Estimated exposure to arsenic in breastfed and formula-fed infants in a United States cohort.
Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding leads to reduced infant exposure to arsenic in regions with lower arsenic concentrations. We estimated the relative contributions of breast milk and formula to arsenic exposure during early infancy in a U.S. We measured arsenic in home tap water (n = 874), urine from 6-week-old infants (n = 72), and breast milk from mothers (n = 9) enrolled in the New Hampshire Birth Cohort Study (NHBCS) using inductively coupled plasma mass spectrometry. Using data from a 3-day food diary, we compared urinary arsenic across infant feeding types and developed predictive exposure models to estimate daily arsenic intake from breast milk and formula. Urinary arsenic concentrations were generally low (median, 0.17 μg/L; maximum, 2.9 μg/L) [corrected] but 7.5 times higher for infants fed exclusively with formula than for infants fed exclusively with breast milk (β = 2.02; 95% CI: 1.21, 2.83; p < 0.0001, adjusted for specific gravity). Similarly, the median estimated daily arsenic intake by NHBCS infants was 5.5 times higher for formula-fed infants (0.22 μg/kg/day) than for breastfed infants (0.04 μg/kg/day). Given median arsenic concentrations measured in NHBCS tap water and previously published for formula powder, formula powder was estimated to account for ~ 70% of median exposure among formula-fed NHBCS infants. Our findings suggest that breastfed infants have lower arsenic exposure than formula-fed infants, and that both formula powder and drinking water can be sources of exposure for U.S. infants.


Forced patterns near a Turing-Hopf bifurcation.
We study time-periodic forcing of spatially extended patterns near a Turing-Hopf bifurcation point. A symmetry-based normal form analysis yields several predictions, including that (i) weak forcing near the intrinsic Hopf frequency enhances or suppresses the Turing amplitude by an amount that scales quadratically with the forcing strength, and (ii) the strongest effect is seen for forcing that is detuned from the Hopf frequency. To apply our results to specific models, we perform a perturbation analysis on general two-component reaction-diffusion systems, which reveals whether the forcing suppresses or enhances the spatial pattern. For the suppressing case, our results are consistent with features of previous experiments on the chlorine dioxide-iodine-malonic acid chemical reaction. However, we also find examples of the enhancing case, which has not yet been observed in experiment. Numerical simulations verify the predicted dependence on the forcing parameters.


Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy.
Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy.


Matcha Green Tea Drinks Enhance Fat Oxidation During Brisk Walking in Females.
Intake of the catechin epigallocatechin gallate and caffeine has been shown to enhance exercise-induced fat oxidation. Matcha green tea powder contains catechins and caffeine and is consumed as a drink. We examined the effect of Matcha green tea drinks on metabolic, physiological, and perceived intensity responses during brisk walking. A total of 13 females (age: 27 ± 8 years, body mass: 65 ± 7 kg, height: 166 ± 6 cm) volunteered to participate in the study. Resting metabolic equivalent (1-MET) was measured using Douglas bags (1-MET: 3.4 ± 0.3 ml·kg-1·min-1). Participants completed an incremental walking protocol to establish the relationship between walking speed and oxygen uptake and individualize the walking speed at 5- or 6-MET. A randomized, crossover design was used with participants tested between Days 9 and 11 of the menstrual cycle (follicular phase). Participants consumed three drinks (each drink made with 1 g of Matcha premium grade; OMGTea Ltd., Brighton, UK) the day before and one drink 2 hr before the 30-min walk at 5- (n = 10) or 6-MET (walking speed: 5.8 ± 0.4 km/hr) with responses measured at 8-10, 18-20, and 28-30 min. Matcha had no effect on physiological and perceived intensity responses. Matcha resulted in lower respiratory exchange ratio (control: 0.84 ± 0.04; Matcha: 0.82 ± 0.04; p < .01) and enhanced fat oxidation during a 30-min brisk walk (control: 0.31 ± 0.10; Matcha: 0.35 ± 0.11 g/min; p < .01). Matcha green tea drinking can enhance exercise-induced fat oxidation in females. However, when regular brisk walking with 30-min bouts is being undertaken as part of a weight loss program, the metabolic effects of Matcha should not be overstated.


Contrast-enhanced 18F-FDG PET/CT: 1-stop-shop imaging for assessing the resectability of pancreatic cancer.
Patients with pancreatic cancer continue to have a poor prognosis, with a 5-y survival rate of less than 5%. Surgery is the only treatment that offers a potential cure. Determining resectability is the principal goal of staging in pancreatic cancer patients. Our objective was to evaluate the value of combined contrast-enhanced (18)F-FDG PET/CT in assessing the resectability of pancreatic cancer and to compare enhanced PET/CT with the performance of PET alone and unenhanced PET/CT. Fifty patients (25 women and 25 men; mean age, 64.3 y; range, 39-84 y) with biopsy-proven pancreatic adenocarcinoma underwent enhanced (18)F-FDG PET/CT for the evaluation of resectability. Criteria for unresectability were distant metastases, peritoneal carcinomatosis, arterial infiltration, or invasion of neighboring organs other than the duodenum. The performance of enhanced PET/CT regarding resectability was compared with that of PET alone and unenhanced PET/CT. Histology, intraoperative findings, and follow-up CT with clinical investigations were used as the reference standard. According to the reference standard, 27 patients had disease that was not resectable because of distant metastases (n=17), peritoneal carcinomatosis (n=5), or local infiltration (n=5). In the assessment of resectability, PET alone had a sensitivity of 100%, specificity of 44%, accuracy of 70%, positive predictive value of 61%, and negative predictive value of 100%; unenhanced PET/CT had respective values of 100%, 56%, 76%, 66%, and 100%; and enhanced PET/CT, 96%, 82%, 88%, 82%, and 96%. In 5 patients, unresectability was missed by all imaging methods and was diagnosed intraoperatively. Enhanced PET/CT was significantly superior to PET alone (P=0.035), and there was a trend for enhanced PET/CT to be superior to unenhanced PET/CT (P=0.070). The use of enhanced PET/CT as a 1-stop-shop imaging protocol for assessing the resectability of pancreatic cancer is feasible and accurate. Enhanced PET/CT is significantly superior to PET alone.


Antibiotics: past, present and future.
The first antibiotic, salvarsan, was deployed in 1910. In just over 100 years antibiotics have drastically changed modern medicine and extended the average human lifespan by 23 years. The discovery of penicillin in 1928 started the golden age of natural product antibiotic discovery that peaked in the mid-1950s. Since then, a gradual decline in antibiotic discovery and development and the evolution of drug resistance in many human pathogens has led to the current antimicrobial resistance crisis. Here we give an overview of the history of antibiotic discovery, the major classes of antibiotics and where they come from. We argue that the future of antibiotic discovery looks bright as new technologies such as genome mining and editing are deployed to discover new natural products with diverse bioactivities. We also report on the current state of antibiotic development, with 45 drugs currently going through the clinical trials pipeline, including several new classes with novel modes of action that are in phase 3 clinical trials. Overall, there are promising signs for antibiotic discovery, but changes in financial models are required to translate scientific advances into clinically approved antibiotics.


Endovascular intervention for delayed stenosis of extracranial-intracranial bypass saphenous vein grafts.
Bypass graft stenosis is an uncommon but significant issue which can be encountered following extracranial-intracranial (EC-IC) bypass surgery and carries significant potential for morbidity and mortality. Angioplasty for graft stenosis (with or without stenting) has been extensively discussed in the cardiothoracic literature but its application for neurosurgical purposes has not been well documented. Cases of EC-IC bypass undergoing endovascular intervention for graft stenosis were retrospectively reviewed; a literature search was performed. Diagnosis, pathology and indications for intervention were reviewed. Three patients underwent 13 endovascular interventions for EC-IC saphenous vein graft stenosis. The indication for the initial bypass was an unsecured intracranial aneurysm in all cases, using an interposition saphenous vein graft. The initial endovascular procedure was needed 9-23 weeks after the bypass surgery, a timeframe suggestive of intimal hyperplasia as the underlying etiology of stenosis. There were nine cases of angioplasty alone, three with stent placement and one case in which vasodilators were infused. Non-invasive phase contrast quantitative MR angiography was effective in predicting graft stenosis. Despite intervention, two grafts ultimately occluded and a third has remained patent only after multiple angioplasties and placement of a drug eluting coronary stent. Although rare, bypass graft stenosis can occur in the subacute period, and likely represents a flow related venopathy. Given the challenges of re-do bypass surgery, endovascular intervention is an attractive treatment option. However, although repeated interventions with diligent follow-up may allow graft salvage, failure of endovascular intervention can also ultimately result in graft occlusion.


Retrospective review and telephone follow-up to evaluate a physical therapy protocol for treating persistent postural-perceptual dizziness: A pilot study.
Persistent postural-perceptual dizziness (PPPD) (formerly chronic subjective dizziness) may be treated using the habituation form of vestibular and balance rehabilitation therapy (VBRT), but therapeutic outcomes have not been formally investigated. This pilot study gathered the first data on the efficacy of VBRT for individuals with well-characterized PPPD alone or PPPD plus neurotologic comorbidities (vestibular migraine or compensated vestibular deficits). Twenty-six participants were surveyed by telephone an average of 27.5 months after receiving education about PPPD and instructions for home-based VBRT programs. Participants were queried about exercise compliance, perceived benefits of therapy, degree of visual or motion sensitivity remaining, disability level, and other interventions. Twenty-two of 26 participants found physical therapy consultation helpful. Fourteen found VBRT exercises beneficial, including 8 of 12 who had PPPD alone and 6 of 14 who had PPPD with co-morbidities. Of the 14 participants who found VBRT helpful, 7 obtained relief of sensitivity to head/body motion, 5 relief of sensitivity to visual stimuli, and 4 complete remission. Comparable numbers for the 12 participants who found VBRT not helpful were 1 (head/body motion), 3 (visual stimuli), and 0 (remission). This pilot study offers the first data supporting the habituation form of VBRT for treatment of PPPD.


Rapid analysis of multiclass antibiotic residues and some of their metabolites in hospital, urban wastewater and river water by ultra-high-performance liquid chromatography coupled to quadrupole-linear ion trap tandem mass spectrometry.
The present work describes the development of a fast and robust analytical method for the determination of 53 antibiotic residues, covering various chemical groups and some of their metabolites, in environmental matrices that are considered important sources of antibiotic pollution, namely hospital and urban wastewaters, as well as in river waters. The method is based on automated off-line solid phase extraction (SPE) followed by ultra-high-performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry (UHPLC-QqLIT). For unequivocal identification and confirmation, and in order to fulfill EU guidelines, two selected reaction monitoring (SRM) transitions per compound are monitored (the most intense one is used for quantification and the second one for confirmation). Quantification of target antibiotics is performed by the internal standard approach, using one isotopically labeled compound for each chemical group, in order to correct matrix effects. The main advantages of the method are automation and speed-up of sample preparation, by the reduction of extraction volumes for all matrices, the fast separation of a wide spectrum of antibiotics by using ultra-high-performance liquid chromatography, its sensitivity (limits of detection in the low ng/L range) and selectivity (due to the use of tandem mass spectrometry) The inclusion of β-lactam antibiotics (penicillins and cephalosporins), which are compounds difficult to analyze in multi-residue methods due to their instability in water matrices, and some antibiotics metabolites are other important benefits of the method developed. As part of the validation procedure, the method developed was applied to the analysis of antibiotics residues in hospital, urban influent and effluent wastewaters as well as in river water samples.


Contribution of genome-wide HCV genetic differences to outcome of interferon-based therapy in Caucasian American and African American patients.
Hepatitis C virus (HCV) has six major genotypes, and patients infected with genotype 1 respond less well to interferon-based therapy than other genotypes. African American patients respond to interferon alpha-based therapy at about half the rate of Caucasian Americans. The effect of HCV's genetic variation on treatment outcome in both racial groups is poorly understood. We determined the near full-length pre-therapy consensus sequences from 94 patients infected with HCV genotype 1a or 1b undergoing treatment with peginterferon alpha-2a and ribavirin through the Virahep-C study. The sequences were stratified by genotype, race and treatment outcome to identify HCV genetic differences associated with treatment efficacy. HCV sequences from patients who achieved sustained viral response were more diverse than sequences from non-responders. These inter-patient diversity differences were found primarily in the NS5A gene in genotype 1a and in core and NS2 in genotype 1b. These differences could not be explained by host selection pressures. Genotype 1b but not 1a African American patients had viral genetic differences that correlated with treatment outcome. Higher inter-patient viral genetic diversity correlated with successful treatment, implying that there are HCV genotype 1 strains with intrinsic differences in sensitivity to therapy. Core, NS3 and NS5A have interferon-suppressive activities detectable through in vitro assays, and hence these activities also appear to function in human patients. Both preferential infection with relatively resistant HCV variants and host-specific factors appear to contribute to the unusually poor response to therapy in African American patients.


Physiological, morphological, and ecological tradeoffs influence vertical habitat use of deep-diving toothed-whales in the Bahamas.
Dive capacity among toothed whales (suborder: Odontoceti) has been shown to generally increase with body mass in a relationship closely linked to the allometric scaling of metabolic rates. However, two odontocete species tagged in this study, the Blainville's beaked whale Mesoplodon densirostris and the Cuvier's beaked whale Ziphius cavirostris, confounded expectations of a simple allometric relationship, with exceptionally long (mean: 46.1 min & 65.4 min) and deep dives (mean: 1129 m & 1179 m), and comparatively small body masses (med.: 842.9 kg & 1556.7 kg). These two species also exhibited exceptionally long recovery periods between successive deep dives, or inter-deep-dive intervals (M. densirostris: med. 62 min; Z. cavirostris: med. 68 min). We examined competing hypotheses to explain observed patterns of vertical habitat use based on body mass, oxygen binding protein concentrations, and inter-deep-dive intervals in an assemblage of five sympatric toothed whales species in the Bahamas. Hypotheses were evaluated using dive data from satellite tags attached to the two beaked whales (M. densirostris, n = 12; Z. cavirostris, n = 7), as well as melon-headed whales Peponocephala electra (n = 13), short-finned pilot whales Globicephala macrorhynchus (n = 15), and sperm whales Physeter macrocephalus (n = 27). Body mass and myoglobin concentration together explained only 36% of the variance in maximum dive durations. The inclusion of inter-deep-dive intervals, substantially improved model fits (R2 = 0.92). This finding supported a hypothesis that beaked whales extend foraging dives by exceeding aerobic dive limits, with the extension of inter-deep-dive intervals corresponding to metabolism of accumulated lactic acid. This inference points to intriguing tradeoffs between body size, access to prey in different depth strata, and time allocation within dive cycles. These tradeoffs and resulting differences in habitat use have important implications for spatial distribution patterns, and relative vulnerabilities to anthropogenic impacts.


Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98.
Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.


New method for assessing cardiac parasympathetic activity using 24 hour electrocardiograms.
Cardiac parasympathetic activity was assessed using 24 hour electrocardiographic recordings by measuring the incidence of larger changes in successive RR intervals, which in normal subjects occur frequently but irregularly. In 25 normal subjects the mean number of times per hour in which the change in successive RR interval was greater than 50 ms was 150-250 during waking and 350-450 during sleeping. By contrast, 30 diabetics with medically denervated hearts (12 with cardiovascular reflex evidence of parasympathetic damage and 18 with additional sympathetic damage) and six cardiac transplant patients with surgically denervated hearts had extremely low counts. Additionally, of 20 diabetics with normal cardiovascular reflexes, about half had abnormally low counts, suggesting that this method is better than currently available reflex tests in detecting early cardiac parasympathetic damage. This technique provides a valid and sensitive way of monitoring cardiac parasympathetic activity over prolonged periods.


Two-Year Follow-Up after Treatment with the Cognitive Behavioral Analysis System of Psychotherapy versus Supportive Psychotherapy for Early-Onset Chronic Depression.
Evidence on the long-term efficacy of psychotherapeutic approaches for chronic depression is scarce. To evaluate the effects of the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) compared to Supportive Psychotherapy (SP) 1 year and 2 years after treatment termination. In this study, we present 1- and 2-year follow-up assessments of a prospective, multicenter, evaluator-blinded, randomized clinical trial of outpatients with early-onset chronic major depression (n = 268). The initial treatment included 32 sessions of CBASP or SP over 48 weeks. The primary outcome was the rate of "well weeks" (Longitudinal Interval Follow-Up Evaluation; no/minimal symptoms) after 1 year and 2 years. The secondary outcomes were, among others, clinician- and self-rated depressive symptoms, response/remission rates, and quality of life. Of the 268 randomized patients, 207 (77%) participated in the follow-up. In the intention-to-treat analysis, there was no statistically significant difference between CBASP and SP patients in experiencing well weeks (CBASP: mean [SD] of 48.6 [36.9] weeks; SP: 39.0 [34.8]; rate ratio 1.26, 95% CI 0.99-1.59, p = 0.057, d = 0.18) and in remission rates (CBASP: 1 year 40%, 2 years 40.2%; SP: 1 year 28.9%, 2 years 33%) in the 2 years after treatment. Statistically significant effects were found in favor of CBASP 1 year after treatment termination regarding the rate of well weeks, self-rated depressive symptoms, and depression-related quality of life. CBASP lost its superiority over SP at some point between the first and the second year. This suggests the necessity of maintenance treatment for early-onset chronically depressed patients remitted with CBASP during the acute therapy phase, as well as the sequential integration of other treatment strategies, including medication for those who did not reach remission.


Local and systemic total antioxidant capacity in periodontitis and health.
The involvement of reactive oxygen species (ROS) in periodontal pathology is unclear but will be modulated by in vivo antioxidant defence systems. The aim of this cross-sectional study was to determine both local (saliva and gingival crevicular fluid (GCF) and peripheral (plasma and serum) antioxidant capacity in periodontal health and disease. Twenty non-smoking volunteers with chronic periodontitis were sampled together with twenty age- and sex-matched, non-smoking controls. After overnight fasting, saliva (whole unstimulated and stimulated) and blood were collected. Total antioxidant capacity (TAOC) was determined using a previously reported enhanced chemiluminescence method. GCF antioxidant concentration was significantly lower (p<0.001) in periodontitis subjects compared to healthy controls. Although mean levels of peripheral and salivary TAOC were also lower in periodontitis the difference was only significant for plasma (p<0.05). Healthy subjects' GCF antioxidant concentration was significantly greater than paired serum or plasma (p<0.001). Data stratified for gender did not alter the findings and a male bias was revealed in all clinical samples except GCF. These findings suggest that the antioxidant capacity of GCF is both qualitatively and quantitatively distinct from that of saliva, plasma and serum. Whether changes in the GCF compartment in periodontitis reflect predisposition to or the results of ROS-mediated damage remains unclear. Reduced plasma total antioxidant defence could result from low-grade systemic inflammation induced by the host response to periodontal bacteria, or may be an innate feature of periodontitis patients.


Tumour burden and interleukin-2 dose affect the interaction between low-dose total body irradiation and interleukin 2.
Low-dose total body irradiation (LTBI) has a synergistic immune-mediated antitumour effect when used in combination with interleukin 2 (IL-2) in a murine metastatic malignant melanoma model. To optimise the use of this combination treatment this study was performed to test the effect of tumour burden and dose of both LTBI and IL-2 on the therapeutic potential of this treatment strategy. Ten-week-old female C57BL/6 mice were inoculated intravenously (day 0) with 1 million B16F1 malignant melanoma cells. Groups of mice received no treatment, a single fraction of LTBI alone, IL-2 treatment alone, or a combination of LTBI and IL-2. Two doses of LTBI and IL-2 were tested. LTBI was given on day +10 and IL-2 treatment started on day +11. On day +18 the mice were killed. The lungs were removed and analysed for tumour burden. Lung sections were also tested for infiltrating leucocytes using immunohistochemical staining. In one experiment, mice were treated at day +7 with low-dose IL-2 with and without LTBI. LTBI (in the two tested doses) showed no independent therapeutic effects. An IL-2 dose of 300,000 Cetus units (CU) that was effective and showed synergism with LTBI when mice were treated on day +7 failed to show a therapeutic effect when mice were treated on day +10, at which time the initial tumour burden had doubled. High-dose IL-2 (600,000 CU), in contrast, led to a significant reduction in metastatic burden compared to the control group. Combining high-dose IL-2 with LTBI led to a further significant reduction in tumour burden. Moreover, this combination was associated with a less severe vascular leakage syndrome compared to IL-2 alone. IL-2 and combination treatment was associated with an increase in the number of tumour-infiltrating immune cells, but only the number of tumour-infiltrating natural killer cells reflected therapeutic efficacy. It was concluded that tumour burden at the time of treatment and IL-2 dose are two crucial factors affecting the synergism between LTBI and IL-2. The combination may not only be more effective than IL-2 alone but also less toxic.


Bluetongue transmission and control in Europe: A systematic review of compartmental mathematical models.
The growing frequency of bluetongue virus (BTV) incursions in Europe in recent years led to the largest BTV outbreak ever recorded in 2006/09, with a dramatic impact on the cattle and sheep industries. The complex epidemiology of this vector-borne disease of ruminants and its recent emergence need to be better understood to identify and implement efficient control strategies. Mathematical models provide useful tools for that purpose; many of them have been developed in the light of the 2006/09 outbreak. We aimed to provide a systematic review of compartmental mathematical models dedicated to BTV occurrence or transmission in European countries, to assess robustness of findings to different modelling approaches and assumptions. We identified relevant papers from PubMed and Scopus databases, 21 of which were included in the review following the selection process laid out in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. We systematically extracted data from these papers to address the diversity and evolution of modelling approaches, and to identify important characteristics for future model development. Then, we summarized the main insights provided into bluetongue epidemiology, and discussed the relevance of these models as tools for risk mapping and for the design of surveillance and control systems. On the whole, the mechanistic models reviewed provided flexible frameworks, yielding mostly epidemiological insights specific to geographical areas and study periods. Despite the limitations of these models that sometimes relied on strong assumptions, we advocate their use to facilitate and inform evidence-based decision-making in animal health.


Disorder profile of nebulin encodes a vernierlike position sensor for the sliding thin and thick filaments of the skeletal muscle sarcomere.
Nebulin is an about 1μm long intrinsically disordered scaffold for the thin filaments of skeletal muscle sarcomere. It is a multifunctional elastic protein that wraps around actin filament, stabilizes thin filaments, and regulates Ca-dependent actomyosin interactions. This study investigates whether the disorder profile of nebulin might encode guidelines for thin and thick filament interactions in the sarcomere of the skeletal muscle. The question was addressed computationally by analyzing the predicted disorder profile of human nebulin (6669 residues, ∼200 actin-binding repeats) by pondr and the periodicity of the A-band stripes (reflecting the locations of myosin-associated proteins) in the electron micrographs of the sarcomere. Using the detrended fluctuation analysis, a scale factor for the A-band stripe image data with respect to the nebulin disorder profile was determined to make the thin and thick filaments aligned to have maximum correlation. The empirical mode decomposition method was then applied to identify hidden periodicities in both the nebulin disorder profile and the rescaled A-band data. The decomposition reveals three characteristic length scales (45 nm, 100 nm, and 200 nm) that are relevant for correlational analysis. The dynamical cross-correlation analyses with moving windows at various sarcomere lengths depict a vernierlike design for both periodicities, thus enabling nebulin to sense position and fine tune sarcomere overlap. This shows that the disorder profile of scaffolding proteins may encode a guideline for cellular architecture.


Antihypertensive drug treatment. Potential, expected, and observed effects on stroke and on coronary heart disease.
The effects of prolonged differences in diastolic blood pressure (DBP) on the risks of stroke and of coronary heart disease (CHD) were estimated from nine major prospective observational studies involving about 420,000 men and women who were followed up for intervals of 6-25 years. The results indicate that a prolonged difference of about 6 mm Hg in DBP was associated with approximately 37% fewer strokes and 23% fewer CHD deaths and nonfatal myocardial infarctions. The effects of equivalent reductions in DBP produced by antihypertensive drug treatment but maintained for only a few years have been estimated in several overviews of randomized trials involving a total of 30,000-40,000 patients. The results of the overviews indicate that treatment reduced the risk of stroke by about 40%, suggesting that most or all the long-term potential benefits for stroke due to lower DBP were achieved within about 3 years of beginning treatment. The risks of nonfatal myocardial infarction and CHD death may have been reduced by about 10% among patients allocated to active treatment; the 95% confidence limits for the difference ranged from about zero to about 20%. Whatever the true effect of treatment on CHD, it would appear somewhat less than the difference in risk estimated from the observational studies for a prolonged difference in DBP of the same size. This apparent shortfall in benefit may reflect a long time-course for changes in DBP to have their full effects on CHD, possible adverse side effects of the principal trial treatments, or both.


Idiopathic subglottic stenosis is associated with activation of the inflammatory IL-17A/IL-23 axis.
Idiopathic subglottic stenosis (iSGS) is a rare and devastating extrathoracic obstruction involving the lower laryngeal and upper tracheal airway. It arises without known antecedent injury or associated disease process. Persistent mucosal inflammation and a localized fibrotic response are hallmarks of the disease. Despite the initial clinical description of iSGS more than 40 year ago, there have been no substantive investigations into the pathogenesis of this enigmatic and progressive airway obstruction. In these studies, we present the initial characterization of the molecular pathogenesis underlying the fibrosing phenotype of iSGS. Utilizing 20 human iSGS and healthy control specimens, we applied histologic, immunohistochemical, molecular, and immunologic techniques. We demonstrate significant activation of the canonical IL-23/IL-17A pathway in the tracheal mucosa of iSGS patients, as well as identify γδ T cells as the primary cellular source of IL-17A. Our results suggest that aberrant mucosal immune activation is a component in of the pathogenesis of iSGS. Most critically, our work offers new targets for future therapeutic intervention. NA Laryngoscope, 126:E356-E361, 2016.


Silicon-in-silica spheres via axial thermal gradient in-fibre capillary instabilities.
The ability to produce small scale, crystalline silicon spheres is of significant technological and scientific importance, yet scalable methods for doing so have remained elusive. Here we demonstrate a silicon nanosphere fabrication process based on an optical fibre drawing technique. A silica-cladded silicon-core fibre with diameters down to 340 nm is continuously fed into a flame defining an axial thermal gradient and the continuous formation of spheres whose size is controlled by the feed speed is demonstrated. In particular, spheres of diameter <500 nm smaller than those produced under isothermal heating conditions are shown and analysed. A fibre with dual cores, p-type and n-type silicon, is drawn and processed into spheres. Spatially coherent break-up leads to the joining of the spheres into a bispherical silicon 'p-n molecule'. The resulting device is measured to reveal a rectifying I-V curve consistent with the formation of a p-n junction.


Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study.
One of the main problems in the therapy of depression is the limited efficacy of antidepressants and the limited utility of augmentation strategies. Zinc, a non competitive NMDA receptor antagonist exhibits preclinical antidepressant efficacy. Moreover, a preliminary clinical report suggests augmentation of antidepressant therapy by zinc in depression. A placebo-controlled, double blind study of zinc supplementation in imipramine therapy was conducted in sixty, 18-55-year old, unipolar depressed patients fulfilling the DSM-IV criteria for major depression without psychotic symptoms. After a one week washout period, patients were randomized into two groups treated with imipramine (approximately 140 mg/day) and receiving once daily either placebo (n=30) or zinc supplementation (n=30, 25 mgZn/day) for 12 weeks. No significant differences in CGI, BDI, HADRS and MADRS scores were demonstrated between zinc-supplemented and placebo-supplemented antidepressant treatment non-resistant patients. However, zinc supplementation significantly reduced depression scores and facilitated the treatment outcome in antidepressant treatment resistant patients. Zinc supplementation augments the efficacy and speed of onset of therapeutic response to imipramine treatment, particularly in patients previously nonresponsive to antidepressant pharmacotherapies. These data suggest the participation of disturbed zinc/glutamatergic transmission in the pathophysiology of drug resistance.


DNase I hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements.
The brain, spinal cord, and neural retina comprise the central nervous system (CNS) of vertebrates. Understanding the regulatory mechanisms that underlie the enormous cell-type diversity of the CNS is a significant challenge. Whole-genome mapping of DNase I-hypersensitive sites (DHSs) has been used to identify cis-regulatory elements in many tissues. We have applied this approach to the mouse CNS, including developing and mature neural retina, whole brain, and two well-characterized brain regions, the cerebellum and the cerebral cortex. For the various regions and developmental stages of the CNS that we analyzed, there were approximately the same number of DHSs; however, there were many DHSs unique to each CNS region and developmental stage. Many of the DHSs are likely to mark enhancers that are specific to the specific CNS region and developmental stage. We validated the DNase I mapping approach for identification of CNS enhancers using the existing VISTA Browser database and with in vivo and in vitro electroporation of the retina. Analysis of transcription factor consensus sites within the DHSs shows distinct region-specific profiles of transcriptional regulators particular to each region. Clustering developmentally dynamic DHSs in the retina revealed enrichment of developmental stage-specific transcriptional regulators. Additionally, we found reporter gene activity in the retina driven from several previously uncharacterized regulatory elements surrounding the neurodevelopmental gene Otx2. Identification of DHSs shared between mouse and human showed region-specific differences in the evolution of cis-regulatory elements. Overall, our results demonstrate the potential of genome-wide DNase I mapping to cis-regulatory questions regarding the regional diversity within the CNS. These data represent an extensive catalogue of potential cis-regulatory elements within the CNS that display region and temporal specificity, as well as a set of DHSs common to CNS tissues. Further examination of evolutionary conservation of DHSs between CNS regions and different species may reveal important cis-regulatory elements in the evolution of the mammalian CNS.


A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms.
We studied 4042 Vietnam era veteran monozygotic and dizygotic male twin pairs to determine the effects of heredity, shared environment, and unique environment on the liability for 15 self-reported posttraumatic stress disorder symptoms included in the symptom categories of reexperiencing the trauma, avoidance of stimuli related to the trauma, and increased arousal. Quantitative genetic analysis reveals that inheritance has a substantial influence on liability for all symptoms. Symptoms in the reexperiencing cluster and one symptom in the avoidance and numbing cluster are strongly associated with combat exposure, and monozygotic pairs are more highly concordant for combat exposure than dizygotic pairs. By fitting a bivariate genetic model, we show that there are significant genetic influences on symptom liability, even after adjusting for differences in combat exposure; genetic factors account for 13% to 30% of the variance in liability for symptoms in the reexperiencing cluster, 30% to 34% for symptoms in the avoidance cluster, and 28% to 32% for symptoms in the arousal cluster. There is no evidence that shared environment contributes to the development of posttraumatic stress disorder symptoms.


[Musculoskeletal disorders among healthcare workers in Belo Horizonte, Minas Gerais State, Brazil].
This cross-sectional study investigated the prevalence of musculoskeletal disorders and associated factors in a sample of 1,808 workers (from a total of 13,602) in the municipal health system in Belo Horizonte, Minas Gerais State, Brazil. Prevalence was calculated according to self-reported pain in the upper or lower limbs and/or back, and size of associations was estimated by univariate (p ≤ 0.20) and multivariate Poisson regression (p ≤ 0.05). Musculoskeletal disorders showed a prevalence of 49.9% and were statistically associated with female gender, living with a partner, physical activity less than twice a week, self-reported common mental disorder, certain job positions (dentists, dental technicians, and community health workers), high physical demand, and inadequate working conditions. The results confirm the complexity of musculoskeletal disorders and suggest areas for development of health promotion programs in health services.


Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1beta scaffolds Aurora B and BRCA2.
The BRCA1-associated ring domain protein 1 (BARD1) interacts with BRCA1 via its RING finger domain. The BARD1-BRCA1 complex participates in DNA repair, cell cycle control, genomic stability, and mitotic spindle formation through its E3 ubiquitin ligase activity. Cancer cells express several BARD1 protein isoforms, including the RING finger-deficient variant BARD1beta. Here, we show that BARD1 has BRCA1-dependent and BRCA1-independent functions in mitosis. BARD1, but not BRCA1, localizes to the midbody at telophase and cytokinesis, where it colocalizes with Aurora B. The 97-kDa full-length (FL) BARD1 coimmunoprecipates with BRCA1, but the 82-kDa BARD1beta coimmunoprecipitates with Aurora B and BRCA2. We used selective small interfering RNAs to distinguish the functions of FL BARD1 and BARD1beta. Depletion of FL BARD1 had only minor effects on cell growth and did not abolish midbody localization of BARD1 staining, but resulted in massive up-regulation of Aurora B. In contrast, suppression of FL BARD1 and BARD1beta led to growth arrest and correlated with various mitotic defects and disappearance of midbody localization of BARD1 staining. Our data suggest a novel function of FL BARD1 in Aurora B ubiquitination and degradation, opposing a proproliferative function of BARD1beta in scaffolding Aurora B and BRCA2. Thus, loss of FL BARD1 and up-regulation of Aurora B, as observed in cancer cells, can be explained by an imbalance of FL BARD1 and BARD1beta.


Improving caregiving competence, stress coping, and mental well-being in informal dementia carers.
To study the effectiveness of Reitman Centre "Coaching, Advocacy, Respite, Education, Relationship, and Simulation" (CARERS) program, which uses problem-solving techniques and simulation to train informal dementia carers. Seventy-three carers for family members with dementia were included in the pilot study. Pre- and post-intervention data were collected from carers using validated measures of depression, mastery, role captivity and overload, caregiving competence and burden, and coping styles. To assess program effectiveness, mean differences for these measures were calculated. One-way ANOVA was used to determine if change in scores is dependent on the respective baseline scores. Clinical effects for measures were expressed as Cohen's D values. Data from 73 carers were analyzed. The majority of these participants were female (79.5%). A total of 69.9% were spouses and 30.1% were children of the care recipient. Participants had an overall mean age of 68.34 ± 12.01 years. About 31.5% of participating carers had a past history of psychiatric illness (e.g., depression), and 34.2% sustained strained relationships with their respective care recipients. Results from carers demonstrated improvement in carers' self-perception of competence (1.26 ± 1.92, P < 0.0001), and significant reduction in emotion-focused coping (measured by the Coping Inventory of Stressful Situations, -2.37 ± 6.73, P < 0.01), Geriatric Depression scale (-0.67 ± 2.63, P < 0.05) and Pearlin's overload scale (-0.55 ± 2.07, P < 0.05), upon completion of the Program. Secondly, it was found that carers with more compromised baseline scores benefited most from the intervention, as they experienced statistically significant improvement in the following constructs: competence, stress-coping style (less emotion-oriented), sense of mastery, burden, overload. Study results supported the effectiveness of the CARERS Program in improving caregiving competence, stress coping ability and mental well-being in carers caring for family members with dementia.


A cellular backline: specialization of host membranes for defence.
In plant-pathogen interactions, the host plasma membrane serves as a defence front for pathogens that invade from the extracellular environment. As such, the lipid bilayer acts as a scaffold that targets and delivers defence responses to the site of attack. During pathogen infection, numerous changes in plasma membrane composition, organization, and structure occur. There is increasing evidence that this facilitates the execution of a variety of responses, highlighting the regulatory role membranes play in cellular responses. Membrane microdomains such as lipid rafts are hypothesized to create signalling platforms for receptor signalling in response to pathogen perception and for callose synthesis. Further, the genesis of pathogen-associated structures such as papillae and the extra-haustorial membrane necessitates polarization of membranes and membrane trafficking pathways. Unlocking the mechanisms by which this occurs will enable greater understanding of how targeted defences, some of which result in resistance, are executed. This review will survey some of the changes that occur in host membranes during pathogen attack and how these are associated with the generation of defence responses.


Lymphaticovenular anastomosis in the treatment of secondary lymphoedema of the legs after cancer treatment.
As survival from cancer continues to improve, greater importance is placed on quality of life after surgery. Lymphoedema is a common and disabling complication of cancer treatment. Lymphaticovenular anastomosis (LVA) is a supermicrosurgical treatment option for lower limb lymphoedema. The aim of this study was to assess the effectiveness of LVA in reducing limb volume and its effect on quality of life of patients with secondary leg lymphoedema following treatment for cancer, including gynaecological cancers. Limb volume and patient rated quality of life were collected prospectively pre-operatively and at every post-operative appointment in this case series. All patients presenting to the clinic with stable or progressive leg lymphoedema despite conservative therapy who were suitable candidates for LVA over a three-year period were included. Twenty-nine patients were treated with LVA, 19 for unilateral lymphoedema and 10 for bilateral. In unilateral cases median limb excess volume reduced from 27% to 16% post-operatively (p < 0.005) and in bilateral cases a median 8% reduction in absolute limb volume was achieved. Significant improvement in patient-reported quality of life was demonstrated, as measured by the LYMQOL: 23% improvement in unilateral and 14% improvement in bilateral patients (both p < 0.05). In selected patients with early stage lymphoedema secondary to cancer treatment, LVA offers a minimally invasive surgical option that can achieve significant volumetric and quality of life improvements.


Collaborative cohort study of an intervention to reduce ventilator-associated pneumonia in the intensive care unit.
To evaluate the impact of a multifaceted intervention on compliance with evidence-based therapies and ventilator-associated pneumonia (VAP) rates. Collaborative cohort before-after study. Intensive care units (ICUs) predominantly in Michigan. We implemented a multifaceted intervention to improve compliance with 5 evidence-based recommendations for mechanically ventilated patients and to prevent VAP. A standardized CDC definition of VAP was used and maintained at each site, and data on the number of VAPs and ventilator-days were obtained from the hospital's infection preventionists. Baseline data were reported and postimplementation data were reported for 30 months. VAP rates (in cases per 1,000 ventilator-days) were calculated as the proportion of ventilator-days per quarter in which patients received all 5 therapies in the ventilator care bundle. Two interventions to improve safety culture and communication were implemented first. One hundred twelve ICUs reporting 3,228 ICU-months and 550,800 ventilator-days were included. The overall median VAP rate decreased from 5.5 cases (mean, 6.9 cases) per 1,000 ventilator-days at baseline to 0 cases (mean, 3.4 cases) at 16-18 months after implementation (P < .001) and 0 cases (mean, 2.4 cases) at 28-30 months after implementation (P < .001). Compared to baseline, VAP rates decreased during all observation periods, with incidence rate ratios of 0.51 (95% confidence interval, 0.41-0.64) at 16-18 months after implementation and 0.29 (95% confidence interval, 0.24-0.34) at 28-30 months after implementation. Compliance with evidence-based therapies increased from 32% at baseline to 75% at 16-18 months after implementation (P < .001) and 84% at 28-30 months after implementation (P < .001). A multifaceted intervention was associated with an increased use of evidence-based therapies and a substantial (up to 71%) and sustained (up to 2.5 years) decrease in VAP rates.


Gingival recession treatment with connective tissue grafts in smokers and non-smokers.
Cigarette smoking can adversely affect the results of many periodontal procedures. The purpose of this study was to determine whether cigarette smoking affects wound healing of subepithelial connective tissue grafts. Seventeen systemically healthy patients with 22 Miller Class I or II mucogingival defects were divided into a non-smoker group or smoker group. Patients were regarded as smokers if they reported smoking 10 to 20 cigarettes per day. The following parameters were documented at the surgery date and 3 and 6 months postoperatively: recession depth (RD), recession width (RW), keratinized gingiva height measured apico-coronally (KG), relative attachment level (RAL), probing depths (PD), bleeding on probing (BOP), and the full-mouth plaque score (FMP). Salivary cotinine samples were taken at the surgery to confirm the smoking history and to quantify cigarette use. Non-smokers (0- to 10-ng/ml cotinine level) healed with statistically more recession coverage than the smokers (>10-ng/ml cotinine level) (98.3% versus 82.3%, respectively; P=0.001). Six months postoperatively, the non-smokers healed with a 0.2-mm mean recession depth compared to a 1.0-mm mean recession depth for the smokers. This difference in recession depth was statistically significant (P=0.014). Root coverage with connective tissue grafts appears to be negatively associated with cigarette smoking. Smokers should consider smoking cessation or reducing the use of cigarettes for optimal results with connective tissue grafts.


Association between household air pollution and nasopharyngeal pneumococcal carriage in Malawian infants (MSCAPE): a nested, prospective, observational study.
Household air pollution from solid fuels increases the risk of childhood pneumonia. Nasopharyngeal carriage of Streptococcus pneumoniae is a necessary step in the development of pneumococcal pneumonia. We aimed to assess the association between exposure to household air pollution and the prevalence and density of S pneumoniae carriage among children. The Malawi Streptococcus pneumoniae Carriage and Air Pollution Exposure study was a nested, prospective, observational study of children participating in the cluster randomised controlled Cooking and Pneumonia Study (CAPS) in the Karonga Health and Demographic Surveillance System (HDSS) area in northern Malawi. CAPS compared the effects of a cleaner burning biomass-fuelled cookstove (intervention group) with traditional open-fire cooking (control group) on the incidence of pneumonia in children. Eligible children aged 6 weeks or 6 months (those recruited a 6 weeks were also followed up at age 6 months) were identified by the Karonga HDSS centre. Nasopharyngeal swabs were taken to detect S pneumoniae, and infant exposure to particulate matter with a diameter of ≤2·5 μm (PM2·5) exposure was assessed by use of a MicroPEM device. The primary outcome was the prevalence of nasopharyngeal S pneumoniae carriage in all children aged 6 months, assessed in all children with valid data on PM2·5. The effects of the intervention stoves (intention-to-treat analysis) and PM2·5 (adjusted exposure-response analysis) on the prevalence of S pneumoniae carriage were also assessed in the study children. Between Nov 15, 2015, and Nov 2, 2017, 485 children were recruited (240 from the intervention group and 245 from the control group). Of all 450 children with available data at age 6 months, 387 (86% [95% CI 82-89]) were positive for S pneumoniae. Geometric mean PM2·5 exposure was 60·3 μg/m3 (95% CI 55·8-65·3) in S pneumoniae-positive children and 47·0 μg/m3 (38·3-57·7) in S pneumoniae-negative children (p=0·044). In the intention-to-treat analysis, a non-significant increase in the risk of S pneumoniae carriage was observed in intervention group children compared with control group children (odds ratio 1·36 [95% CI 0·95-1·94]; p=0·093). In the exposure-response analysis, a significant association between PM2·5 exposure and S pneumoniae carriage was observed; a one unit increase in decile of PM2·5 was found to significantly increase the risk of S pneumoniae carriage by 10% (1·10 [1·01-1·20]; p=0·035), after adjustment for age, sex, 13-valent pneumococcal conjugate vaccination status, season, current use of antibiotics, and MicroPEM run-time. Despite the absence of effect from the intervention cookstove, household air pollution exposure was significantly associated with the prevalence of nasopharyngeal S pneumoniae carriage. These results provide empirical evidence for the potential mechanistic association between exposure to household air pollution and childhood pneumonia. Bill & Melinda Gates Foundation.


Follistatin Targets Distinct Pathways To Promote Brown Adipocyte Characteristics in Brown and White Adipose Tissues.
We previously demonstrated that Fst expression is highest in brown adipose tissue (BAT) and skeletal muscle, but is also present at substantial levels in epididymal and subcutaneous white adipose tissues (WATs). Fst promotes mouse brown preadipocyte differentiation and promotes browning during differentiation of mouse embryonic fibroblasts. Fst-transgenic (Fst-Tg) mice show substantial increases in circulating Fst levels and increased brown adipose mass. BAT of Fst-Tg mice had increased expression of brown adipose-associated markers including uncoupling protein 1 (UCP1), PRDM16, PGC-1α, and Glut4. WATs from Fst-Tg mice show upregulation of brown/beige adipose markers and significantly increased levels of phosphorylated p38 MAPK/ERK1/2 proteins compared with the wild-type (WT) mice. Pharmacological inhibition of pp38 MAPK/pERK1/2 pathway of recombinant mouse Fst (rFst) treated differentiating 3T3-L1 cells led to significant blockade of Fst-induced UCP1 protein expression. On the other hand, BAT from Fst-Tg mice or differentiating mouse BAT cells treated with rFst show dramatic increase in Myf5 protein levels as well as upregulation of Zic1 and Lhx8 gene expression. Myf5 levels were significantly downregulated in Fst knock-out embryos and small inhibitory RNA-mediated inhibition of Myf5 led to significant inhibition of UCP1, Lhx8, and Zic1 gene expression and significant blockade of Fst-induced induction of UCP1 protein expression in mouse BAT cells. Both interscapular BAT and WAT tissues from Fst-Tg mice display enhanced response to CL316,243 treatment and decreased expression of pSmad3 compared with the WT mice. Therefore, our results indicate that Fst promotes brown adipocyte characteristics in both WAT and BAT depots in vivo through distinct mechanisms.


Are there long-term effects of early child care?
Effects of early child care on children's functioning from 4(1/2) years through the end of 6th grade (M age=12.0 years) were examined in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (n=1,364). The results indicated that although parenting was a stronger and more consistent predictor of children's development than early child-care experience, higher quality care predicted higher vocabulary scores and more exposure to center care predicted more teacher-reported externalizing problems. Discussion focuses on mechanisms responsible for these effects, the potential collective consequences of small child-care effects, and the importance of the ongoing follow-up at age 15.


Accelerometer use in a physical activity intervention trial.
This paper describes the application of best practice recommendations for using accelerometers in a physical activity (PA) intervention trial, and the concordance of different methods for measuring PA. A subsample (n = 63; 26%) of the 239 healthy, sedentary adults participating in a PA trial (mean age = 47.5; 82% women) wore the ActiGraph monitor at all 3 assessment time points. ActiGraph data were compared with self-report (i.e., PA weekly recall and monthly log) and fitness variables. Correlations between the PA recall and ActiGraph for moderate intensity activity ranged from 0.16-0.48 and from 0.28-0.42 for vigorous intensity activity. ActiGraph and fitness [estimated VO(2)(ml/kg/min)] had correlations of 0.15-0.45. The ActiGraph and weekly self-report were significantly correlated at all time points (correlations ranged from 0.23 to 0.44). In terms of detecting intervention effects, intervention groups recorded more minutes of at least moderate-intensity PA on the ActiGraph than the control group at 6 months (min = 46.47, 95% CI = 14.36-78.58), but not at 12 months. Limitations of the study include a small sample size and only 3 days of ActiGraph monitoring. To obtain optimal results with accelerometers in clinical trials, the authors recommend following best practice recommendations: detailed protocols for monitor use, calibration of monitors and validation of data quality, and use of validated equations for analysis. The ActiGraph has modest concordance with other assessment tools and is sensitive to change over time. However, until more information validating the use of accelerometry in clinical trials becomes available, properly administered self-report measures of PA should remain part of the assessment battery.


Bsr, a nuclear-retained RNA with monoallelic expression.
The imprinted Dlk1-Gtl2 and Prader-Willi syndrome (PWS) regions are characterized by a complex noncoding transcription unit spanning arrays of tandemly repeated C/D RNA genes. These noncoding RNAs (ncRNAs) are thought to play an essential but still poorly understood role. To better understand the intracellular fate of these large ncRNAs, fluorescence in situ hybridization was carried out at the rat Dlk1-Gtl2 domain. This locus contains a approximately 100-kb-long gene cluster comprising 86 homologous RBII-36 C/D RNA gene copies, all of them intron-encoded within the ncRNA gene Bsr. Here, we demonstrate that the Bsr gene is monoallelically expressed in primary rat embryonic fibroblasts as well as in hypothalamic neurons and yields a large amount of unspliced and spliced RNAs at the transcription site, mostly as elongated RNA signals. Surprisingly, spliced Bsr RNAs released from the transcription site mainly concentrate as numerous, stable nuclear foci that do not colocalize with any known subnuclear structures. On drug treatments, a fraction of Bsr RNA relocalizes to the cytoplasm and associates with stress granules (SGs), but not with P-bodies, pointing to a potential link between SGs and the metabolism of ncRNA. Thus, Bsr might represent a novel type of nuclear-retained transcript.


Awareness and Performance of Iranian Nurses with Regard to Health Economics: A Cross-Sectional Study.
Health costs have risen everywhere, worldwide, and nurses play a pivotal role in cost savings and in contributing to the financial stability of hospitals. This study evaluated the awareness and performance of Iranian nursing staff, with regard to health economics. A total of 175 nurses who worked in three teaching hospitals in Mashhad (Iran) were selected for this descriptive cross-sectional study, and data were gathered via a 27-item questionnaire. Statistical analysis was performed using one-way analysis of variance, multiple regression analysis, and Pearson's correlation coefficient. A total of 78% (n = 39) of nurses did not have a good awareness of health economics. The overall mean score for economic awareness was 5.9 ± 2.1 (possible range, 0-16), and for economic performance was 26.6 ± 4 (possible range, 0-44). There was a significant relationship between the economic awareness and performance of nurses, and nurses in higher positions had a greater awareness of health economics. Considering the inadequacy of the health economics awareness and performance of nurses, it is essential that efforts are made to enhance their knowledge and behavior with regard to economic issues and cost saving in all the fields of nursing, through the use of continuing education courses and workshops.


Activation of cellular functions in macrophages by venom secretory Asp-49 and Lys-49 phospholipases A(2).
The in vitro effects of myotoxin III (MT-III), an Asp-49 catalytically-active phospholipase A(2), and myotoxin II (MT-II), a catalytically-inactive Lys-49 variant, isolated from Bothrops asper snake venom, on phagocytosis and production of hydrogen peroxide (H(2)O(2)) by thioglycollate-elicited macrophages were investigated. MT-II and MT-III were cytotoxic to mouse peritoneal macrophages at concentrations higher than 25 microg/ml. At non-cytotoxic concentrations, MT-II stimulated Fcgamma, complement, mannose and beta-glucan receptors-mediated phagocytosis, whereas MT-III stimulated only the mannose and beta-glucan receptors-mediated phagocytosis. Moreover, both myotoxins induced the release of H(2)O(2) by thioglycollate-elicited macrophages, MT-III being the most potent stimulator. MT-II induced the release of H(2)O(2) only at a concentration of 3.2 microg/ml (130% increment) while MT-III induced this effect at all concentrations tested (0.5-2.5 microg/ml; average of 206% increment). It is concluded that, at non-cytotoxic concentrations, MT-II and MT-III activate defense mechanisms in macrophages up regulating phagocytosis, mainly via mannose and beta-glucan receptors, and the respiratory burst.


The impact of chromatin modifiers on the timing of locus replication in mouse embryonic stem cells.
The time of locus replication during S-phase is tightly regulated and correlates with chromatin state. Embryonic stem (ES) cells have an unusual chromatin profile where many developmental regulator genes that are not yet expressed are marked by both active and repressive histone modifications. This poised or bivalent state is also characterized by locus replication in early S-phase in ES cells, while replication timing is delayed in cells with restricted developmental options. Here we used a panel of mutant mouse ES cell lines lacking important chromatin modifiers to dissect the relationship between chromatin structure and replication timing. We show that temporal control of satellite DNA replication is sensitive to loss of a variety of chromatin modifiers, including Mll, Eed, Dnmt1, Suv39h1/h2 and Dicer. The replication times of many single copy loci, including a 5 Mb contiguous region surrounding the Rex1 gene, were retained in chromatin modifier mutant ES cells, although a subset of loci were affected. This analysis demonstrates the importance of chromatin modifiers for maintaining correct replication of satellite sequences in pluripotent ES cells and highlights the sensitivity of some single copy loci to the influence of chromatin modifiers. Abundant histone acetylation is shown to correlate well with early replication. Surprisingly, loss of DNA methylation or histone methylation was tolerated by many loci, suggesting that these modifications may be less influential for the timing of euchromatin replication.


Head capsule width as an instar indicator for larvae of the cranberry fruitworm (Lepidoptera: Pyralidae) in southeastern New Brunswick.
The objective of this study was to determine the number of instars of the cranberry fruitworm Acrobasis vaccinii Riley in southeastern New Brunswick based on the distribution of head capsule widths from field and laboratory observations. In 2000, head capsules from field samples were measured across their widest point, and the results were plotted against observed frequencies. The data from field samples suggested that A. vaccinii exhibited five instars in 2000. In 2001, larvae were reared in the laboratory until the final molt, and head capsules were counted and measured. The results were also plotted against observed frequencies. None of the laboratory specimens exhibited more than five instars, supporting the results of the previous year. Various factors are invoked to explain the difference between these results and those of a previous study conducted 50 yr earlier and 200 km away, in which six instars and larger head capsules were reported.


Clarification of Governance Relevant to the Sustainable Management of Marine Species and Habitats within the United Kingdom: An Overview of Regional, National and International Authorities, Advisories, Legislation and Designation Types with Summary Schematic Tool.
Marine management developments are occurring across the United Kingdom with the major aim to ensure economic growth and security of marine resources via the provision of legislative guidelines for sustainable management of activities within the marine environment. Many of these directives also provide guidance for maintaining ecologically valuable and/or endangered species and habitats that exist alongside, and may also support, marine activities/use. Marine governance is largely guided by several key directives laid out and implemented by governing authorities of Europe, the United Kingdom and those countries comprising the United Kingdom, and in line with several international conventions. The directives set out by each authority or convention may act discretely but more often tend to overlap, which can lead to confusion about the relevant marine conservation requirements and objectives that must be fulfilled for a given region, site or feature. Additionally, management objectives driven by the same legislation may oppose one another, adding further complexity to the matter. This article aims to provide an overview of governance that holds relevance to managing marine habitats and species, especially those deemed sensitive, ecologically valuable and/or endangered. A general overview and summary schematic tool of the marine governance, legislation and designations within each level of authority for the United Kingdom are provided. Additional consideration of the implications for legislation upon the United Kingdom leaving the EU is briefly discussed and a comparative case study of two marine habitats of high conservation value is provided to demonstrate how different sites/features may have considerably different management requirements.


Adolescent and Youth Experiences With Contraceptive Self-Injection in Uganda: Results From the Uganda Self-Injection Best Practices Project.
We used qualitative and quantitative data to evaluate the differing experiences of adolescents and adult women in the contraceptive self-injection program in primary care settings in Uganda. From these results, we assessed barriers to adolescent DMPA-SC self-injection access and continuation and provide recommendations to address them. The Self-Injection Best Practices (2017-2019) project in four districts trained clinic-based providers and Village Health Teams to provide self-injection training in clinics, community settings, and small group meetings for adolescent girls and young women. More than 12,000 women of reproductive age received self-injection services through the program, including 2,215 under 20 years. Structured surveys (n = 1,060) and in-depth interviews (n = 36) were conducted with randomly selected adolescent participants between July and November 2018. Mixed-effects logistic regression was used to assess quantitative differences in outcomes of interest between age groups. The study found no significant difference in self-injection proficiency or continuation between adolescents and adult women; 86.1% of adolescents self-injected independently when due for reinjection. Adolescents were significantly less likely than adults to report first hearing about self-injection from a community health worker. More adolescents expressed concern over discovery when seeking contraception at a clinic and fear of their DMPA-SC units being discovered at home. Adolescents were significantly less likely than adult women to mention convenience as a rationale for self-injecting, and more likely to mention wanting to learn a new skill and/or that friends recommended self-injection. Self-injection is a promising method of contraception for adolescents in Uganda, given comparable proficiency and continuation relative to adult women. Policies and programs should ensure rights-based access to a range of methods, including self-injection for this age group.


iPSC-Derived Enterocyte-like Cells for Drug Absorption and Metabolism Studies.
Intestinal cell models have been widely studied and used to evaluate absorption and metabolism of drugs in the small intestine, constituting valuable tools as a first approach to evaluate the behavior of new drugs. However, such cell models might not be able to fully predict the absorption mechanisms and metabolic pathways of the tested compounds. In recent years, induced pluripotent stem cells (iPSCs) differentiated into enterocyte-like cells have been proposed as more biorelevant intestinal models. In this review, we describe mechanisms underlying the differentiation of iPSCs into enterocyte-like cells, appraise the usefulness of these cells in tridimensional intestinal models, and discuss their suitability to be used in the future for drug screening.


Evaluating the cost-effectiveness of fall prevention programs that reduce fall-related hip fractures in older adults.
To model the incremental cost-utility of seven interventions reported as effective for preventing falls in older adults. Mathematical epidemiological model populated by data based on direct clinical experience and a critical review of the literature. Model represents population level interventions. No human subjects were involved in the study. MEASUREMENS: The last Cochrane database review and meta-analyses of randomized controlled trials categorized effective fall-prevention interventions into seven groups: medical management (withdrawal) of psychotropics, group tai chi, vitamin D supplementation, muscle and balance exercises, home modifications, multifactorial individualized programs for all elderly people, and multifactorial individualized treatments for high-risk frail elderly people. Fall-related hip fracture incidence was obtained from the literature. Salary figures for health professionals were based on Bureau of Labor Statistics data. Using an integrated healthcare system perspective, healthcare costs were estimated based on practice and studies on falls in older adults. Base case incremental cost utility ratios were calculated, and probabilistic sensitivity analyses were conducted. Medical management of psychotropics and group tai chi were the least-costly, most-effective options, but they were also the least studied. Excluding these interventions, the least-expensive, most-effective options are vitamin D supplementation and home modifications. Vitamin D supplementation costs less than home modifications, but home modifications cost only $14,794/quality-adjusted life year (QALY) gained more than vitamin D. In probabilistic sensitivity analyses excluding management of psychotropics and tai chi, home modification is most likely to have the highest economic benefit when QALYs are valued at $50,000 or $100,000. Of single interventions studied, management of psychotropics and tai chi reduces costs the most. Of more-studied interventions, home modifications provide the best value. These results must be interpreted in the context of the multifactorial nature of falls.


Effect of ascorbic acid and alpha-tocopherol supplementations on serum leptin, tumor necrosis factor alpha, and serum amyloid A levels in individuals with type 2 diabetes mellitus.
Diabetes mellitus Type 2 is one of the most widespread chronic metabolic diseases. In most cases, this type of diabetes is associated with alterations in levels of some inflammatory cytokines and hormones. Considering anti-inflammatory properties of plant extracts rich in ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E), anti-diabetic properties of these two well-known antioxidant vitamins were investigated through measurement of serum levels of high-sensitivity C-reactive protein (hs-CRP), insulin, leptin, tumor necrosis factor alpha (TNF-α), and serum amyloid A (SAA) in patients with diabetes mellitus type 2. Male patients (n=80) were randomly divided into two groups each consisted of 40 subjects. Test groups were supplemented with ascorbic acid (1000 mg/day) or alpha-tocopherol (300 mg/day) orally during four weeks. Before and after treatment, serum biochemical factors of subjects were measured and compared. Our results showed that both ascorbic acid and alpha-tocopherol could induce significant anti-inflammatory effects by decreasing the level of inflammatory factors such as TNF-α, SAA, and hs-CRP in diabetes mellitus type 2 patients. Effects of alpha-tocopherol and ascorbic acid in decreasing serum leptin level were similar. Ascorbic acid in contrast to alpha-tocopherol diminished fasting insulin and HOMA index but had no effect on LDL serum level. Concerning the obtained results, it is concluded that consumption of supplementary vitamins C and E could decrease induced inflammatory response in patients with diabetes mellitus type 2. It is also possible that vitamin C and vitamin E supplementation can attenuate incidence of some proposed pathological effects of diabetes mellitus.


LiF, an underestimated supercontinuum source in femtosecond transient absorption spectroscopy.
We present supercontinua generated in LiF and CaF(2) revealing that LiF is advantageous especially in the near UV region since it pushes the cut-off wavelength about 17 nm towards lower wavelengths and the occurrence of color centers, which has been considered as a drawback up to now, is not a limitation for its applicability in femtosecond transient absorption spectroscopy. Even though the color centers occur within a short time of illumination, they do not influence the supercontinuum generation significantly and they can furthermore, if desired, be eliminated from the substrate simply by heating. Thus LiF is a promising substrate for broad band measurements in the UV/vis range.


Results From Wales' 2016 Report Card on Physical Activity for Children and Youth: Is Wales Turning the Tide on Children's Inactivity?
This is the second Active Healthy Kids Wales Report Card. The 2016 version consolidates and translates research related to physical activity (PA) among children and youth in Wales, and aims to raise the awareness of children's engagement in PA and sedentary behaviors. Ten PA indicators were graded using the Active Healthy Kids-Canada Report Card methodology involving a synthesis and expert consensus of the best available evidence. Grades were assigned as follows: Overall PA, D+; Organized Sport Participation, C; Active and Outdoor Play, C; Active Transportation, C; Sedentary Behaviors, D-; Physical Literacy, INC; Family and Peer Influences, D+; School, B; Community and the Built Environment, C; and National Government Policy, Strategies, and Investments, B-. Despite the existence of sound policies, programs, and infrastructure, PA levels of children and youth in Wales are one of the lowest and sedentary behavior one of the highest globally. From the 2014 Report Card, the Family and Peer Influences grade improved from D to D+, whereas Community and the Built Environment dropped from B to C. These results indicate that a concerted effort is required to increase PA and decrease sedentary time in children and young people in Wales.


Interrelationships of psychiatric symptom severity, medical comorbidity, and functioning in schizophrenia.
This cross-sectional study aimed to evaluate the interrelationships of psychiatric symptom severity, medical comorbidity, and psychosocial functioning in a sample of patients with schizophrenia by utilizing the baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). This study utilized baseline data from a multisite trial of antipsychotic pharmacotherapy, which collected data from 1,460 patients with schizophrenia at more than 50 sites in the United States between 2001 and 2003. Bivariate correlations were used to evaluate associations between schizophrenia symptoms and medical comorbidity, and multivariate regression models were used to determine the independent association between medical comorbidity and psychosocial functioning. Of the 1,424 participants in the study sample, 58 percent had at least one medical condition: 20 percent had hypertension, 11 percent had diabetes mellitus, and 9 percent had four or more medical conditions. Medical comorbidity was associated with poorer neurocognitive functioning and greater depressive symptoms. The number of medical conditions was not associated with more severe schizophrenia symptoms. Both the number of medical conditions and physical health status were only weak correlates of psychosocial functioning. In this sample of persons with schizophrenia, medical comorbidity was associated with depression and neurocognitive impairment but was a weaker correlate of psychosocial functioning or employment status than psychotic symptoms, depression, and neurocognitive impairment.


Habitats as complex odour environments: how does plant diversity affect herbivore and parasitoid orientation?
Plant diversity is known to affect success of host location by pest insects, but its effect on olfactory orientation of non-pest insect species has hardly been addressed. First, we tested in laboratory experiments the hypothesis that non-host plants, which increase odour complexity in habitats, affect the host location ability of herbivores and parasitoids. Furthermore, we recorded field data of plant diversity in addition to herbivore and parasitoid abundance at 77 grassland sites in three different regions in Germany in order to elucidate whether our laboratory results reflect the field situation. As a model system we used the herb Plantago lanceolata, the herbivorous weevil Mecinus pascuorum, and its larval parasitoid Mesopolobus incultus. The laboratory bioassays revealed that both the herbivorous weevil and its larval parasitoid can locate their host plant and host via olfactory cues even in the presence of non-host odour. In a newly established two-circle olfactometer, the weeviĺs capability to detect host plant odour was not affected by odours from non-host plants. However, addition of non-host plant odours to host plant odour enhanced the weeviĺs foraging activity. The parasitoid was attracted by a combination of host plant and host volatiles in both the absence and presence of non-host plant volatiles in a Y-tube olfactometer. In dual choice tests the parasitoid preferred the blend of host plant and host volatiles over its combination with non-host plant volatiles. In the field, no indication was found that high plant diversity disturbs host (plant) location by the weevil and its parasitoid. In contrast, plant diversity was positively correlated with weevil abundance, whereas parasitoid abundance was independent of plant diversity. Therefore, we conclude that weevils and parasitoids showed the sensory capacity to successfully cope with complex vegetation odours when searching for hosts.


Molecular analysis of adenovirus isolates from vaccinated and unvaccinated young adults.
Infections of adenovirus type 4 (Ad4) and Ad7 were discovered among previously vaccinated individuals through febrile respiratory illness surveillance at military recruit camps. Genetic analysis was performed on these isolates and a sample of adenovirus isolates from unvaccinated patients. Antigenic regions of the adenovirus hexon gene from 21 vaccinated and 31 unvaccinated patients were sequenced and compared to homologous regions of Ad4 and Ad7 vaccine strains and of other representative hexon sequences archived in GenBank. The phylogenetic distribution of sequences from vaccinated individuals closely resembled those from unvaccinated individuals. The most common Ad7 strain was the Ad7d2 hexon genotype, and the most common Ad4 strain was a genotype nearly identical to the recently discovered Z-G 95-873 Ad4 variant. Near exclusive isolation of Ad4 since 1999 indicates that the Ad4 variant is currently responsible for the vast majority of adenovirus morbidity in military recruit camps. Different ratios of nonsynonymous to synonymous nucleotide substitution rates in known antigenic regions compared to nonantigenic regions indicated positive selection for diversity in the antigenic regions and purifying selection in the nonantigenic regions.


Rationalization of the pKa values of alcohols and thiols using atomic charge descriptors and its application to the prediction of amino acid pKa's.
In a first step toward the development of an efficient and accurate protocol to estimate amino acids' pKa's in proteins, we present in this work how to reproduce the pKa's of alcohol and thiol based residues (namely tyrosine, serine, and cysteine) in aqueous solution from the knowledge of the experimental pKa's of phenols, alcohols, and thiols. Our protocol is based on the linear relationship between computed atomic charges of the anionic form of the molecules (being either phenolates, alkoxides, or thiolates) and their respective experimental pKa values. It is tested with different environment approaches (gas phase or continuum solvent-based approaches), with five distinct atomic charge models (Mulliken, Löwdin, NPA, Merz-Kollman, and CHelpG), and with nine different DFT functionals combined with 16 different basis sets. Moreover, the capability of semiempirical methods (AM1, RM1, PM3, and PM6) to also predict pKa's of thiols, phenols, and alcohols is analyzed. From our benchmarks, the best combination to reproduce experimental pKa's is to compute NPA atomic charge using the CPCM model at the B3LYP/3-21G and M062X/6-311G levels for alcohols (R(2) = 0.995) and thiols (R(2) = 0.986), respectively. The applicability of the suggested protocol is tested with tyrosine and cysteine amino acids, and precise pKa predictions are obtained. The stability of the amino acid pKa's with respect to geometrical changes is also tested by MM-MD and DFT-MD calculations. Considering its strong accuracy and its high computational efficiency, these pKa prediction calculations using atomic charges indicate a promising method for predicting amino acids' pKa in a protein environment.


What is working memory capacity, and how can we measure it?
A latent variable study examined whether different classes of working-memory tasks measure the same general construct of working-memory capacity (WMC). Data from 270 subjects were used to examine the relationship between Binding, Updating, Recall-N-back, and Complex Span tasks, and the relations of WMC with secondary memory measures, indicators of cognitive control from two response-conflict paradigms (Simon task and Eriksen flanker task), and fluid intelligence. Confirmatory factor analyses support the concept of a general WMC factor. Results from structural-equation modeling show negligible relations of WMC with response-conflict resolution, and very strong relations of WMC with secondary memory and fluid intelligence. The findings support the hypothesis that individual differences in WMC reflect the ability to build, maintain and update arbitrary bindings.


Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.
Health authorities worldwide, especially in the Asia Pacific region, are seeking effective public-health interventions in the continuing epidemic of severe acute respiratory syndrome (SARS). We assessed the epidemiology of SARS in Hong Kong. We included 1425 cases reported up to April 28, 2003. An integrated database was constructed from several sources containing information on epidemiological, demographic, and clinical variables. We estimated the key epidemiological distributions: infection to onset, onset to admission, admission to death, and admission to discharge. We measured associations between the estimated case fatality rate and patients' age and the time from onset to admission. After the initial phase of exponential growth, the rate of confirmed cases fell to less than 20 per day by April 28. Public-health interventions included encouragement to report to hospital rapidly after the onset of clinical symptoms, contact tracing for confirmed and suspected cases, and quarantining, monitoring, and restricting the travel of contacts. The mean incubation period of the disease is estimated to be 6.4 days (95% CI 5.2-7.7). The mean time from onset of clinical symptoms to admission to hospital varied between 3 and 5 days, with longer times earlier in the epidemic. The estimated case fatality rate was 13.2% (9.8-16.8) for patients younger than 60 years and 43.3% (35.2-52.4) for patients aged 60 years or older assuming a parametric gamma distribution. A non-parametric method yielded estimates of 6.8% (4.0-9.6) and 55.0% (45.3-64.7), respectively. Case clusters have played an important part in the course of the epidemic. Patients' age was strongly associated with outcome. The time between onset of symptoms and admission to hospital did not alter outcome, but shorter intervals will be important to the wider population by restricting the infectious period before patients are placed in quarantine.


Yoga for depression: a systematic review and meta-analysis.
Mind-body medical interventions are commonly used to cope with depression and yoga is one of the most commonly used mind-body interventions. The aim of this review was to systematically assess and meta-analyze the effectiveness of yoga for depression. Medline/PubMed, Scopus, the Cochrane Library, PsycINFO, and IndMED were searched through January 2013. Randomized controlled trials (RCTs) of yoga for patients with depressive disorders and individuals with elevated levels of depression were included. Main outcomes were severity of depression and remission rates, secondary outcomes were anxiety, quality of life, and safety. Twelve RCTs with 619 participants were included. Three RCTs had low risk of bias. Regarding severity of depression, there was moderate evidence for short-term effects of yoga compared to usual care (standardized mean difference (SMD) = -0.69; 95% confidence interval (CI) -0.99, -0.39; P < .001), and limited evidence compared to relaxation (SMD = -0.62; 95%CI -1.03, -0.22; P = .003), and aerobic exercise (SMD = -0.59; 95% CI -0.99, -0.18; P = .004). Limited evidence was found for short-term effects of yoga on anxiety compared to relaxation (SMD = -0.79; 95% CI -1.3, -0.26; P = .004). Subgroup analyses revealed evidence for effects in patients with depressive disorders and in individuals with elevated levels of depression. Due to the paucity and heterogeneity of the RCTs, no meta-analyses on long-term effects were possible. No RCT reported safety data. Despite methodological drawbacks of the included studies, yoga could be considered an ancillary treatment option for patients with depressive disorders and individuals with elevated levels of depression.


Multiple endocrine neoplasia type 1 with multiple leiomyomas linked to a novel mutation in the MEN1 gene.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited syndrome. MEN1 is characterized by the presence of functioning and nonfunctioning tumors or hyperplasia of the pituitary gland, parathyroid glands, and pancreatic islet cells. In addition, MEN1 carriers can have adrenal or thyroid tumors and non-endocrine tumors, such as lipomas, angiofibromas, and leiomyomas. Although leiomyoma is not a major component of MEN1, it is thought to occur more frequently than expected. However, there has been no report of a case of MEN1 with leiomyoma in Korea so far. This report describes a patient with multiple leiomyomas in MEN1. A 50-year-old woman was referred for further evaluation of elevated calcium levels and osteoporosis. Biochemical abnormalities included hypercalcemia with elevated parathyroid hormone. There was hyperprolactinemia with pituitary microadenoma in sella MRI. An abdominal MRI demonstrated adrenal nodules and leiomyomas in the bladder and uterus. Endoscopic ultrasonography demonstrated esophageal leiomyoma and pancreatic islet cell tumor. A subtotal parathyroidectomy with thymectomy was performed. Sequencing of the MEN1 gene in this patient revealed a novel missense mutation (D350V, exon 7). This is the first case of MEN1 accompanied with multiple leiomyomas, parathyroid adenoma, pituitary adenoma, pancreatic tumor, and adrenal tumor.


Investigating and modeling the differential DNA methylation for early lung adenocarcinoma diagnosis.
Background: Aberrant DNA methylations serve as rich sources of diagnostic biomarkers, but a further improvement in their accuracy and clinical utility is warranted. Methods: Large panel bisulfite sequencing was performed on paired normal and stage I/IV tumors from 226 lung adenocarcinoma cancer patients to characterize the differentially methylated regions (DMRs). Results: Random forest model achieved high prediction accuracy (sensitivity 96% and specificity 97.56%) to separate normal controls from both early and advanced cancer samples, which is superior to most previous prediction models tested in lung adenocarcinoma. Conclusion: Our results suggest that combining the random forest model with targeted bisulfite sequencing have great clinical potential to accurately predict and diagnose lung adenocarcinoma early during cancer screening.


Oxidative stress management in the hair follicle: Could targeting NRF2 counter age-related hair disorders and beyond?
Widespread expression of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2), which maintains redox homeostasis, has recently been identified in the hair follicle (HF). Small molecule activators of NRF2 may therefore be useful in the management of HF pathologies associated with redox imbalance, ranging from HF greying and HF ageing via androgenetic alopecia and alopecia areata to chemotherapy-induced hair loss. Indeed, NRF2 activation has been shown to prevent peroxide-induced hair growth inhibition. Multiple parameters can increase the levels of reactive oxygen species in the HF, for example melanogenesis, depilation-induced trauma, neurogenic and autoimmune inflammation, toxic drugs, environmental stressors such as UV irradiation, genetic defects and aging-associated mitochondrial dysfunction. In this review, the potential mechanisms whereby NRF2 activation could prove beneficial in treatment of redox-associated HF disorders are therefore discussed.


Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E2 and 15-deoxy-Δ(12,14)-PGJ2.
Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E(2), PGD(2) and its dehydration end product 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE(2) directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD(2) and 15d-PGJ(2) in the absence or presence of PGE(2) on IL-6 synthesis in human chondrocytes have yet to be determined. It is believed that dysregulated overproduction of IL-6 is responsible for the systemic inflammatory manifestations and abnormal laboratory findings in RA patients. Using the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE(2) and PGD(2)/15d-PGJ(2) exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE(2) stimulates Toll-like receptor 4 (TLR4) synthesis, which is in turn responsible for the activation of the ERK1/2, PI3K/Akt and PKA/CREB pathways that phosphorylate the NF-κB p65 subunit leading to NF-κB activation. Binding of the activated NF-κB p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD(2) or 15d-PGJ(2) concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE(2)-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-κB-dependent IL-6 synthesis in chondrocytes. We have delineated the signaling cascade by which PGE(2) and PGD(2)/15d-PGJ(2) exert opposing effects on IL-6 synthesis in human chondrocytes. Elucidation of the molecular pathway of IL-6 synthesis and secretion by chondrocytes will provide insights for developing strategies to reduce inflammation and pain in RA patients.


Telbivudine for the treatment of chronic hepatitis B infection.
This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of telbivudine for the treatment of chronic hepatitis B (CHB) in adults based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from one randomised controlled trial (RCT) (GLOBE) of reasonable methodological quality comparing telbivudine with lamivudine. One other RCT that appeared to meet the inclusion criteria was excluded from the submission. For the primary outcome of therapeutic response telbivudine was statistically superior to lamivudine at weeks 52 and 104 for hepatitis B e antigen (HBeAg)-positive patients, and at week 104 for HBeAg-negative patients. There were statistically significant differences in favour of telbivudine for some secondary outcomes at 2 years including hepatitis B virus (HBV) DNA reduction, HBV DNA non-detectability and alanine aminotransferase normalisation though not for HBeAg-positive patients. In HBeAg-positive patients there was no significant difference between treatment groups for HBeAg loss or seroconversion at any time point. The incidence of adverse events was similar between treatments. Two RCTs comparing entecavir with lamivudine were included in the indirect comparison; however, this was poorly conducted and the results should be treated with caution. The manufacturer developed two economic models to determine the cost-effectiveness of telbivudine. Evidence on the efficacy of telbivudine and lamivudine was taken from the GLOBE trial; efficacy of adefovir was based on assumption. There was a lack of critical assessment and assurance of the quality of the data used to populate the models. The manufacturer concluded that telbivudine is a cost-effective option compared with lamivudine using evidence from the viral load model [HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 19,087 pounds/49,003 pounds, mean quality-adjusted life-year (QALY) gain 1.30/4.67, incremental cost-effectiveness ratio (ICER) 14,665 pounds/10,497 pounds per QALY]. Resubmitted results after a request for clarification by the ERG gave less favourable ICERs (HBeAg-positive patients/HBeAg-negative patients: mean incremental cost 23,983 pounds/41,910 pounds, mean QALY gain 1.56/2.07, ICER 15,377 pounds/20,256 pounds per QALY). The manufacturer concluded that telbivudine is a cost-effective option (on its own or followed by adefovir) for patients who have developed resistance to first-line telbivudine treatment; however, the presentation of the results was not ideal. In conclusion, although telbivudine was statistically superior to lamivudine for most antiviral outcomes, the difference was not clinically significant; in addition, the cost-effectiveness evidence for telbivudine presented in the manufacturer's submission was limited. The NICE guidance issued as a result of the STA states that telbivudine is not recommended for the treatment of chronic hepatitis B and that people currently receiving telbivudine should have the option to continue therapy until they and their clinicians consider it appropriate to stop.