Association Between Vitamin D Status and COPD Phenotypes

Background

It has been suggested that identifying phenotypes in chronic obstructive pulmonary disease (COPD) might improve treatment outcome and the accuracy of prediction of prognosis. In observational studies vitamin D deficiency has been associated with decreased pulmonary function, presence of emphysema and osteoporosis, upper respiratory tract infections, and systemic inflammation. This could indicate a relationship between vitamin D status and COPD phenotypes. The aim of this study was to assess the association between vitamin D levels and COPD phenotypes. In addition, seasonality of vitamin D levels was examined.

Methods

A total of 91 patients from a Danish subpopulation of the “Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points” cohort took part in a biomarker substudy. Vitamin D concentration was measured from blood samples taken at two visits, approximately 6 months apart. The participants were 40–75-year-old patients with COPD and had a smoking history of >10 pack-years.

Results

Fifty-six patients had 25-hydroxyvitamin D measured from blood samples from both visits. In the final model of the multivariate analyses, the factors that were associated with vitamin D deficiency at the first visit were age (OR: 0.89, p = 0.02) and summer season (OR: 3.3, p = 0.03). Factors associated with vitamin D level also at the first visit were age (B: 0.9, p = 0.02) and 6 min walking distance (B: 0.05, p = 0.01).

Conclusion

Vitamin D was not associated with COPD phenotypes and season did not seem to be a determinant of vitamin D levels in patients with moderate to severe COPD.     

Bisphenol A replacement chemicals,BPF and BPS,induce protumorigenic changes in human mammary gland organoid morphology and proteome

Environmental chemicals such as bisphenol A (BPA) are thought to contribute to carcinogenesis through their endocrine-disrupting properties. Due to accumulating evidence about negative human health effects, BPA is being phased out, but in parallel, exposures to replacement chemicals such as bisphenol S (BPS) and bisphenol F (BPF) are increasing. Little is known about their biologic effects, but because of their high degree of chemical relatedness, they may have overlapping as well as distinct actions as compared with BPA. We investigated this theory using a nonmalignant, human breast tissue-derived organoid system and two end points: morphologic and proteomic alterations. At low-nanomolar doses, replacement chemicals—particularly BPS—disrupted normal mammary organoid architecture and led to an increased branching phenotype. Treatment with the various bisphenols (vs. 17-β-estradiol or a vehicle control) produced distinct proteomic changes. For example, BPS up-regulated Cdc42-interacting protein 4, which supports the formation of invadopodia and a mesenchymal phenotype. In summary, this study used a highly physiologically relevant organoid system to provide evidence that replacement bisphenols have protumorigenic effects on the mammary gland at morphologic and proteomic levels, highlighting the importance of studies to evaluate the potential harmful effects of structurally related environmental chemicals.

Bisphenols, of which the most prevalent is bisphenol A (BPA), are environmental chemicals that are used as plasticizers in a variety of goods, including plastic bottles, children''s toys, eyeglass lenses, food containers, and some types of thermal paper (e.g., cash register receipts). They leach from these products, contaminating humans (and animals) either directly or indirectly via other environmental media, such as household dust. Thus, in most adults, BPA is detected in serum, tissues, and urine (1, 2). Children (ages 6 to 11) have the highest concentrations of urinary BPA (3, 4). This chemical has structural similarities to estrogen (17-β-estradiol [E2]) and as a result, weakly mimics its activity (5). Hormones and growth factors play an important role in controlling prenatal mammary gland development and later on, the morphologic and functional alterations that occur during puberty, pregnancy, and eventually, menopause. Due to this plasticity, the mammary gland is particularly susceptible to the actions of endocrine-disrupting chemicals (EDCs), such as BPA (6–8). In vivo and in vitro studies have consistently shown that exposures to BPA at crucial developmental stages impair mammary gland development and increase neoplastic transformation (9–12). Treating rats with BPA results in mammary epithelial hyperplasia and enhances proliferation (13), common features of precancerous lesions. Additionally, BPA induces cell cycle progression and increases proliferation of human breast cancer cells in vitro via the up-regulated expression of estrogen-dependent genes (14).Based on these and other data, BPA has been removed from many commercial products. Most commonly, this chemical of concern is replaced by bisphenol S (BPS) and bisphenol F (BPF) compounds that share close structural similarities with BPA. However, little is known about their endocrine effects and more broadly, their biological activities. Marketing a product as “BPA free” suggests to the consumer that a product is safer, but research shows that replacement bisphenols have adverse effects similar to, or even greater than, BPA. For example, studies in zebrafish, rodents, and human cell culture models show that BPS and BPF have endocrine-disrupting activities. In zebrafish, despite species-specific differences in estrogen receptor (ER) affinity and specificity, BPF and BPS have estrogenic activities similar to BPA (15–17). In rats, exposure to BPF induces uterine growth, which suggests estrogenic effects (18). BPA, BPF, and BPS promote estrogen-dependent cell cycle progression, proliferation, and migration of human MCF-7 breast cancer cells along with epigenetic changes (19, 20). BPS exposure of pregnant and lactating mice limits milk production, suggesting alterations in mammary gland composition (21). In addition to estrogen signaling, BPF affects other endocrine pathways; in rats, oral administration of this compound alters thyroid hormone levels (22).Current research on bisphenol actions is mainly focused on endocrine effects. It is less well understood whether these chemicals have additional protumorigenic effects independent of their endocrine-disrupting activity. Moreover, tumor development is a multistep process involving heterogeneous cell types and numerous factors, including the potential roles of a variety of environmental chemicals (23, 24). Recapitulating this complexity in an experimental setup is challenging. In this context, tissue organoids are valuable models for understanding the early steps of carcinogenesis. They can be derived from nonmalignant primary tissues ex vivo. When grown for short periods of time in vitro, they maintain many of the genetic and epigenetic features of their normal cognates. Also, organoids have the added advantage of consisting of multiple cell types that are representative of the complexity of the tissue from which they are derived (25, 26).In this study, we exploited the strengths of the human mammary gland organoid culture system to understand the impact of the BPA replacements, BPF and BPS. Organoids established from nonmalignant human mammary gland tissues were exposed to one of the bisphenols, E2, or the vehicle control. The results showed that BPA replacements, in particular BPS, disrupted organoid architecture, enhanced branching, and caused compound-specific proteomic alterations—effects that were mostly E2 independent. Together, these observations suggested that the mammary gland effects of BPA substitutes should be equally or more concerning than those of the compound they are replacing.     

Pathogenesis of Rickets and Osteomalacia in Familial Hypophosphataemia

Calcium and/or phosphate tolerance tests were performed on patients with familial hypophosphataemia, normal control subjects, and patients with vitamin D deficient osteomalacia.Intestinal calcium absorption was similar in patients with familial hypophosphataemia and control subjects. The phosphate tolerance test, which is known to be `flat'' in patients with familial hypophosphataemia, was normal in patients with vitamin D deficient osteomalacia.These findings suggest that rickets and osteomalacia in familial and some cases of non-familial hypophosphataemia are unrelated to abnormal metabolism of vitamin D. This hypothesis is supported by the fact that intestinal calcium absorption as measured by calcium tolerance test is normal in familial hypophosphataemia.It is suggested that the primary abnormality in familial hypophosphataemia is a partial metabolic block in the intestinal absorption and renal tubular reabsorption of phosphate.     

Predictive factors of anemia within the first year post renal transplant

BACKGROUND: The aim of our study was to identify the independent factors that might predict anemia at 6 (M6) and 12 (M12) months posttransplantation. METHODS: Postrenal transplant anemia (PTA) was defined as having a hemoglobin (Hb) level below 13 g/dl for men and below 12 g/dL for women. In this study, we included all the recipients who received a renal transplant in 2001 at our department, and for whom the graft was still functioning 1 year later (n=92). RESULTS: Anemia was observed in 78%, 35.5% and 25% of patients at day (D)0 and at M6 and M12, respectively. Iron deficiency was found in 14% of patients at D0 and in 13% of patients at M12. A total of 59.8% of patients had received at least one blood transfusion in the postoperative period, whereas 41.3% of patients had received recombinant erythropoietin (rEpo) therapy within the first months posttransplantation. In multivariate analysis, the independent predictive factors of anemia at M6 were Epo level at D0, initial nephropathy (polycystic kidney disease vs. others), posttransplantation rEpo therapy, hematocrit at M3, platelets at D7, and sirolimus therapy. The independent predictive factors of anemia at M12 were Epo level at D0, platelets at D7, delayed graft function (DGF), creatinine clearance at M12, serum creatinine at M12, and Hb level at M6. CONCLUSIONS: The prevalence of PTA was 25% at M12. DGF, renal function at M12, and anemia at M6 were independent risk factors for still having anemia at M12.     

The evolution of the hypervariable region-1 of hepatitis C virus may predict liver fibrosis outcome after renal transplantation

The aim of our study was to assess hepatitis C virus (HCV) evolution and long term liver histology outcome in anti-HCV(+)/RNA(+) renal-transplant (RT) patients. Fifty-five anti-HCV(+)/RNA(+) RT patients underwent every 3-4 years after transplantation liver biopsies (LB) (2 LBs, N = 55; 3 LBs, N = 44; 4 LBs, N = 10). The hypervariable region (HVR)-1 of the HCV genome from all patients was characterized over time. Overall, the rate of liver fibrosis progression was 0.07 +/- 0.03 Metavir units/year. We identified three groups of patients: those in whom liver fibrosis remained stable (group I, N = 21), those with progressing liver fibrosis (group II, N = 21), and those with a regression in liver fibrosis (group III, N = 13). Initial fibrosis stage and high diversification of the HVR-1 of HCV genome between the transplantation and the first liver biopsy were independent factors associated with liver fibrosis regression. In conclusion, in this study, after renal transplantation, HCV infection is not harmful upon liver histology in more than fifty percent of the patients. The diversification of the HVR-1 of the HCV genome might be used to predict liver fibrosis outcome.     

Villous atrophy induced by mycophenolate mofetil in renal-transplant patients

Leucopenia and diarrhoea are the main side effects observed after the use of mycophenolate mofetil (MMF) in renal-transplant patients. The mechanism of diarrhoea remains unknown. We report on four cases presenting with severe diarrhoea, which appeared, respectively, at 4, 10, 24, and 66 months after MMF therapy had been started. All patients presented with weight loss and biological signs of malabsorption syndrome. Oesophago-gastroduodenoscopy revealed duodenal villous atrophy, which was confirmed by pathology examination. Anti-endomysium antibodies were negative. In all patients, diarrhoea disappeared within 1 month of MMF withdrawal without a gluten-free diet. A control oesophago-gastroduodenoscopy was performed in one patient 6 months later and was considered normal. None of the patients showed evidence of cytomegalovirus in enterocytes or cytomegalovirus-positive viraemia. In conclusion, villous atrophy induced by MMF might be one of the mechanisms of diarrhoea. It is mandatory to differentiate coeliac disease from MMF-induced villous atrophy because, in the latter case, a gluten-free diet is not required.     

Convenient biological assay for polyethylene glycol-interferons in patients with hepatitis C

The vesicular stomatitis virus cytopathic effect reduction assay is suitable to quantify polyethylene glycol-alpha interferon 2a (PEG-IFN-alpha 2a) and PEG-IFN-alpha 2b. Human serum and ribavirin did not interfere with the assay. This bioassay was successfully used for assaying PEG-IFN-alpha 2a and PEG-IFN-alpha 2b in serum samples from patients undergoing combination therapy.