RHS6 coordinately regulates the Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4.

BACKGROUND: Asthma is a Th2 cell-driven inflammatory disease and a major public health concern. The cis-acting element Rad50 hypersensitive site 6 (RHS6) in the Th2 locus control region is essential for regulation of the Th2 cytokine genes; however, its role in allergic airway inflammation and underlying molecular mechanisms of the regulation by RHS6 are poorly understood. OBJECTIVE: We sought to understand the role of RHS6 in the development of allergic airway inflammation and its molecular mechanism for Th2 cytokine expression. METHODS: We used an ovalbumin-induced allergic inflammation model with RHS6-deficient mice to examine the role of RHS6 in this process. To examine molecular mechanism of RHS6 for Th2 cytokine expression, we used DNA affinity chromatography and mass spectrometry, quantitative RT-PCR, ELISA, intracellular cytokine staining, chromatin immunoprecipitation, and co-immunoprecipitation. RESULTS: Deletion of RHS6 caused a dramatic resistance to allergic airway inflammation. RHS6 recruited transcription factors GATA3, SATB1, and IRF4, which play important roles in expression of all three Th2 cytokine genes. RHS6 deficiency caused inhibition of transcription factor-induced Th2 cytokine gene expression. CONCLUSION: RHS6 is a critical regulatory element for allergic airway inflammation and for coordinate regulation of Th2 cytokine genes by recruiting GATA3, SATB1, and IRF4.

Association of the interferon-γ gene (CA)n repeat polymorphism with endometriosis.

OBJECTIVE: To investigate whether the interferon-γ (IFN-γ) gene (CA)(n) repeat polymorphism is associated with susceptibility to endometriosis. DESIGN: Case-control study. SETTING: University Department of Obstetrics and Gynaecology. POPULATION: Women with (n = 622) and without (n = 442) endometriosis. METHODS: Genotyping was performed by fluorescent polymerase chain reaction (PCR) and gene-scan analysis. MAIN OUTCOME MEASURES: Genotype distribution and allele frequency of the dinucleotide (CA)(n) repeat polymorphism in the IFN-γ gene. RESULTS: Seven alleles (12-18 repeats) of the IFN-γ gene (CA)(n) repeat polymorphism were found. In both patients with endometriosis and controls the most common allele was composed of 13 repeats, followed by an allele of 15 repeats, and then by an allele of 12 repeats. Patients with endometriosis had a significantly higher incidence of genotypes with alleles composed of fewer repeats (12-13 repeats), compared with the controls (92.0 versus 84.4%, respectively, P < 001). CONCLUSIONS: Our results suggest that the (CA)(n) repeat polymorphism in the IFN-γ gene may be associated with a risk of endometriosis in the South Korean population.

Socio-economic disparities in behavioural risk factors for cancer and use of cancer screening services in Korean adults aged 30 years and older: the Third Korean National Health and Nutrition Examination Survey, 2005 (KNHANES III).

OBJECTIVES: To estimate the current status of cancer-related health disparities in cancer risk factors and the use of cancer screening services by Korean adults. STUDY DESIGN: Cross-sectional survey study. METHODS: The disparities of behavioural cancer risk factors and use of cancer screening services according to equivalent monthly household income were evaluated, using multivariate logistic regression analysis, among 6466 subjects aged ≥30 years and who completed the health promotion knowledge, attitude and practice survey, which is part of the Third Korean National Health and Nutrition Examination Survey. RESULTS: In men, smoking (P for trend = 0.05) and physical inactivity (P for trend = 0.05) were more common in the lower-income group, while high-risk drinking (P for trend <0.01) was more common in the higher-income group. In women, physical inactivity (P for trend <0.01) was more common in the lower-income group, while smoking and high-risk drinking showed no income disparities. Income disparities were also found in the degree of participation in cancer screening programmes. Men in the highest income quintile underwent more screening for both colorectal and gastric cancer than men in the lowest income quintile and men in the second to fourth income quintiles (P for trend <0.01 for both). Women in the highest income quintile underwent more screening for cervical (P for trend <0.01) and gastric (P for trend = 0.04) cancer, while income disparities were not seen for participation in colorectal or breast cancer screening. CONCLUSIONS: In order to decrease behavioural risk factors and promote participation in cancer screening programmes, more targeted efforts are needed for cancer prevention among lower-income Koreans.

Melt processing of polypropylene-grafted-maleic anhydride/Chitosan polymer blend functionalized with montmorillonite for the removal of lead ions from aqueous solutions.

Heavy metals such as lead ions Pb (II) are a primary concern in the aquatic environment. These is because Pb (II) is poisonous at a threshold limit above 0.01 mg/L, when consumed over a long period of time. Pb (II) poisoning is very harmful to various organs viz. heart, intestine and kidneys. Besides, it affects bones, tissues, nervous and reproductive systems. Hence, it is important to remove Pb (II) from aquatic environment. Polypropylene (PP) and polypropylene grafted-maleic-anhydride (PP-g-MA) based nanocomposites reinforced with Chitosan (CS) and modified montmorillonite clay nanofiller (CL120DT) were successfully fabricated using twin screw melt extrusion for adsorption of Pb (II). The resulting nanocomposites were characterized by XRD to analyze the dispersion properties of the material, TEM and SEM for surface morphology, FTIR analysis for the functional groups and TGA for thermal stability. Pure PP showed two sharp peaks, but there was decreased in the intensity upon adding of CS and CL120DT. Among series of nanocomposites 2.0 phr and 4.0 phr loaded samples shows better storage module than that of pure PP. The uptake of Pb (II) from lead nitrate aqueous solution by PP + PP-g-MA/CL120DT-CS 2.0 phr nanocomposites followed the Langmuir isotherm model, with a remediation of 90.9% at pH 8 and was verified by pseudo-second order kinetic model. These results indicate that PP + PP-g-MA//CL120DT-CS 2.0 phr nanocomposites performed as a superabsorbent for the Pb (II) ion removal from aqueous solution.

Impact of resistance to first-line and injectable drugs on treatment outcomes in MDR-TB.

Recently, resistance to additional first-line and injectable drugs was reported to be an independent risk factor for adverse outcomes in multidrug-resistant (MDR) tuberculosis (TB) patients. The aim of the present study was to confirm these observations in MDR-TB patients without HIV infection. MDR-TB patients treated at a tertiary referral hospital in South Korea between January 1996 and December 2005 were included. The unadjusted and adjusted odds ratios of adverse treatment outcome were calculated for resistance to each drug and combination of drugs using simple or multiple logistic regressions. None of the resistance to additional first-line or injectable drugs was associated with higher odds for adverse treatment outcome in 155 MDR but nonextensively drug-resistant (non-XDR) TB patients. However, streptomycin resistance was associated with 12 times the odds for adverse treatment outcome in 42 extensively drug-resistant (XDR) TB patients. Neither combinations of first-line drugs nor those of injectable drugs were associated with increased odds for adverse treatment outcomes in non-XDR MDR-TB patients or XDR-TB patients. Only streptomycin resistance among the first-line or injectable drugs was associated with adverse treatment outcomes in extensively drug-resistant tuberculosis patients without HIV infection.

Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1.

Cells of the monocyte-macrophage lineage are targets for human immunodeficiency virus-1 (HIV-1) infection in vivo. However, many laboratory strains of HIV-1 that efficiently infect transformed T cell lines replicate poorly in macrophages. A 20-amino acid sequence from the macrophage-tropic BaL isolate of HIV-1 was sufficient to confer macrophage tropism on HTLV-IIIB, a T cell line--tropic isolate. This small sequence element is in the V3 loop, the envelope domain that is the principal neutralizing determinant of HIV-1. Thus, the V3 loop not only serves as a target of the host immune response but is also pivotal in determining HIV-1 tissue tropism.

Identification of envelope V3 loop as the major determinant of CD4 neutralization sensitivity of HIV-1.

Laboratory isolates of human immunodeficiency virus type-1 (HIV-1) such as HTLV-IIIB are generally T cell line-tropic and highly sensitive to neutralization by soluble CD4 (sCD4), a potential antiviral agent that is undergoing clinical trial. However, many primary HIV-1 isolates are macrophage-tropic and sCD4-resistant. Envelope V3 loop sequences derived from primary HIV-1 isolates were sufficient to confer on HTLV-IIIB not only the tissue tropism but also the degree of sCD4 neutralization resistance characteristic of their HIV-1 strains of origin. Single amino acid changes in the V3 loop enhanced sCD4 resistance by up to tenfold. These observations suggest that the tissue tropism and sCD4 neutralization sensitivity of HIV-1 isolates are regulated by similar mechanisms.

Supine sleep positioning in preterm and term infants after hospital discharge from 2000 to 2011.

OBJECTIVE: Supine sleep positioning (SSP) has been shown to reduce the risk of sudden infant death syndrome (SIDS) and preterm infants are at higher risk for SIDS. Population-based estimates of SSP are lacking for the preterm population. The objectives of this study are: (1) compare the prevalence of SSP after hospital discharge for preterm and term infants in the United States; and (2) assess racial/ethnic disparities in SSP for preterm and term infants. STUDY DESIGN: We analyzed the 2000 to 2011 data from the Pregnancy Risk Assessment Monitoring System of Centers for Disease Control and Prevention from 35 states. We measured prevalence of SSP by preterm and term gestational age (GA) categories. We calculated adjusted prevalence ratios (APR) to evaluate the likelihood of SSP for each GA category compared with term infants and the likelihood of SSP for non-Hispanic black (NHB) and Hispanic infants compared with non-Hispanic white (NHW) infants. RESULTS: Prevalence of SSP varied by GA: ⩽27, 59.7%; 28 0/7 to 33 6/7, 63.7%; 34 0/7 to 36 6/7 (late preterm), 63.6%; and 37 0/7 to 42 6/7 (term) weeks, 66.8% (P<0.001). In the adjusted analyses, late preterm infants were slightly less likely to be placed in SSP compared with term infants (APR: 0.96, confidence interval: 0.95 to 0.98). There were racial/ethnic disparities in SSP for all GA categories when NHB and Hispanic infants were compared with NHW infants. CONCLUSIONS: All infants had suboptimal adherence to SSP indicating a continued need to better engage families about SSP. Parents of late preterm infants and families of NHB and Hispanic infants will also require greater attention given their decreased likelihood of SSP.

Treatments of depression and the functional capacity to work.

This study evaluated the effects of antidepressants and psychotherapy on work impairment in depressed patients. Original databases from 10 published treatment studies were compiled and analyzed (N = 827). Functional work impairment was common at baseline, manifested by unemployment (11%) or on-the-job performance problems (absenteeism, decreased productivity, interpersonal problems, 44%). Generally, work outcomes were good when treatment was symptomatically effective, but the trajectories of work restoration and symptom remission were different, with work recovery appearing to take considerably longer. Relapse was an important determinant of long-term occupational outcome, particularly for seriously ill patients for whom relapse meant rehospitalization or other profound social disruption. Affective impairment was distinguished from functional impairment, with the former characterizing milder depression and the latter characterizing moderate to severe depression. Some methodological recommendations are discussed.

Home care practices for preterm and term infants after hospital discharge in Massachusetts, 2007 to 2010.

OBJECTIVE: The objective of this study was to compare the prevalence of home care practices in very to moderately preterm (VPT), late preterm (LPT) and term infants born in Massachusetts. STUDY DESIGN: Using 2007 to 2010 Massachusetts Pregnancy Risk Assessment Monitoring System data, births were categorized by gestational age (VPT: 23 to 33 weeks; LPT: 34 to 36 weeks; term: 37 to 42 weeks). Home care practices included breastfeeding initiation and continuation, and infant sleep practices (supine sleep position, sleeping in a crib, cosleeping in an adult bed). We developed multivariate models to examine the association of infant sleep practices and breastfeeding with preterm status, controlling for maternal sociodemographic characteristics. RESULTS: Supine sleep position was more prevalent among term infants compared with VPT and LPT infants (77.1%, 71.5%, 64.4%; P=0.02). In the adjusted model, LPT infants were less likely to be placed in supine sleep position compared with term infants (adjusted prevalence ratio=0.86; 95% confidence interval: 0.75 to 0.97). Breastfeeding initiation and continuation did not differ among preterm and term groups. Nearly 16% of VPT and 18% of LPT and term infants were not sleeping in cribs and 14% of LPT and term infants were cosleeping on an adult bed. CONCLUSION: Compared with term infants, LPT infants were less likely to be placed in supine sleep position after hospital discharge. A significant percent of preterm and term infants were cosleeping on an adult bed. Hospitals may consider improving their safe sleep education, particularly to mothers of LPT infants.

Implementation of safe sleep practices in the neonatal intensive care unit.

OBJECTIVE: To increase the percentage of eligible infants engaging in safe sleep practices (SSP) in two level III neonatal intensive care units (NICUs) in the Boston, Massachusetts area. STUDY DESIGN: On the basis of eligibility criteria (⩾34 weeks or ⩾1800 g without acute medical conditions), all infants were eligible for two sleep practices: SSP or NICU therapeutic positioning (NTP) depending on their gestational age, weight, clinical illness and need for therapeutic interventions. Compliance with SSP was defined as: (1) supine positioning, (2) in a flat crib with no incline, (3) without positioning devices and (4) without toys, comforters or fluffy blankets. NTP comprised usual NICU care. Nursing education was comprised of a web-based learning module and in-person teaching sessions with a study team member. Double-sided crib cards (SSP one side and NTP on the other) were attached to the bedside of every infant. Pre- and postintervention audits of all infants were carried out at both study sites. We compared compliance across all time points using generalized estimating equations to account for correlated data (SAS v9.3, Cary, NC, USA). RESULT: Of 755 cases, 395 (52.3%) were assessed to be eligible for SSP. From the pre- to post-intervention period, there was a significant improvement in overall compliance with SSP (25.9 to 79.7%; P-value<0.001). Adherence to each component of SSP also improved significantly following the intervention. CONCLUSION: Safe infant sleep practices can be integrated into the routine care of preterm infants in the NICU. Modeling SSP to families far in advance of hospital discharge may improve adherence to SSP at home and reduce the risk of sleep-related morbidity and mortality in this vulnerable population of infants.

Tuberculosis is frequently diagnosed within 12 months of diabetes mellitus.

BACKGROUND: Evidence regarding the effects of tuberculosis (TB) screening among patients with diabetes mellitus (DM) in intermediate TB burden countries is insufficient, and the most appropriate time point for TB screening is unclear. OBJECTIVE: To investigate trends in TB incidence among newly diagnosed DM patients. DESIGN: A retrospective cohort study of the claims database of the Health Insurance Review and Assessment Service in Korea was performed. Participants were newly diagnosed with type 2 DM in 2009. The study outcome was TB incidence between 2009 and 2011 among participants according to duration of type 2 DM. RESULTS: A cohort of 331,601 patients with newly diagnosed type 2 DM in 2009 was identified. During the 3-year follow-up period, 1533 patients were diagnosed with TB. The estimated incidence of TB among newly diagnosed type 2 DM patients was 18/10,000 patient-years (py) (95%CI 17.5-19.4). TB incidence was 33/10,000 py (95%CI 30.0-35.6) in the first 6 months, and 19/10,000 py (95%CI 16.5-20.6) in the following 6-month period. CONCLUSIONS: The risk of developing TB was increased among DM patients, particularly during the first 12 months after DM diagnosis.

Effect of noise on the detection of rib fractures by residents.

RATIONALE AND OBJECTIVES: The authors assessed the effect of noise on the detectability of rib fractures by residents. METHODS: Eight radiology residents read chest posterior-anterior radiographs of 92 subjects with rib fracture(s) and 28 normal subjects to detect rib fracture(s) according to a five-point scale of confidence, under quiet and "noisy" conditions. Each individual's attitude toward noise was measured by a multiple-choice questionnaire. RESULTS: The readers were divided into two groups depending on the questionnaire result: group A readers were accustomed to a quiet environment, and group B readers were accustomed to noisy environments or were unaffected by noise. Group A's performance, measured by the area (Az) under the receiver operating characteristic (ROC) curve, was better in quiet conditions when compared with their performance in noisy conditions; however, the opposite tendency was observed for group B. There was a significant individual difference of performance in response to noise. CONCLUSION: Effect of noise on the detection of rib fractures depends on an individual's attitude toward sound and noise.

Evaluation of diurnal variation in fentanyl clearance.

Drug disposition kinetics are commonly assumed to be time-invariant as a first approximation. In a preliminary study, 6 healthy volunteers received a constant intravenous infusion of 50 micrograms/h for 48 hours; the serum fentanyl concentration at 36 hours was lower than that at 24 hours for all 6 subjects. This suggested possible diurnal variations in fentanyl clearance. In 2 subsequent studies, with healthy volunteers receiving short infusions of fentanyl (n = 9, 150 micrograms/h for 0.33 hours every 4 hours; n = 12, 150 micrograms/h for 0.33 hours every hour, respectively), the area under the serum fentanyl concentration curve appeared to be independent of the time of infusion. Thus, there was no evidence to support a large diurnal change in fentanyl clearance. The serum fentanyl concentration-time profiles, corrected for carryover from previous doses, within each study were superimposable. This suggests that there are no diurnal changes in the distribution kinetics of fentanyl.

In vitro and in vivo evaluation of a once-daily controlled-release pseudoephedrine product.

The functionality of a once-daily, osmotic dosage form--gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)--was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)--240 and 120 mg--were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed-release 12-hour pseudoephedrine capsule given every 12 hours in a randomized 4-way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14-17%). A one-to-one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high-fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites.

Drug absorption through the skin can vary according to the application site. The nicotine transdermal system, Nicoderm (Alza Corp., Palo Alto, CA) contains a rate-controlling membrane designed to regulate delivery of nicotine to the skin and thus limit variability in nicotine plasma levels. Plasma nicotine concentrations were compared after application of NTS 14 mg/day to three different skin sites (upper back, upper outer arm, upper chest) in a randomized, crossover study involving 12 healthy male smokers. Plasma nicotine profiles from all three sites were similar: nicotine concentrations increased rapidly within 2 to 4 hours, reached broad peaks of approximately 11 to 14 ng/mL, and then remained relatively constant between 8 and 24 hours after application. The mean nicotine maximum peak plasma concentration values for nicotine transdermal system application to the arm, back, and chest were equivalent (13.8, 14.6, and 13.2 ng/mL, respectively). The mean time to reach peak concentration (tmax) (3 to 6 hours), and area under the curve (168, 186, and 183 ng.h/mL) values for the arm, back, and chest, respectively, were not significantly different. Thus, bioequivalent plasma nicotine concentrations were achieved irrespective of the application site on the upper body.

Comparison of the nicotine pharmacokinetics of Nicoderm (nicotine transdermal system) and half-hourly cigarette smoking.

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half-hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half-hourly intervals on days 1 and 5; ad libitum smoking on days 2-4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.

Transdermal testosterone administration in hypogonadal men: comparison of pharmacokinetics at different sites of application and at the first and fifth days of application.

In this study of 13 hypogonadal men (25-69 years of age), three open-label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration-time curve from 0 to 27 hours (AUC0-27) values for testosterone after one-day applications to the upper buttocks, upper arm, and back were 9,560 ng.hr/dL, 8,651 ng.hr/dL, and 8,988 ng.hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days.

Testosterone pharmacokinetics after application of an investigational transdermal system in hypogonadal men.

This open-label, randomized, placebo lead-in, three-treatment crossover study in 19 hypogonadal men (27-82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

Primary amyloidoma of the cervical spine.

Primary solitary amyloidoma of the spine is a disease characterized by localized deposits of amyloid. We describe and illustrate the radiologic appearance of primary solitary amyloidoma of the spine on plain radiographs, CT scans, and MR images. The imaging findings revealed features of a nonspecific soft-tissue mass with calcifications. Epidural extension of the amyloidoma caused spinal cord compression.