Serum 25-hydroxyvitamin D cutoffs for functional bone measures in postmenopausal osteoporosis.

This study sought to determine the minimal serum 25-hydroxyvitamin D [25(OH)D] concentration required to maintain bone health in postmenopausal women with low bone mass. A serum 25(OH)D concentration of 20 ng/mL rather than 30 ng/mL was appropriate for bone health. INTRODUCTION: There is no consensus on the minimal serum 25-hydroxyvitamin D [25(OH)D] concentration required to maintain bone health. The aim of this study was to investigate the relationship between 25(OH)D measured via liquid chromatography-mass spectrometry (LC-MS/MS), which is the current gold standard, and biochemical markers of bone turnover, PTH, and bone mineral densitometry (BMD). METHODS: The medical records of 750 postmenopausal women newly diagnosed with osteoporosis or osteopenia at Samsung Medical Center from 2009 to 2014 were investigated. Subjects were divided into four groups according to serum 25(OH)D concentration: <10, 10-20, 20-30, and ≥30 ng/mL. Serum concentrations of bone-specific alkaline phosphatase (BS-ALP), carboxy-terminal cross-linking telopeptide of type 1 collagen (CTx), intact PTH (iPTH), and BMD were compared among the four groups using analysis of covariance. Thresholds of 25(OH)D were then assessed using spline plots and locally weighted regression smoothing (LOESS) plots. RESULTS: 25(OH)D was negatively correlated with serum BS-ALP, CTx, and iPTH. Only femur neck and total femur BMD had significant positive relationships with 25(OH)D. Cutoff values of 11.9 and 9.7 ng/mL were estimated from the spline plots of femur neck and total femur BMD, respectively. For iPTH, the LOESS plot showed a steep decrease to a serum 25(OH)D concentration of about 20 ng/mL, followed by a plateau. CONCLUSIONS: According to this study, a serum 25(OH)D concentration of 20 ng/mL, rather than 30 ng/mL, was appropriate for bone health.

Increment of serum bilirubin as an independent marker predicting new-onset type 2 diabetes mellitus in a Korean population.

BACKGROUND AND AIMS: Several cross-sectional studies reported that serum bilirubin concentrations had an inverse association with type 2 diabetes mellitus (T2DM) prevalence. The aim of the current study was to investigate the relationship between percentage change in bilirubin levels (PCB) and incident risk of T2DM using a longitudinal model. METHODS AND RESULTS: 22,084 participants who received regular health check-ups between 2006 and 2012 were enrolled. Multivariable-adjusted Cox regression models were used to determine the hazard ratio (HR) of incident T2DM based on PCB. PCB was determined by subtracting baseline serum bilirubin level (BB) from the bilirubin level at the end of follow-up or a year before the last date of diagnosis, dividing by BB and multiplying by 100. Compared to non-diabetics, BB was lower in the diabetic group at the initial visit. There were 20,098 participants without T2DM at the initial visit; 1253 new cases occurred during follow-up. As PCB increased, T2DM incidence also increased (P < 0.001). After adjusting for confounders, the HR of incident T2DM in the highest PCB quartile was 2.08 (95% confidence interval [CI] 1.76-2.46). This trend remained significant when PCB was analyzed as a continuous variable (HR for 1-SD increment, 1.25; 95% CI 1.19-1.31). Additional analysis comparing the rate of PCB during the follow-up period revealed that the serum bilirubin level of the Incident T2DM group increased before T2DM development and decreased rapidly thereafter compared to others (P < 0.001). CONCLUSIONS: Bilirubin level increment over time is associated with T2DM development.

Neutrophils negatively regulate induction of mucosal IgA responses after sublingual immunization.

Induction of mucosal immunoglobulin-A (IgA) capable of providing a first line of defense against bacterial and viral pathogens remains a major goal of needle-free vaccines given via mucosal routes. Innate immune cells are known to play a central role in induction of IgA responses by mucosal vaccines, but the relative contribution of myeloid cell subsets to these responses has not firmly been established. Using an in vivo model of sublingual vaccination with Bacillus anthracis edema toxin (EdTx) as adjuvant, we examined the role of myeloid cell subsets for mucosal secretory IgA responses. Sublingual immunization of wild-type mice resulted in a transient increase of neutrophils in sublingual tissues and cervical lymph nodes. These mice later developed Ag-specific serum IgG responses, but not serum or mucosal IgA. Interestingly, EdTx failed to increase neutrophils in sublingual tissues and cervical lymph nodes of IKKß(ΔMye) mice, and these mice developed IgA responses. Partial depletion of neutrophils before immunization of wild-type mice allowed the development of both mucosal and serum IgA responses. Finally, co-culture of B cells with neutrophils from either wild-type or IKKß(ΔMye) mice suppressed secretion of IgA, but not IgM or IgG. These results identify a new role for neutrophils as negative regulators of IgA responses.

IKKß in intestinal epithelial cells regulates allergen-specific IgA and allergic inflammation at distant mucosal sites.

Regulation of allergic responses by intestinal epithelial cells (IECs) remains poorly understood. Using a model of oral allergen sensitization in the presence of cholera toxin as adjuvant and mice with cell-specific deletion of inhibitor-κB kinase (IKKß) in IECs (IKKß(ΔIEC)), we addressed the contribution of IECs to allergic sensitization to ingested antigens and allergic manifestations at distant mucosal site of the airways. Cholera toxin induced higher pro-inflammatory responses and altered the profile of the gut microbiota in IKKß(ΔIEC) mice. Antigen-specific immunoglobulin E (IgE) responses were unaltered in IKKß(ΔIEC) mice, but their IgA antibodies (Abs), T helper type 1 (Th1) and Th17 responses were enhanced. Upon nasal antigen challenge, these mice developed lower levels of allergic lung inflammation, which correlated with higher levels of IgA Abs in the airways. The IKKß(ΔIEC) mice also recruited a higher number of gut-sensitized T cells in the airways after nasal antigen challenge and developed airway hyper-responsiveness, which were suppressed by treatment with anti-interleukin-17A. Fecal microbiota transplant during allergic sensitization reduced Th17 responses in IKKß(ΔIEC) mice, but did not affect IgA Ab responses. In summary, we show that IKKß in IECs shapes the gut microbiota and immune responses to ingested antigens and influences allergic responses in the airways via regulation of IgA Ab responses.

Biochemical changes as enzymatic defense system of phenanthrene exposure in olive flounder, Paralichthys olivaceus.

The objective of this study was to investigate early biological response in olive flounder exposed to sub-lethal concentrations of waterborne phenanthrene (0.5, 1 or 2 microM). The fish were exposed for 4 weeks and we analyzed their enzymatic defense system, antioxidant and phase II enzyme activities, to evaluate the chronic exposure toxicity of phenanthrene. Waterborne phenanthrene affected antioxidant enzymes and glutathione-mediated detoxification as enzyme defense system. Hepatic, gill and kidney glutathione reductase as well as glutathione S-transferase, and catalase activities were markedly elevated after two or four weeks of exposure. These enzymes activities of olive flounder, Paralichthys olivaceus seem to be a convenient tool for monitoring pollution in coastal areas against PAHs pollution including phenanthrene.

Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA.

In vertebrates, the biological consequences of DNA methylation are often mediated by protein factors containing conserved methyl-CpG binding domains (MBDs). Mutations in the MBD protein MeCP2 cause the neurodevelopmental disease Rett syndrome. We report here the solution structure of the MBD of the human methylation-dependent transcriptional regulator MBD1 bound to methylated DNA. DNA binding causes a loop in MBD1 to fold into a major and novel DNA binding interface. Recognition of the methyl groups and CG sequence at the methylation site is due to five highly conserved residues that form a hydrophobic patch. The structure indicates how MBD may access nucleosomal DNA without encountering steric interference from core histones, and provides a basis to interpret mutations linked to Rett syndrome in MeCP2.

Tyrosinase-induced cross-linking of tyrosine-containing peptides investigated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Tyrosinase-induced oxidation of tyrosine is known to lead to melanin by cross-linking of 5,6-dihydroxyindole (DHI) and indole-5,6-quinone intermediates. However, tyrosinase-induced cross-linking of tyrosine-containing peptides has not been reported. We observed tyrosinase-induced adducts of tyrosine-containing peptides by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). MALDI-TOFMS was also used to observe tyrosine adducts at various levels of oxidation derived from acid hydrolysis of the peptide adducts. The rate of tyrosinase-induced browning of lys-tyr-lys was about half of that of tyrosine. These results indicate that tyrosinase-induced browning of tyrosine-containing peptides via direct oxidation and cross-linking of the benzene ring of the tyrosine residue occurs at a significant rate and needs to be considered in melanogenesis.

Tracking the State Children's Health Insurance Program with hospital data: national baselines, state variations, and some cautions.

State and federal agencies are concerned with the impact of the State Children's Health Insurance Program (CHIP) on the health care of enrolled children. As part of a broad program evaluation, and at relatively low cost, analysts can track data on hospital admissions for ambulatory care sensitive (ACS) conditions. This article uses hospital data for 19 states to calculate baseline ACS rates and to discuss trends and cross-state variations just prior to the start of the CHIPs. A few cautions and limitations are discussed. An unexpected result in the exploration was a substantial increase in the rate of ACS admissions for self-pay and Medicaid-enrolled children during the period of 1990-1995. During that same period, the admission rate for other insured children fell by more than a third. The comparisons across states are meant to be illustrative; they do reveal a relationship between the rate of asthma admissions and the proportion of self-pay plus Medicaid-enrolled cases.

Differential expression of O6-methylguanine-DNA methyltransferase during diethylnitrosamine-induced carcinogenesis and liver regeneration in Sprague-Dawley male rats.

Differential expression of DNA-O6MeG: protein-L-cysteine S-methyltransferase (MGMT) activity and posttranslational modification of the protein during liver regeneration and carcinogenesis were compared in Sprague-Dawley male rats after partial hepatectomy and/or single i.p injection of diethylnitrosamine (DEN, 200 mg/kg). Regenerating hepatocytes after partial hepatectomy induced MGMT transiently within 3 days; however, the induction of MGMT was persistent for 2 weeks after DEN injection, and the combined treatment of DEN and partial hepatectomy maintained the elevated MGMT level for up to 4 weeks. The increased activity was transcriptionally regulated, when analyzed by Northern blot hybridization. The major active form of MGMT protein in the partially hepatectomized or DEN-treated rats was a 26-kDa or 24-kDa species respectively, which was confirmed by Western blot analysis and gel slice assay. The biological significance of the differential induction of MGMT during partial hepatectomy or DEN-induced carcinogenesis is not obvious; however, further studies on possible posttranslational modifications of MGMT protein might shed some light on the functional aspect of MGMT induction.

Late-onset bleb leaks after glaucoma filtering surgery.

OBJECTIVE: To determine the incidence of focal, late-onset, conjunctival bleb leaks after glaucoma filtering surgery. DESIGN: Prospective, cross-sectional analysis. SETTING: Tertiary care outpatient referral center. PATIENTS: Consecutive patients who underwent glaucoma filtering surgery prior to June 1996 presenting for evaluation from September 2,1996, through November 15,1996. Five hundred twenty-five eyes of 525 consecutive patients were enrolled in the study. INTERVENTION: Bleb height (elevated or flat), area (diffuse or localized), and wall thickness (thin, thick, or encapsulated) were classified. Each bleb was tested for focal leakage using a moistened fluorescein strip, cobalt blue illumination, and slit-lamp biomicroscopy. Diffuse transconjunctival aqueous flow did not qualify as a focal leak. MAIN OUTCOME MEASURE: Seidel-positive aqueous leakage. RESULTS: Bleb leakage occurred in 14 eyes following trabeculectomy (mitomycin C treatment, 10 eyes; 5-fluorouracil treatment, 3 eyes; no antifibrosis agent, 1 eye) and in 1 eye following combined cataract and glaucoma surgery with adjunctive mitomycin C therapy. Bleb leakage occurred more frequently in eyes that received mitomycin C (10 [3.7%] of 273 eyes) than 5-fluorouracil (3 [1.4%] of 213 eyes) or no antifibrosis agent (1 [2.6%] of 39 eyes), using Kaplan-Meier estimates (P=.008, log-rank test). Conjunctival blebs were significantly thinner after trabeculectomy with mitomycin C than with 5-fluorouracil (P=.001). Bleb wall thickness was greater following combined cataract and glaucoma surgery than following trabeculectomy alone (P=.008). Age (P=.84), sex (P=.68), race (P=.77), duration of mitomycin C exposure (P=.62), number of antiglaucoma medications (P=.16), and total 5-fluorouracil dose (P=.85) were not associated with late-onset leaks. CONCLUSIONS: The risk of late-onset focal bleb leakage increases following trabeculectomy with mitomycin C therapy. Late leakage after combined cataract and glaucoma surgery is infrequent.