocorticoids dexamethasone and prednisolone suppress fibroblast growth factor 23 (FGF23)

Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH

Glucocorticoids dexamethasone and prednisolone suppress fibroblast growth factor 23 (FGF23)

Fibroblast growth factor 23 (FGF23) is a hormone mainly secreted by bone cells. Its most prominent effects are the regulation of renal phosphate reabsorption and calcitriol (active vitamin D, 1,25(OH)2D3) formation, effects dependent on its co-receptor αKlotho. Besides these actions, further paracrine and endocrine effects exist. The production of FGF23 is regulated by 1,25(OH)2D3, parathyroid hormone, dietary phosphate intake, iron status, as well as inflammation. Glucocorticoids are hormones with anti-inflammatory properties and are, therefore, widely used for acute and chronic inflammatory diseases, autoimmune disorders, and malignancies. The present study explored whether glucocorticoids influence the production of FGF23 in vitro as well as in mice. Fgf23 transcription was analyzed by semi-quantitative real-time PCR. Serum concentrations of FGF23 and 1,25(OH)2D3 were measured by ELISA. Urinary phosphate and Ca2+ excretion were determined in metabolic cages. As a result, in UMR106 rat osteoblast-like cells and in MC3T3-E1 cells, both, dexamethasone and prednisolone, downregulated Fgf23 transcription and FGF23 protein synthesis. Dexamethasone increased Dmp1 and Phex (encoding FGF23-regulating genes) as well as Nfkbia (encoding NFκB inhibitor IκBα) transcription in UMR106 cells. In mice, a single injection of dexamethasone or prednisolone was followed by a significant decrease of serum C-terminal and intact FGF23 concentration and bone Fgf23 mRNA expression within 12 h. These effects were paralleled by increased renal phosphate excretion and enhanced 1,25(OH)2D3 formation. We conclude that a single glucocorticoid treatment strongly downregulates the FGF23 plasma concentration