Effects of tibolone on bone quality in ovariectomized monkeys

OBJECTIVE: The purpose of this report is to examine the effects of two doses of tibolone on bone quality (bone biomarkers, bone density, and bone strength) in ovariectomized cynomolgus monkeys fed high-fat diets. DESIGN: Ovariectomized cynomolgus monkeys were randomized into one of five treatment groups: placebo-treated control, tibolone (0.2 mg/kg/day), tibolone (0.05 mg/kg/day), conjugated equine estrogens (Premarin, 0.042 mg/kg/day), and conjugated equine estrogens plus medroxyprogesterone acetate (0.042 and 0.167 mg/kg/day, respectively). Bone quality was assessed by determining bone strength and density in vertebrae and femora collected after 24 months of treatment. RESULTS: Monkeys treated for 24 months with tibolone had increased bone mineral density in the distal femur and improved biomechanical properties in the midshaft femur compared with placebo-treated ovariectomized monkeys, as did monkeys treated with conjugated equine estrogens with or without medroxyprogesterone acetate. No treatment effects were seen in lumbar vertebra bone density or strength. There was no significant difference between tibolone and estrogen on biomechanical properties of the femur. CONCLUSION: These data show that tibolone is comparable to conjugated equine estrogens with or without medroxyprogesterone acetate in decreasing bone turnover and increasing bone strength in ovariectomized monkeys.     

Differences in outcomes between cholecalciferol and ergocalciferol supplementation in veterans with inflammatory bowel disease

Aim: Vitamin D deficiency is a global health issue associated with increased health‐care costs, and could play a role in the pathogenesis and management of inflammatory bowel disease. Prior studies show a high prevalence of vitamin D deficiency in veterans with inflammatory bowel disease. We aimed to examine the outcome differences in patients with inflammatory bowel disease, comparing treatment with ergocalciferol to cholecalciferol. Methods: A retrospective review of electronic medical records of patients with inflammatory bowel disease at a Veterans Affairs Medical Facility in the Southeastern United States was carried out. Those with at least one serum 25(OH) vitamin D level were included. Initial and follow‐up vitamin D values were recorded. The type of vitamin D supplementation, whether cholecalciferol or ergocalciferol, was documented. Costs in the year after measurement of vitamin D were divided into separate inpatient and outpatient categories. Results: Veterans (n = 108) with ulcerative colitis or Crohn's disease and an available 25(OH) vitamin D level were studied. There were differences in follow‐up vitamin D levels; those who received weekly ergocalciferol had higher subsequent levels than those who received cholecalciferol, especially at a second follow up, although differences did not achieve statistical significance. However, those who received vitamin D3 were less likely to use laboratory, pharmacy, radiology and fee‐based services, and had lower laboratory and pharmacy costs. Conclusions: Our data suggest that cholecalciferol replacement might improve outcomes to a greater extent than ergocalciferol, and might be better in limiting health‐care costs and expenses in patients with inflammatory bowel disease. Geriatr Gerontol Int 2012; 12: 475–480.     

Cutis laxa,exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG

Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. > 100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542 T > G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H⁺-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the β-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.     

Human primary T lymphocytes have a low capacity to amplify MLV-based amphotropic RCR and the virions produced are largely noninfectious

The presence of replication-competent retrovirus (RCR) in retroviral-based gene therapy products poses a potential safety risk for patients. Therefore, RCR testing of clinical gene therapy products and monitoring of patients enrolled in gene therapy trials is required to assure viral safety. The requirement to test ex vivo-transduced cells originates from the presumed amplification of adventitious RCR during the transduction procedure. However, data on the capacity of different cell types to do so are lacking. In this study, we sought to analyze the amplification potential of primary human T lymphocytes after infection with amphotropic MLV-based RCR. The total number of viral particles produced after 1 or 2 weeks was measured by a quantitative 4070A env-specific RT-PCR assay. The fraction of infectious replication-competent viral particles was analyzed in the PG-4 S+L- assay. From this study, we conclude that the total number of viral particles RCR produced by T lymphocytes is 2-4 logs lower than the number produced by NIH-3T3 cells. Surprisingly, less than 1% of the viral particles produced by primary T lymphocytes appeared to be infectious, while nearly all virions produced by NIH-3T3 were. We conclude that primary human T lymphocytes are low producers of MLV-based amphotropic RCR.     

Tibolone: a compound with tissue specific inhibitory effects on sulfatase

While many transforming growth factor-β (TGFβ) superfamily ligands such as TGFβ, activin, and the bone morphogenic proteins (BMPs) are critical to the control of growth, differentiation, and cell fate, inhibin has a more limited role and is primarily responsible for the regulation of one hormone from one cell-type in the anterior pituitary. Inhibin is an endocrine hormone, produced by the gonads, that inhibits follicle stimulating hormone (FSH) release from the pituitary gonadotrope. The other hormones in the superfamily do not appear to act in an endocrine fashion, but rather control cell function in a paracrine or autocrine manner. Many components of the TGFβ/activin/BMP signal transduction pathway have been elegantly defined; however, the mechanism of inhibin action has not been completely dissected. Several cell surface proteins that associate with inhibin have been identified recently, and these molecules may provide the clues necessary to understand how inhibin regulates reproductive function.     

Desloratadine and depression,a drug safety signal based on worldwide spontaneous reporting of side effects

Abstract

Objective: Desloratadine, a third-generation antihistamine, is claimed to cause fewer central nervous system (CNS) adverse drug reactions (ADRs) than antihistamines of the first- and second-generation. While literature is inconclusive regarding the possible CNS effects, symptoms like somnolence and hallucinations are acknowledged ADRs of desloratadine, indeed suggesting some passage of this drug across the blood–brain barrier. Depression is currently not described as an ADR in the approved desloratadine product labelling.

Materials and methods: In a joint signal detection workshop with the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb, case reports of suspected drug–ADR associations were analysed.

Results: Forty-nine unique case reports of desloratadine associated with depression or depressed mood were detected in the WHO global ADR database. In these reports, the median time to onset of depression was three days. Most patients recovered after withdrawal of desloratadine, and in five patients the symptoms of depression recurred after re-administration of desloratadine.

Conclusion: We hypothesize that desloratadine may enter the CNS and that it hence in rare cases may cause a clinically relevant state of depression, a relation that patients and their treating physicians should be made aware of.     

Human T47D-ERβ breast cancer cells with tetracycline-dependent ERβ expression reflect ERα/ERβ ratios in rat and human breast tissue

T47D-ERβ breast cancer cells with tetracycline-dependent ERβ expression and constant ERα expression can be used to investigate effects of varying ERα/ERβ ratios on estrogen-induced cellular responses. This study defines conditions at which ERα/ERβ ratios in T47D-ERβ cells best mimic ERα/ERβ ratios in breast and other estrogen-sensitive tissues in vivo in rat as well as in human.Protein and mRNA levels of ERα and ERβ were analyzed in T47D-ERβ cells exposed to a range of tetracycline concentrations and compared to ERα and ERβ levels found in breast, prostate, and uterus from rat and human origin.The ERα/ERβ ratio in T47D-ERβ cells exposed to >150 ng/ml tetracycline is comparable to the ratio found in rat mammary gland and in human breast tissue. The ERα/ERβ ratio of other estrogen-sensitive rat and human tissues can also be mimicked in T47D-ERβ cells. The ERα/ERβ ratio found in MCF-7 and native T47D breast cancer cell lines did not reflect ratios in analyzed rat and human tissues, which further supports the use of T47D-ERβ cells as model for estrogen-responsive tissues. Using 17β-estradiol and the T47D-ERβ cells under the conditions defined to mimic various tissues it could be demonstrated how these different tissues vary in their proliferative response.     

Periodontal manifestation of leukocyte adhesion deficiency type I

BACKGROUND: Leukocyte adhesion deficiency type I (LAD-I) is an autosomal recessive immunodeficiency disorder characterized by defects in the integrin receptors of white blood cells that lead to impaired adhesion and chemotaxis. Affected patients are susceptible to recurrent bacterial and fungal infections, impaired pus formation, delayed wound healing, and periodontitis. METHODS: A case of generalized advanced periodontal destruction of the permanent and deciduous dentition in a young Jordanian girl with a severe phenotype of LAD-I is presented in this report. The medical diagnosis was made based on the characteristic clinical and laboratory findings, in particular the total absence of CD18, CD11b, and CD11c as determined by flow cytometry sorting. RESULTS: Periodontal findings in this patient include the early onset of the disease, which affected the primary teeth and permanent dentitions, the intense redness and inflammation of the gingiva, and the rapid periodontal destruction that seems refractory to conventional non-surgical periodontal therapy. CONCLUSION: This report emphasizes the importance of the differential diagnosis of severe immunodeficiency disorders in children and adolescents and mandates the importance of combined care by medical and dental practitioners to prevent tooth loss and control oral infection.     

Effect of 16 months of treatment with tibolone on bone mass, turnover, and biomechanical quality in mature ovariectomized rats.

Tibolone (Org OD14) is a tissue-specific steroid with estrogenic effects on the bone and vagina but not endometrium or breast and has been shown to prevent ovariectomy-induced bone loss in young and old rats. We evaluated the effect of long-term tibolone treatment on bone parameters in mature ovariectomized (OVX) rats. Six-month-old rats were allotted to one of six groups (n = 8). Sham-operated and control OVX groups received vehicle, whereas other groups (all OVX) received tibolone (125, 250, or 500 microg/day orally) or 17alpha-ethinylestradiol (EE; 24 microg/day orally) for 16 months. Treatment with tibolone prevented ovariectomy-induced bone loss in peripheral (femur and tibia) and axial (L1-L2 and L4) skeleton. In peripheral skeleton, tibolone and EE prevented loss of bone mass and quality to a similar extent. Tibolone dose-dependently inhibited trabecular bone volume loss in L1-L2 and tibia, and at 500 microg/day it inhibited 88% of L1-L2 and 55% of tibial volume loss (p < or = 0.05 in each case). Tibolone, 500 microg, resulted in 10% greater cortical strength of femur (p < or = 0.05) and 60% greater compressive strength of L4 (p < or = 0.05) compared with vehicle-treated OVX rats. Tibolone and EE inhibited bone resorption and turnover, assessed by urinary deoxypyridinoline/ creatinine and plasma osteocalcin, respectively. We conclude that 16 months of tibolone treatment prevents ovariectomy-induced deterioration of axial and peripheral skeleton and preserves cortical and trabecular bone strength by reducing bone resorption.