Effects of Cord Blood Serum (CBS) on viability of retinal Müller glial cells under in vitro injury.
Oxidative stress and inflammation determine retinal ganglion cell degeneration, leading to retinal impairment and vision loss. Müller glial cells regulate retinal repair under injury, through gliosis. Meanwhile, reactive gliosis can turn in pathological effects, contributing to neurodegeneration. In the present study, we tested whether Cord Blood Serum (CBS), rich of growth factors, might improve the viability of Müller cells under in vitro damage. BDNF, NGF, TGF-α, GDNF and EGF levels were measured in CBS samples by Human Magnetic Luminex Assay. CBS effects were evaluated on rat (rMC-1) and human (MIO-M1) Müller cells, under H2O2 and IL-1β damage. Cells grown with FBS or CBS both at 5% were exposed to stress and analyzed in terms of cell viability, GFAP, IL-6 and TNF-α expression. CBS was also administrated after treatment with K252a, inhibitor of the neurotrophin receptor Trk. Cell viability of rMC-1 and MIO-M1 resulted significantly improved when pretreated with CBS and exposed to H2O2 and IL-1β, in comparison to the standard culture with FBS. Accordingly, the gliosis marker GFAP resulted down-regulated following CBS priming. In parallel, we observed a lower expression of the inflammatory mediators in rMC-1 (TNF-α) and MIO-M1 (IL-6, TNF- α), especially in presence of inflammatory damage. Trk inhibition through K252a administration impaired the effects of CBS under stress conditions on MIO-M1 and rMC-1 viability, not significantly different from FBS condition. CBS is enriched with neurotrophins and its administration to rMC-1 and MIO-M1 attenuates the cytotoxic effects of H2O2 and IL-1β. Moreover, the decrease of the main markers of gliosis and inflammation suggests a promising use of CBS for neuroprotection aims. This study is a preliminary basis that prompts future investigations to deeply explore and confirm the CBS potential.


Intercellular Communication: Renal, Urinary Bladder, Sensory, and Salivary Gland Cells.
In four epithelial cell systems (salivary gland, renal, urinary bladder, and sensory cells) cells are interconnected as far as much of their ion content is concerned. In the salivary gland and renal epithelia, all cells of the epithelium are interconnected; and communication between a given cell and any of its nearest neighbors is equally good. In the bladder and sensory epithelia, communication appears to be more restricted, manifesting itself in chains of connected cells in the former, and in small groups of connected cells in the latter. The permeability of the cell membrane at the junction between connected cells is several orders of magnitude greater than it is at the cell surface bordering the exterior of the cells. Each connected cell ensemble functions as a system with a fairly continuous cytoplasmic core bounded by a diffusion barrier which is continuous along the entire outer surface of the system. As a result, ions move rather freely from cell to cell, but not from cell interior to exterior. Intercellular communication in at least three epithelia is associated with the presence of certain close-junctional membrane complexes.


Testing the use of septum-capped vials for 13C-isotope abundance analysis of carbon dioxide.
Studying ecosystem processes in the context of carbon cycling and climate change has never been more important. Stable carbon isotope studies of gas exchange within terrestrial ecosystems are commonly undertaken to determine sources and rates of carbon cycling. To this end, septum-capped vials ('Exetainers') are often used to store samples of CO(2) prior to mass spectrometric analysis. To evaluate the performance of such vials for preserving the isotopic integrity (delta(13)C) and concentration of stored CO(2) we performed a rigorous suite of tests. Septum-capped vials were filled with standard gases of varying CO(2) concentrations (approximately 700 to 4000 ppm), delta(13)C values (approx. -26.5 to +1.8 per thousand(V-PDB)) and pressures (33 and 67% above ambient), and analysed after a storage period of between 7 and 28 days. The vials performed well, with the vast majority of both isotope and CO(2) concentration results falling within the analytical uncertainty of chamber standard gas values. Although the study supports the use of septum-capped vials for storing samples prior to mass spectrometric analysis, it does highlight the need to ensure that sampling chamber construction is robust (air-tight).


Roles of ion channels in carotid body chemotransmission of acute hypoxia.
In this review, we have highlighted the roles of ion channels in carotid body chemotransmission of acute hypoxia. With the application of new technologies, significant breakthroughs have been made in the last decade. The discovery of oxygen-sensitive K(+) channels in rabbit glomus cells has generated the membrane model of hypoxic chemotransmission: the inhibition of oxygen-sensitive K(+) channels by hypoxia initiates the depolarization of glomus cells and increases the firing frequency of glomus cells. The depolarization of glomus cells activates voltage-gated Ca(2+) channels, elevating intracellular Ca(2+) which triggers the release of neurotransmitters. The correlation of these events in rabbit glomus cells has been shown. However, a large corpus of data indicates that various mechanisms may be involved in different species. In rats, Ca(2+)-activated K(+) channels are inhibited by hypoxia. The role of this inhibition on rat glomus cell function is controversial, and the contribution of leak-type K(+) channels to rat glomus cell depolarization has recently been proposed. On the other hand, in cats, nicotinic ACh receptors (ligand-gated cation channels) may play a key role in initiating the depolarization of glomus cells and increasing the cytosolic Ca(2+) of glomus cells in response to hypoxia. Hypoxic inhibition of oxygen-sensitive K(+) channels would participate to further depolarize cat glomus cells. Additionally, the activity of Cl(-) channels and the modulation of ion channels by neurotransmitters may influence the excitability of glomus cells. For generating action potentials in chemoreceptor afferent nerves, nicotinic ACh receptors appear to be involved in cats and rats.


Further refinement of the Patient-Reported Impact of Dermatological Diseases (PRIDD) measure using classical test theory and item response theory.
Existing dermatology-specific patient-reported outcome measures (PROMs) do not fully capture the substantial physical, psychological, and social impact of dermatological conditions on patients' lives and are not recommended for use according to the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) criteria. Most were developed with insufficient patient involvement and relied on classical psychometric methods. We are developing the new Patient-Reported Impact of Dermatological diseases (PRIDD) measure for use in research and clinical practice in partnership with patients. To examine the factor structure of PRIDD, determine the definitive selection of items for each subscale, and establish structural validity and internal consistency through classical and modern psychometric methods. Two cross-sectional online surveys. Adults (≥ 18 years) worldwide living with a dermatological condition were recruited through the International Alliance of Dermatology Patient Organizations' (GlobalSkin) membership network. They completed PRIDD and a demographics questionnaire via an online survey. We examined missing data and distribution of scores for each item. The factor structure was assessed using confirmatory and exploratory factor analysis (Survey 1). Internal consistency was examined using Cronbach's alpha. Rasch measurement theory analyses were conducted, including iterative assessment of rating scale function, fit to the Rasch model, unidimensionality, reliability, local dependence, targeting and differential item functioning (DIF)(Survey 1 and 2). 483 and 504 people participated in Survey 1 and 2, respectively. All items had ≤3% missing scores and all five response options were used. A four-factor model showed best fit. PRIDD and all four subscales were internally consistent but showed some misfit to the Rasch measurement model. Adjustments were made to rectify disordered thresholds, remove misfitting items, local dependency and DIF, and improve targeting. The resultant 16-item version and subscales fit the Rasch model, showed no local dependency or DIF at the test level, and were well-targeted. This field test study produced the final PRIDD consisting of 16 items across four domains. The data triangulated and refined the conceptual framework of impact and provide evidence of PRIDD's structural validity and internal consistency. The final step in PRIDD's development and validation is to test the remaining measurement properties.


Toward a more accurate estimate of the prevalence of hepatitis C in the United States.
Data from the 2003-2010 National Health and Nutrition Examination Survey (NHANES) indicate that about 3.6 million people in the United States have antibodies to the hepatitis C virus, of whom 2.7 million are currently infected. NHANES, however, excludes several high-risk populations from its sampling frame, including people who are incarcerated, homeless, or hospitalized; nursing home residents; active-duty military personnel; and people living on Indian reservations. We undertook a systematic review of peer-reviewed literature and sought out unpublished presentations and data to estimate the prevalence of hepatitis C in these excluded populations and in turn improve the estimate of the number of people with hepatitis C in the United States. The available data do not support a precise result, but we estimated that 1.0 million (range 0.4 million-1.8 million) persons excluded from the NHANES sampling frame have hepatitis C virus antibody, including 500,000 incarcerated people, 220,000 homeless people, 120,000 people living on Indian reservations, and 75,000 people in hospitals. Most are men. An estimated 0.8 million (range 0.3 million-1.5 million) are currently infected. Several additional sources of underestimation, including nonresponse bias and the underrepresentation of other groups at increased risk of hepatitis C that are not excluded from the NHANES sampling frame, were not addressed in this study. The number of US residents who have been infected with hepatitis C is unknown but is probably at least 4.6 million (range 3.4 million-6.0 million), and of these, at least 3.5 million (range 2.5 million-4.7 million) are currently infected; additional sources of potential underestimation suggest that the true prevalence could well be higher.


Comparative Study for Alignment of Extramedullary Guides versus Portable, Accelerometer-Based Navigation in Total Knee Arthroplasty.
The use of portable, accelerometer-based navigation (PN) devices for positioning of the components of total knee arthroplasty (TKA) is emerging as an alternative to standard extramedullary (EM) systems, which was needed to the image intensifier. The aim of our study was to compare the accuracy of component positioning in TKA using an EM and PN systems. Data from 100 consecutive primary TKAs, performed by multiple surgeons in 87 patients between October 2010 and June 2015, were analyzed. Coronal and sagittal plane alignments of the TKA components, relative to the mechanical axis of the limb, were evaluated by radiography. The mean postoperative coronal alignment angle of the femoral (α) and tibial (β) components was comparable between the groups (α: PN, 89.9 ± 2.2 degrees; EM, 89.9 ± 1.6 degrees and β: PN, 90.1 ± 1.4 degrees; EM, 89.6 ± 1.3 degrees). Groups were also comparable with regard to mean postoperative sagittal alignment angle of the femoral and tibial components (γ: PN, 2.3 ± 3.3 degrees; EM, 1.8 ± 1.7 degrees and σ: PN, 89.7 ± 2.5 degrees; EM, 90.1 ± 1.3 degrees). The incidence rate of a component malalignment > 3 degrees in the coronal and sagittal planes of the mechanical axis of the knee was comparable between the groups. In conclusion, the coronal and sagittal alignments for the femoral components was less accurate compared with tibial component alignment, especially in the PN group, and the sagittal alignment of the femoral component was less accurate than coronal alignment for both groups. Both the PN and EM systems provide satisfactory coronal and sagittal component alignments in TKA. Further technical improvement of the PN system could further improve its application for accurate component implantation in TKAs.


Study on the bZIP-Type Transcription Factors NapA and RsmA in the Regulation of Intracellular Reactive Species Levels and Sterigmatocystin Production of Aspergillus nidulans.
Basic leucine zipper (bZIP) transcription factors play a crucial role in the environmental stress response of eukaryotes. In this work, we studied the effect of gene manipulations, including both deletions and overexpressions, of two selected bZIP transcription factors, NapA and RsmA, in the oxidative stress response and sterigmatocystin production of Aspergillus nidulans. We found that NapA was important in the oxidative stress response by negatively regulating intracellular reactive species production and positively regulating catalase activities, whereas RsmA slightly negatively regulated catalase activities. Concerning sterigmatocystin production, the highest concentration was measured in the ΔrsmAΔnapA double deletion mutant, but elevated sterigmatocystin production was also found in the OErsmA OEnapA strain. Our results indicate that NapA influences sterigmatocystin production via regulating reactive species level whereas RsmA modulates toxin production independently of the redox regulation of the cells.


[Alcohol and atrial fibrillation].
Atrial fibrillation (AF) is the most common heart rhythm disorder, with an increasing prevalence, currently estimated at 3 % of the world population. It has long been well known, as the holiday heart syndrome, that acute alcohol consumption (binge drinking) may trigger an episode of AF, most often benign, during or immediately after consumption. Meta-analyses of observational studies have clearly shown a significant association between a high level of alcohol consumption and the risk of AF. According to the studies included in meta-analyses, the conclusions may differ regarding the association between low and moderate levels of alcohol consumption and the risk of AF. The association probably only exists from a level of consumption of at least one drink per day. Heavy alcohol consumption appears to increase the risk of complications in patients with AF, while light or moderate alcohol consumption does not. The causal nature of the relationship between alcohol consumption and AF cannot currently be confirmed or denied, given the contradictory results of Mendelian randomization studies published to date. However, in patients diagnosed with AF, the recommendation to abstain from alcohol, resulting in a strong reduction in consumption, made it possible to significantly reduce the recurrence of AF episodes.


Spontaneous particle desorption and "Gorgon" drop formation from particle-armored oil drops upon cooling.
We study how the phenomenon of drop "self-shaping" (Denkov et al., Nature, 528, 2015, 392), in which oily emulsion drops undergo a spontaneous series of shape transformations upon emulsion cooling, is affected by the presence of adsorbed solid particles, like those used in Pickering emulsion stabilization. Experiments with several types of latex particles, and with added surfactant of low concentration to enable drop self-shaping, revealed several new unexpected phenomena: (1) adsorbed latex particles rearranged into regular hexagonal lattices upon freezing of the surfactant adsorption layer. (2) Spontaneous particle desorption from the drop surface was observed at a certain temperature - a remarkable phenomenon, as the solid particles are known to irreversibly adsorb on fluid interfaces. (3) Very strongly adhered particles to drop surfaces acted as a template to enable the formation of tens to hundreds of semi-liquid fibres, growing outwards from the drop surface, thus creating a shape resembling the Gorgon head from Greek mythology. Mechanistic explanations of all observed phenomena are provided using our understanding of the rotator phase formation on the surface of the cooled drops. The surface rotator phase creates positive line tension at the contact line formed between the particle surface and the fluid interface, which causes the particle ejection from the drop surface.


Gene expression analysis of CL-20-induced reversible neurotoxicity reveals GABA(A) receptors as potential targets in the earthworm Eisenia fetida.
The earthworm Eisenia fetida is one of the most used species in standardized soil ecotoxicity tests. End points such as survival, growth, and reproduction are eco-toxicologically relevant but provide little mechanistic insight into toxicity pathways, especially at the molecular level. Here we apply a toxicogenomic approach to investigate the mode of action underlying the reversible neurotoxicity of hexanitrohexaazaisowurtzitane (CL-20), a cyclic nitroamine explosives compound. We developed an E. fetida-specific shotgun microarray targeting 15119 unique E. fetida transcripts. Using this array we profiled gene expression in E. fetida in response to exposure to CL-20. Eighteen earthworms were exposed for 6 days to 0.2 μg/cm(2) of CL-20 on filter paper, half of which were allowed to recover in a clean environment for 7 days. Nine vehicle control earthworms were sacrificed at days 6 and 13, separately. Electrophysiological measurements indicated that the conduction velocity of earthworm medial giant nerve fiber decreased significantly after 6-day exposure to CL-20, but was restored after 7 days of recovery. Total RNA was isolated from the four treatment groups including 6-day control, 6-day exposed, 13-day control, and 13-day exposed (i.e., 6-day exposure followed by 7-day recovery), and was hybridized to the 15K shotgun oligo array. Statistical and bioinformatic analyses suggest that CL-20 initiated neurotoxicity by noncompetitively blocking the ligand-gated GABA(A) receptor ion channel, leading to altered expression of genes involved in GABAergic, cholinergic, and Agrin-MuSK pathways. In the recovery phase, expression of affected genes returned to normality, possibly as a result of autophagy and CL-20 dissociation/metabolism. This study provides significant insights into potential mechanisms of CL-20-induced neurotoxicity and the recovery of earthworms from transient neurotoxicity stress.


A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals.
A protective vaccine against HIV-1 will likely require the elicitation of a broadly neutralizing antibody (bNAb) response. Although the development of an immunogen that elicits such antibodies remains elusive, a proportion of HIV-1 infected individuals evolve broadly neutralizing serum responses over time, demonstrating that the human immune system can recognize and generate NAbs to conserved epitopes on the virus. Understanding the specificities that mediate broad neutralization will provide insight into which epitopes should be targeted for immunogen design and aid in the isolation of broadly neutralizing monoclonal antibodies from these donors. Here, we have used a number of new and established technologies to map the bNAb specificities in the sera of 19 donors who exhibit among the most potent cross-clade serum neutralizing activities observed to date. The results suggest that broad and potent serum neutralization arises in most donors through a limited number of specificities (1-2 per donor). The major targets recognized are an epitope defined by the bNAbs PG9 and PG16 that is associated with conserved regions of the V1, V2 and V3 loops, an epitope overlapping the CD4 binding site and possibly the coreceptor binding site, an epitope sensitive to a loss of the glycan at N332 and distinct from that recognized by the bNAb 2G12 and an epitope sensitive to an I165A substitution. In approximately half of the donors, key N-linked glycans were critical for expression of the epitopes recognized by the bNAb specificities in the sera.


Mortality prediction in acute heart failure: scores or biomarkers?
Acute heart failure (AHF) is a complex and heterogeneous syndrome not only associated with a concerning rise in incidence, but also with still unacceptably high rates of mortality and morbidity. As this dismal outcome is at least in part due to a mismatch between the severity of AHF and the intensity of its management, both in-hospital and immediately after discharge, early and accurate risk prediction could contribute to more effective, risk-adjusted management. Biomarkers are noninvasive and highly reproducible quantitative tools that have improved the understanding of AHF pathophysiology. They can help guide the intensity of AHF management. In addition, using a statistical model to estimate risk from a combination of several predictor variables such as vital signs or demographics has gained more and more attention over recent years. In this context, the aim of a statistical model, which gives a so-called risk score, is to help clinicians to make more standardised decisions. This review highlights recent advances and remaining uncertainties regarding risk stratification in AHF by characterising and comparing the potential of biomarkers and risk scores. &nbsp.


Inheritance of most X-linked traits is not dominant or recessive, just X-linked.
The existence of X-linked disorders in humans has been recognized for many centuries, based on lessons in religious texts and observations of specific human families (e.g., color blindness or Daltonism). Our modern concepts of Mendelian (including X-linked) inheritance originated just after the turn of the last century. Early concepts of dominance and recessiveness were first used in conjunction with autosomal traits, and then applied to "sex"-linked traits to distinguish X-linked recessive and X-linked dominant inheritance. The former was defined as vertical transmission in which carrier women pass the disorder to affected sons, while the latter was defined as vertical transmission in which daughters of affected males are always affected, transmitting the disorder to offspring of both sexes. However, many X-linked disorders such as adrenoleukodystrophy, fragile X syndrome, and ornithine transcarbamylase deficiency do not fit these rules. We reviewed the literature on 32 X-linked disorders and recorded information on penetrance and expressivity in both sexes. As expected, penetrance and an index of severity of the phenotype (defined in our Methods) were both high in males, while the severity index was low in females. Contrary to standard presentations of X-linked inheritance, penetrance was highly variable in females. Our analysis classified penetrance as high in 28% of the disorders studied, intermediate in 31%, and low in 40%. The high proportion of X-linked disorders with intermediate penetrance is difficult to reconcile with standard definitions of X-linked recessive and dominant inheritance. They do not capture the extraordinarily variable expressivity of X-linked disorders or take into account the multiple mechanisms that can result in disease expression in females, which include cell autonomous expression, skewed X-inactivation, clonal expansion, and somatic mosaicism. We recommend that use of the terms X-linked recessive and dominant be discontinued, and that all such disorders be simply described as following "X-linked" inheritance.


Ethnic differences in the prevalence of cryptogenic cirrhosis.
Nonalcoholic steatohepatitis (NASH) associated with obesity and type 2 diabetes mellitus (DM) is postulated to be the cause of most cases of cryptogenic cirrhosis (CC). While ethnic differences in the prevalence of obesity and DM in the United States are well documented, there is little information regarding prevalence of CC or NASH among different U.S. ethnic groups. This study was performed to assess the demographic characteristics of patients with CC at a U.S. county hospital with a racially and ethnically diverse patient population. Medical records and pathology databases were reviewed to identify patients at Parkland Memorial Hospital, Dallas County, Texas from 1990 to 2001 with CC or cirrhosis attributed to NASH. Forty-one patients (12 men, 29 women) were found to meet these criteria. Of these, 68% were obese (BMI > or = 30) and/or had type 2 DM and 74% of liver biopsies revealed one or more features of NASH. Of patients with CC 68% were Hispanic while only 7% were African American, despite the fact that Hispanics comprised < 26% and African Americans > 40% of adult medicine patients. Prevalence of CC among Hispanic and African American patients was 3.1-fold higher and 3.9-fold lower, respectively, than among European American patients despite similar prevalence of DM among Hispanics and African Americans. These findings support the hypothesis that NASH associated with obesity and DM is responsible for the majority of cases of CC among Hispanics and European Americans. However, the current findings also indicate that this form of cirrhosis is unexpectedly rare among African Americans.


Targeting β-amyloid plaques and oligomers: development of near-IR fluorescence imaging probes.
Evidence indicated that shifting treatment to a presymptomatic stage may produce significant benefits to prevent/alleviate the progression of Alzheimer's disease (AD); in particular, early incorporation of noninvasive imaging and biomarker testing will be significantly beneficial for AD drug development. Based on amyloid cascade hypothesis and its revised version, both β-amyloid deposition and soluble oligomeric species could be good diagnostic biomarkers for AD. Near-IR fluorescence (NIRF) imaging, which so far is limited to animal studies, is a promising method for its incomparable advantages such as low cost, high-throughput and easy operation. This review focuses on recent reported NIRF probes that showed excellent binding to plaques and oligomers. We hope that this review will shed light on the future of NIRF probes' discovery.


Toxicity study of compound granules of Hedyotis diffusa: Acute toxicity and long-term toxicity.
The clinical efficacy of the hospital preparation compound granules of Hedyotis diffusa (CGHD), which is composed of Hedyotis diffusa Willd, Smilax china L., Solanum lyratum Thunb., has accumulated a good reputation over the past decades. However, because it is a hospital preparation, few researchers have paid attention to it, resulting in a lack of systematic basic research studies. Thus, it is not clear whether there are safety concerns that restrict its clinical application, and toxicological evaluation of CGHD is needed. The aim of this study was to evaluate the safety of CGHD by conducting acute toxicity and long-term toxicity experiments, with the objective of providing evidence for its clinical safety and a theoretical foundation for its clinical application. KM mice were selected for the acute toxicity experiment and were administered water or CGHD-E 3 times within 24 h. The reactions of the animals to CGHD treatment were observed and recorded within 1 h after administration and then once a day for 14 consecutive days. SD rats were selected to conduct the long-term toxicity experiment. The drug-treated groups were administered different doses of CGHD-E, which were equivalent to 10 times, 20 times and 50 times the clinical dose in humans. The rats were administered the drug for 28 consecutive days. After 28 days, the animals were sacrificed, and routine blood tests, blood coagulation function analysis, liver and kidney function tests, and glycolipid metabolism related tests were conducted. The major organs of the rats were collected to calculate organ coefficients and perform hematoxylin-eosin (HE) staining. In the CGHD-E acute toxicity experiment, the drug-treated groups did not show adverse reactions or poisoning symptoms, and the maximum tolerated dose of CGHD-E in mice was greater than 45.072 g/kg. In the long-term toxicity experiment, drug-treated rats generally exhibited a good condition, but continuous administration decreased on body weight and food intake, especially in male rats. Coagulation function alterations and the impact on the liver during long-term drug administration were also assessed, which should be emphasized in clinical applications. No significant toxic effects were observed according to routine blood tests or test of liver and kidney function, glucose and lipid metabolism, or ion metabolism. The results of this study showed that CGHD was nontoxic or had low toxicity, providing not only a scientific basis for its clinical application, determining the appropriate clinical dose and monitoring clinical toxicity but also theoretical support for subsequent clinical drug trials.


Progress and analytic goals in clinical chemistry.
The data that have been accumulated by the Survey program of the College of American Pathologists for analysis of 12 serum constituents for the five-year period 1969-1973 are reviewed. The data include approximately 2 million individual analyses provided by the majority of the clinical laboratories in the United States. The data show clear evidence of progressive improvement. The values reported by the participants for each analysis have agreed more closely in each successive year. The improvements have stemmed partly from improved performance of individual methods and partly from increased use of methods with good precision. Closer standardization between laboratories may have played a role. The findings are used for proposing a set of goals for the analysis of these constituents in serum. Comparison of the goals with the actual levels of current performance shows that for many analyses the current levels are adequate, while for others the current levels fall short of the desired goals. Achieving the goals from some analyses may be beyond the present limits of the technology of clinical laboratory analysis.


Identification and characterization of a twist ortholog in the polychaete annelid Platynereis dumerilii reveals mesodermal expression of Pdu-twist.
The basic helix-loop-helix transcription factor twist plays a key role during mesoderm development in Bilateria. In this study, we identified a twist ortholog in the polychaete annelid Platynereis dumerilii and analyze its expression during larval development, postlarval growth up to the adult stage, and caudal regeneration after amputation of posterior segments. At late larval stages, Pdu-twist is expressed in the mesodermal anlagen and in developing muscles. During adulthood and caudal regeneration, Pdu-twist is expressed in the posterior growth zone, in mesodermal cells within the newly forming segments and budding parapodia. Our results indicate that Pdu-twist is involved in mesoderm formation during larval development, posterior growth, and caudal regeneration.


Cancer Screening in the Elderly: A Review of Breast, Colorectal, Lung, and Prostate Cancer Screening.
There are relatively limited data on outcomes of screening older adults for cancer; therefore, the decision to screen older adults requires balancing the potential harms of screening and follow-up diagnostic tests with the possibility of benefit. Harms of screening can be amplified in older and frail adults and include discomfort from undergoing the test itself, anxiety, potential complications from diagnostic procedures resulting from a false-positive test, false reassurance from a false-negative test, and overdiagnosis of tumors that are of no threat and may result in overtreatment. In this paper, we review the evidence and guidelines on breast, colorectal, lung and prostate cancer as applied to older adults. We also provide a general framework for approaching cancer screening in older adults by incorporating evidence-based guidelines, patient preferences, and patient life expectancy estimates into shared screening decisions.


A Pilot Study Comparing Observational and Questionnaire Surrogate Measures of Pesticide Exposure Among Residents Impacted by the Ecuadorian Flower Industry.
Self-reported measures of residential pesticide exposure are commonly used in epidemiological studies, especially when financial and logistical resources are limited. However, self-reporting is prone to misclassification bias. This pilot study assesses the agreement between self-report of residential pesticide exposure with direct observation measures, in an agricultural region of Ecuador, as a cross-validation method in 26 participants (16 rose workers and 10 controls), with percent agreement and kappa statistics calculated. Proximity of homes to nearby flower farms was found to have only fair agreement (kappa =.35). The use of discarded plastics (kappa =.06) and wood (kappa =.13) were found to have little agreement. Results indicate that direct observation or measurement may provide more accurate appraisals of residential exposures, such as proximity to industrial farmland and the use of discarded materials obtained from the flower farms.


Translation of tobacco policy into practice in disadvantaged and marginalized subpopulations: a study of challenges and opportunities in remote Australian Indigenous communities.
In Australia generally, smoking prevalence more than halved after 1980 and recently commenced to decline among Australia's disadvantaged Indigenous peoples. However, in some remote Indigenous Australian communities in the Northern Territory (NT), extremely high rates of up to 83% have not changed over the past 25 years. The World Health Organisation has called for public health and political leadership to address a global tobacco epidemic. For Indigenous Australians, unprecedented policies aim to overcome disadvantage and close the 'health gap' with reducing tobacco use the top priority. This study identifies challenges and opportunities to implementing these important new tobacco initiatives in remote Indigenous communities. With little empirical evidence available, we interviewed 82 key stakeholders across the NT representing operational- and management-level service providers, local Indigenous and non-Indigenous participants to identify challenges and opportunities for translating new policies into successful tobacco interventions. Data were analysed using qualitative approaches to identify emergent themes. The 20 emergent themes were classified using counts of occasions each theme occurred in the transcribed data as challenge or opportunity. The 'smoke-free policies' theme occurred most frequently as opportunity but infrequently as challenge while 'health workforce capacity' occurred most frequently as challenge but less frequently as opportunity, suggesting that policy implementation is constrained by lack of a skilled workforce. 'Smoking cessation support' occurred frequently as opportunity but also frequently as challenge suggesting that support for individuals requires additional input and attention. These results from interviews with local and operational-level participants indicate that current tobacco policies in Australia targeting Indigenous smoking are sound and comprehensive. However, for remote Indigenous Australian communities, local and operational-level participants' views point to an 'implementation gap'. Their views should be heard because they are in a position to provide practical recommendations for effective policy implementation faithful to its design, thereby translating sound policy into meaningful action. Some recommendations may also find a place in culturally diverse low- and middle-income countries. Key words: tobacco policy implementation, challenges, opportunities, remote Indigenous Australian communities.


Peripheral administration of brain-derived neurotrophic factor to Rett syndrome animal model: a possible approach for the treatment of Rett syndrome.
Rett syndrome (RTT) is a postnatal, severe, disabling neurodevelopmental disorder occurring almost exclusively in females and is the second most common cause for genetic mental retardation in girls. In the majority of cases it is caused by mutations in gene (MECP2) encoding methyl-CpG-binding protein 2. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis and plasticity. Animal studies suggested that abnormalities in BDNF homeostasis may contribute to the pathogenesis in Mecp2 null mice, and BDNF administration in the Mecp2 mutant brain led to later onset/slower disease progression, suggesting that increased BDNF in the brain could be therapeutic for this disease. Mature BDNF is a 14 kDa protein that may have poor blood-brain barrier penetrability. However, recent animal studies demonstrated that peripheral administration of BDNF, either by intravenous injection or intranasal delivery, could increase BDNF levels in the brain. Thus it is proposed that peripheral administration of BDNF in the early stage could have therapeutic potential for RTT subjects. Furthermore, the combination use of mannitol may temporarily open the blood-brain barrier and facilitate the entry of BDNF into brain. The potential therapeutic effect of peripheral BDNF administration could be tested in RTT animal models such as Mecp2 KO mice, which may provide a new intervention for this devastating disease.


Functional and molecular characterization of NHE3 expression during ontogeny in rat jejunal epithelium.
Ontogenic changes occur in intestinal brush-border membrane vesicle (BBMV) Na+/H+ exchange activity. The present studies were designed to investigate ontogenic changes in Na+/H+ exchanger (NHE) isoform 3 in rat jejunum. pH-dependent Na+ uptake was assayed in four age groups of rats in the presence of 0, 50, or 800 microM HOE-694, a specific NHE inhibitor with differential sensitivities for NHE2 [inhibition constant (Ki) = 5 microM in PS120 fibroblasts] and NHE3 (Ki = 650 microM). Results showed that NHE2 and NHE3 contribute to basal BBMV uptake at all ages. Uptake levels were highest in 6-wk-old rats, lower in adult rats, and lowest in 2-wk-old (suckling) and 3-wk-old (weanling) rats, NHE3 contribution ranged from 92% at 6 wk of age to 59% at 2 and 3 wk of age. NHE3 inhibition by 800 microM HOE-694 was 38-45%. Statistical analysis showed that HOE-694 had a significant effect at both concentrations at all ages and that differences were present between all ages except 2- and 3-wk rats (at all HOE-694 concentrations). Northern blot analyses of jejunal mucosa showed lowest NHE3 mRNA levels in 2-wk animals and higher levels in all other age groups. Polyclonal antibodies were developed against an NHE3 COOH-terminal fusion protein, and antiserum was characterized with NHE3-transfected PS120 cells and by immunohistochemistry. Western blot analyses showed lowest protein levels in 2-wk animals and higher levels in the other ages. Suckling rats were subcutaneously injected with methylprednisone (MP) for 2 days and killed 1 day later. Northern blot analyses showed a twofold increase in NHE3 mRNA expression with MP treatment. Immunoblot analyses showed a 2.5-fold increase in NHE3 immunoreactive protein levels with MP injection. Overall, these data suggest that NHE3 is regulated during ontogeny and that ontogenic changes are most apparent around the time of weaning. Furthermore, the data suggest that NHE3 is regulated at transcriptional and posttranscriptional levels during mammalian intestinal development.


Understanding of binding energy calibration in XPS of lanthanum oxide by in situ treatment.
Rare earth oxides have seen increased usage over the years in batteries and catalysts. Due to their unique electronic properties, they are the subject of fundamental and practical interest. However, the complexity in their electronic structures makes unambiguous characterization, such as X-ray photoelectron spectroscopy (XPS), very challenging. Lanthanum oxide (La2O3) has attracted special attention as a promising catalyst for the oxidative coupling of methane (OCM) reaction. In this work, a new and reliable way of XPS calibration is developed by applying various in situ preparations for a nanorod La2O3 catalyst to intentionally form different lanthanum compounds, followed by XPS characterization and corroboration with first principles calculations. To form different compounds, five sample treatments were performed including heating in vacuum and treatment with O2, CH4, CO2, and H2O, which are all relevant to OCM reaction conditions. Adventitious carbon or lattice oxygen, as conventional calibration standard species for energy scale, is only suitable for one or few in situ prepared surfaces. Our results also clearly demonstrate the vital difference between performing the ex situ analysis after exposure of the sample to the atmosphere and the in situ analysis. By carefully comparing the spectra of various photoemission peaks of different compounds, we conclude that the binding energy of 102.2 eV for the La 4d7/2 peak can be used as the internal calibration standard for all considered samples. Furthermore, different oxygen species were unambiguously identified by matching the oxygen 1s binding energies from the in situ measurements and first principles predictions.


Predictors of emergency department use by adolescents and adults with autism spectrum disorder: a prospective cohort study.
To determine predictors of emergency department (ED) visits in a cohort of adolescents and adults with autism spectrum disorder (ASD). Prospective cohort study. Community-based study from Ontario, Canada. Parents reported on their adult sons and daughters with ASD living in the community (n=284). ED visits for any reason, ED visits for medical reasons and ED visits for psychiatric reasons over 1 year. Among individuals with ASD, those with ED visits for any reason were reported to have greater family distress at baseline (p<0.01), a history of visiting the ED during the year prior (p<0.01) and experienced two or more negative life events at baseline (p<0.05) as compared with those who did not visit the ED. Unique predictors of medical versus psychiatric ED visits emerged. Low neighbourhood income (p<0.01) and living in a rural neighbourhood (p<0.05) were associated with medical but not psychiatric ED visits, whereas a history of aggression (p<0.05) as well as being from an immigrant family (p<0.05) predicted psychiatric but not medical emergencies. A combination of individual and contextual variables may be important for targeting preventative community-based supports for individuals with ASD and their families. In particular, attention should be paid to how caregiver supports, integrative crisis planning and community-based services may assist in preventing or minimising ED use for this vulnerable population.


Changes in judgment of duration with different patterns of auditory information for individuals confined to bed.
A theoretical proposition that changes in the organization and structure of auditory information result in changes in temporal experience was tested in this study. Changes were measured in the judgment of duration of a 40-second interval that occurred in three different patterns of auditory information among individuals confined to bed. The sample consisted of 90 men and 90 women aged 18 to 35 years who had no known physical or mental health problems. Subjects rested in bed in a comfortable room for two and one-half hours. Each subject received one of three forms of auditory information-called decoded, coded, and ambient auditory information. At four periods during the 150 minutes of auditory information (25 minutes, 75 minutes, 120 minutes, 150 minutes) the subject was directed by a lighted sign to produce a 40-second interval by depressing a button. The button was connected to a microtimer which timed the interval to the nearest tenth second. None of the three hypotheses-1) that time would seem to pass more slowly in the coded than in the decoded condition: 2) that time would pass more slowly in the decoded than ambient condition: and 3) that as the period of bedrest progressed differences in duration experience would occur among the three groups--was supported by the data. The produced interval for ambient auditory information was expected to be the longest of the three groups, but the opposite effect occurred; it was the shortest. The significant overestimation that occurred in the ambient condition relative to the decoded condition appeared to be related to the methodological imposition of vigilance, lack of structuring information, and the condition of waiting. The coded auditory input did not effect changes in duration relative to the decoded and ambient auditory information as subjects were able to reorder the coded information.


Immunohistochemical analysis of Ku70/86 expression of breast cancer tissues.
DNA-dependent protein kinase (DNA-PK) has an important role in DNA double-strand break repair. We previously demonstrated the association of DNA-PK activity in peripheral blood lymphocytes (PBL) with incidence of chromosomal aberrations and risk of cancer. In this study, we examined the expression of Ku70 and Ku86 in breast cancer tissue and normal breast tissue with immunohistochemistry. We also measured the DNA-PK activity in PBL of the same patient. One hundred and ten breast cancer patients were included in this study. The expression of Ku70, and Ku86 in normal mammary epithelial cells and breast cancer cells obtained from surgical specimens was immunohistochemically examined. DNA-PK activity of PBL was measured by DNA-pull-down assay. The expression of Ku70 and that of Ku86 tended to parallel each other in normal and cancer tissues. There was also a relationship in the expression of Ku70 and Ku86 between cancer tissues and normal tissues in the same samples. Lower expression of Ku70 or Ku86 tended to be associated with higher malignant nuclear grade of cancer cells and higher frequency of axillary lymph node metastasis. The staining score of Ku70 or Ku86 of normal mammary epithelial cells or breast cancer cells had no significant relationship with DNA-PK activity of PBL. In conclusion, breast cancer cells inherited the characteristics of expression of Ku proteins from original mammary epithelial cells. The staining score of Ku70 or Ku86 of normal or cancer cells had no significant relationship with DNA-PK activity of PBL. This may be due to limitations in the assay sensitivity of immunohistochemistry.


FTT0831c/FTL_0325 contributes to Francisella tularensis cell division, maintenance of cell shape, and structural integrity.
The Francisella FTT0831c/FTL_0325 gene encodes amino acid motifs to suggest it is a lipoprotein and that it may interact with the bacterial cell wall as a member of the OmpA-like protein family. Previous studies have suggested that FTT0831c is surface exposed and required for virulence of Francisella tularensis by subverting the host innate immune response (M. Mahawar et al., J. Biol. Chem. 287:25216-25229, 2012). We also found that FTT0831c is required for murine pathogenesis and intramacrophage growth of Schu S4, but we propose a different model to account for the proinflammatory nature of the resultant mutants. First, inactivation of FTL_0325 from live vaccine strain (LVS) or FTT0831c from Schu S4 resulted in temperature-dependent defects in cell viability and morphology. Loss of FTT0831c was also associated with an unusual defect in lipopolysaccharide O-antigen synthesis, but loss of FTL_0325 was not. Full restoration of these properties was observed in complemented strains expressing FTT0831c in trans, but not in strains lacking the OmpA motif, suggesting that cell wall contact is required. Finally, growth of the LVS FTL_0325 mutant in Mueller-Hinton broth at 37°C resulted in the appearance of membrane blebs at the poles and midpoint, prior to the formation of enlarged round cells that showed evidence of compromised cellular membranes. Taken together, these data are more consistent with the known structural role of OmpA-like proteins in linking the OM to the cell wall and, as such, maintenance of structural integrity preventing altered surface exposure or release of Toll-like receptor 2 agonists during rapid growth of Francisella in vitro and in vivo.


Variations by state in physician disciplinary actions by US medical licensure boards.
To investigate the variation in the rate of state medical board physician disciplinary actions between US states. Longitudinal study of state medical board physician disciplinary action rates using the US National Practitioner Data Bank and American Medical Association estimates of physician demographics across all 50 states and the District of Columbia from 2010 to 2014. Results were reliability adjusted using a multilevel logistic model controlling for year of disciplinary action, physicians per capita in each state and the rate of malpractice claims per physician in each state. From 2010 to 2014, there were a total of 5046 506 physician licensure years present. Medical boards reported a total of 21 647 disciplinary actions, of which 5137 (23.7%) were major disciplinary actions involving revocation, suspension or surrender of licence. The mean, reliability-adjusted rate of all disciplinary actions was 3.76 (95% CI 3.21 to 4.42) with a significant variation between states. State rates ranged from 2.13 (95% CI 1.86 to 2.45) to 7.93 (95% CI 6.33 to 9.93) actions per 1000 physicians. The mean rate of major disciplinary actions was 2.71 (95% CI 1.93 to 3.82), ranging from 0.64 (95% CI 0.53 to 0.76) to 2.71 (95% CI 1.93 to 3.82) actions per 1000 physicians. The correlation between the rate of major disciplinary action and minor disciplinary actions was 0.34. There is a significant, fourfold variation in the annual rate of medical board physician disciplinary action by state in the USA. When indicated, state medical boards should consider policies aimed at improving standardisation and coordination to provide consistent supervision to physicians and ensure public safety.


Finding memory in search: the effect of visual working memory load on visual search.
There is now substantial evidence that during visual search, previously searched distractors are stored in memory to prevent them from being reselected. Studies examining which memory resources are involved in this process have indicated that while a concurrent spatial working memory task does affect search slopes, depleting visual working memory (VWM) resources does not. In the present study, we confirm that VWM load indeed has no effect on the search slope; however, there is an increase in overall reaction times that is directly related to the number of items held in VWM. Importantly, this effect on search time increases proportionally with the memory load until the capacity of VWM is reached. Furthermore, the search task interfered with the number of items stored in VWM during the concurrent change-detection task. These findings suggest that VWM plays a role in the inhibition of previously searched distractors.


Experimental verification of the 'stability profile of mutant protein' (SPMP) data using mutant human lysozymes.
The stability profile of mutant protein (SPMP) (Ota,M., Kanaya,S. and Nishikawa,K., 1995, J. Mol. Biol., 248, 733-738) estimates the changes in conformational stability due to single amino acid substitutions using a pseudo-energy potential developed for evaluating structure-sequence compatibility in the structure prediction method, the 3D-1D compatibility evaluation. Nine mutant human lysozymes expected to significantly increase in stability from SPMP were constructed, in order to experimentally verify the reliability of SPMP. The thermodynamic parameters for denaturation and crystal structures of these mutant proteins were determined. One mutant protein was stabilized as expected, compared with the wild-type protein. However, the others were not stabilized even though the structural changes were subtle, indicating that SPMP overestimates the increase in stability or underestimates negative effects due to substitution. The stability changes in the other mutant human lysozymes previously reported were also analyzed by SPMP. The correlation of the stability changes between the experiment and prediction depended on the types of substitution: there were some correlations for proline mutants and cavity-creating mutants, but no correlation for mutants related to side-chain hydrogen bonds. The present results may indicate some additional factors that should be considered in the calculation of SPMP, suggesting that SPMP can be refined further.


Interaction of insulin with Burkholderia pseudomallei may be caused by a preservative.
To re-examine the previously reported in vitro interaction of insulin with Burkholderia pseudomallei, in the light of a suggestion that the interaction may have resulted from the presence of the preservative m-cresol in commercial preparations. Broth culture studies of B pseudomallei were performed with and without the addition of m-cresol and various preparations of insulin. Growth of B pseudomallei was inhibited by m-cresol at the concentrations found in pharmaceutical insulin preparations, and by the insulin preparation Humulin R, but not by pure insulin. The results of previous experiments may have been confounded by the presence of the preservative m-cresol.


[Secretory activity of polymorphonuclear leukocytes].
The author's own data and those from the literature concerning the secretory activity of neutrophilic granulocytes as a process disconnected in time and associated with various periods of myeloid tissue cells differentiation are summarized. The previously unknown phenomenon of formation of promyelocytic granules devoid of peroxidase is characterized. A notion of "proexocytosis" and "nondegranulation exocytosis" as a peculiar form of secretory activity of neutrophilic granulocytes during phagocytosis and inflammation had been put forward. The ultrastructural mechanisms of formation of the non-phagocyte type of resistance and resorptive cell resistance are considered. A microtest for determination of the secretory activity of neutrophilic granulocytes (lysosome cation test) is proposed for diagnostic purposes. Preliminary data suggest that this test may prove useful in some diseases for the evaluation of their severity and stage, the efficacy of the therapy given, and for prognosis.


The role of microRNAs in cancer: diagnostic and prognostic biomarkers and targets of therapies.
miRNAs are noncoding RNAs that target specific mRNA with subsequent regulation of particular genes, implicated in various biological processes. In cancer, miRNAs could show a different expression from normal tissues. miRNAs have a role as oncogenes when they target tumor suppressor genes and similarly they are tumor suppressors when they target oncogenes. In this review, areas covered include the role of miRNAs in cancer diagnosis, prognosis and research for achievement of therapeutic strategies implicating miRNAs in oncology. As biogenesis of miRNAs is fundamental to understand their usefulness, this has also been discussed. Both miRNA expression profiles in cancer tissues and miRNA levels in peripheral blood were studied for improvement in the management of cancer patients. miRNAs have the potential for better understanding of tumor biology, but could also provide clinical advancement in management and therapy of various malignancies. The possibility of miRNA detection in peripheral blood would allow an eager expansion of their application in various clinical settings for cancer. The applicability of miRNA expression profiles still needs to be defined.


Extrinsic Cognitive Load Impairs Spoken Word Recognition in High- and Low-Predictability Sentences.
Listening effort (LE) induced by speech degradation reduces performance on concurrent cognitive tasks. However, a converse effect of extrinsic cognitive load on recognition of spoken words in sentences has not been shown. The aims of the present study were to (a) examine the impact of extrinsic cognitive load on spoken word recognition in a sentence recognition task and (b) determine whether cognitive load and/or LE needed to understand spectrally degraded speech would differentially affect word recognition in high- and low-predictability sentences. Downstream effects of speech degradation and sentence predictability on the cognitive load task were also examined. One hundred twenty young adults identified sentence-final spoken words in high- and low-predictability Speech Perception in Noise sentences. Cognitive load consisted of a preload of short (low-load) or long (high-load) sequences of digits, presented visually before each spoken sentence and reported either before or after identification of the sentence-final word. LE was varied by spectrally degrading sentences with four-, six-, or eight-channel noise vocoding. Level of spectral degradation and order of report (digits first or words first) were between-participants variables. Effects of cognitive load, sentence predictability, and speech degradation on accuracy of sentence-final word identification as well as recall of preload digit sequences were examined. In addition to anticipated main effects of sentence predictability and spectral degradation on word recognition, we found an effect of cognitive load, such that words were identified more accurately under low load than high load. However, load differentially affected word identification in high- and low-predictability sentences depending on the level of sentence degradation. Under severe spectral degradation (four-channel vocoding), the effect of cognitive load on word identification was present for high-predictability sentences but not for low-predictability sentences. Under mild spectral degradation (eight-channel vocoding), the effect of load was present for low-predictability sentences but not for high-predictability sentences. There were also reliable downstream effects of speech degradation and sentence predictability on recall of the preload digit sequences. Long digit sequences were more easily recalled following spoken sentences that were less spectrally degraded. When digits were reported after identification of sentence-final words, short digit sequences were recalled more accurately when the spoken sentences were predictable. Extrinsic cognitive load can impair recognition of spectrally degraded spoken words in a sentence recognition task. Cognitive load affected word identification in both high- and low-predictability sentences, suggesting that load may impact both context use and lower-level perceptual processes. Consistent with prior work, LE also had downstream effects on memory for visual digit sequences. Results support the proposal that extrinsic cognitive load and LE induced by signal degradation both draw on a central, limited pool of cognitive resources that is used to recognize spoken words in sentences under adverse listening conditions.


Therapeutic effects of vitamin D analogs on cardiac hypertrophy in spontaneously hypertensive rats.
Vitamin D inhibits renin expression and blocks the compensatory induction of renin associated with the use of renin-angiotensin system inhibitors. Here we test the therapeutic effects of two commonly used vitamin D analogs and their combination with losartan on the development of left ventricular hypertrophy. One-month-old male spontaneously hypertensive rats were treated with vehicle, losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol for 2 months. Blood pressure was markedly reduced by losartan, but not by paricalcitol or doxercalciferol alone. Echocardiograpy demonstrated a 65 to 80% reduction in left ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy and almost complete prevention of left ventricular hypertrophy with the combination therapies. Attenuation of cardiac and cardiomyocyte hypertrophy, and suppression of atrial and brain natriuretic peptides, were most marked in the combination therapy groups. These changes were well correlated with left ventricular gene and microRNA expression profiles in the different treatment groups. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. The same vitamin D analogs suppressed plasma renin activity in patients receiving chronic hemodialysis. These data demonstrate that vitamin D analogs have potent antihypertrophic activity in part via suppression of renin in the kidney and heart, and combination of these analogs with losartan achieves much better therapeutic effects because of the blockade of the compensatory renin increase.


Micro-costing the provision of emotional support and information in UK eye clinics.
Sight loss has wide ranging implications for an individual in terms of education, employment, mobility and mental health. Therefore there is a need for information and support to be provided in eye clinics at the point of diagnosis of sight threatening conditions, but these aspects of care are often missing from clinics. To meet these needs, some clinics employ an Eye Clinic Liaison Officer (ECLO) but the position has yet to be widely implemented. The aims of this study were:(1) To evaluate the forms of advice and emotional support in eye clinics provided by ECLOs.(2) To determine the cost of the ECLO service per patient. Micro-costing was carried out using interviews, a survey and administrative data. The survey was completed by 18 of the 49 accredited ECLOs in the UK (37%) and provided information on the activities performed by ECLOs, numbers of patients seen per day, training costs incurred and the salary of the ECLOs. ECLOs provided information about the services in eye clinics and the community, referral to social services, emotional support to patients and also other advice. The cost of an ECLO per patient per contact was £17.94 based on an average annual ECLO salary of £23,349.60 per year, reviewing on average 9.1 patients per day, in a 42 week year. This study provides the first costing of support services in hospital eye clinics, providing a range of estimates to suit the circumstances of different clinics. The information can be used by local decision makers to estimate the cost of implementing an ECLO service.


Vascular effects of phytoestrogens and alternative menopausal hormone therapy in cardiovascular disease.
Phytoestrogens are estrogenic compounds of plant origin classified into different groups including isoflavones, lignans, coumestans and stilbenes. Isoflavones such as genistein and daidzein are the most studied and most potent phytoestrogens, and are found mainly in soy based foods. The effects of phytoestrogens are partly mediated via estrogen receptors (ERs): ERα, ERβ and possibly GPER. The interaction of phytoestrogens with ERs is thought to induce both genomic and non-genomic effects in many tissues including the vasculature. Some phytoestrogens such as genistein have additional non-ER-mediated effects involving signaling pathways such as tyrosine kinase. Experimental studies have shown beneficial effects of phytoestrogens on endothelial cells, vascular smooth muscle, and extracellular matrix. Phytoestrogens may also affect other pathophysiologic vascular processes such as lipid profile, angiogenesis, inflammation, tissue damage by reactive oxygen species, and these effects could delay the progression of atherosclerosis. As recent clinical trials showed no vascular benefits or even increased risk of cardiovascular disease (CVD) and CV events with conventional menopausal hormone therapy (MHT), phytoestrogens are being considered as alternatives to pharmacologic MHT. Epidemiological studies in the Far East population suggest that dietary intake of phytoestrogens may contribute to the decreased incidence of postmenopausal CVD and thromboembolic events. Also, the WHO-CARDIAC study supported that consumption of high soybean diet is associated with lower mortalities from coronary artery disease. However, as with estrogen, there has been some discrepancy between the experimental studies demonstrating the vascular benefits of phytoestrogens and the data from clinical trials. This is likely because the phytoestrogens clinical trials have been limited in many aspects including the number of participants enrolled, the clinical end points investigated, and the lack of long-term follow-up. Further investigation of the cellular mechanisms underlying the vascular effects of phytoestrogens and careful evaluation of the epidemiological evidence and clinical trials of their potential vascular benefits would put forward the use of phytoestrogens as an alternative MHT for the relief of menopausal symptoms and amelioration of postmenopausal CVD.


Value and role of surgical margins in transoral laser microsurgery of the larynx, literature review and clinical considerations.
There is no agreement on the most appropriate post-operative pathway for the management of positive margins after laser cordectomy for early stage glottic tumours (T1-2N0M0). This literature review and meta-analysis aim to evaluate the post-operative treatment with the best oncological results among follow-up, radiotherapy (RT) and surgical second look. The parameters utilized were incidence of recurrence, overall (OS), disease-specific (DSS) and disease-free (DFS) survival and larynx preservation (LP). The articles were found through a string typed into PubMed from 2007 to 2022. The studies with detailed oncological results were selected according to inclusion criteria, and then the meta-analysis was carried out. Sixteen studies met the inclusion criteria for 2808 patients. The positive margin was found in 748 patients (26.6%), of which 416 were referred to follow-up, 89 to RT and 242 to a surgical second look. A false positive margin was found in 58/104 patients (56%). The recurrence rate in patients with positive margins was significantly higher (p = 0.003). In OS, DSS, DFS and LP, the odds ratio (OR) value was always greater than 1, assessing the role of the positive margin as a risk factor. Prospective studies will be necessary to establish the role of positive margin as a prognostic factor. A surgical second look in case of positive margin seems to be the best option for the patient in terms of lower risk of recurrence and better oncological results. Better collaboration between surgeon and pathologist would be desirable to limit the real and false positive margins.


Lianas suppress tree regeneration and diversity in treefall gaps.
Treefall gaps are hypothesized to maintain diversity by creating resource-rich, heterogeneous habitats necessary for species coexistence. This hypothesis, however, is not supported empirically for shade-tolerant trees, the dominant plant group in tropical forests. The failure of gaps to maintain shade-tolerant trees remains puzzling, and the hypothesis implicated to date is dispersal limitation. In central Panama, we tested an alternative 'biotic interference' hypothesis: that competition between growth forms (lianas vs. trees) constrains shade-tolerant tree recruitment, survival and diversity in gaps. We experimentally removed lianas from eight gaps and monitored them for 8 years, while also monitoring nine un-manipulated control gaps. Removing lianas increased tree growth, recruitment and richness by 55, 46 and 65%, respectively. Lianas were particularly harmful to shade-tolerant species, but not pioneers. Our findings demonstrate that competition between plant growth forms constrains diversity in a species-rich tropical forest. Because lianas are abundant in many tropical systems, our findings may apply broadly.


An automated hand hygiene compliance system is associated with improved monitoring of hand hygiene.
Consistent hand hygiene is key to reducing health care-associated infections (HAIs) and assessing compliance with hand hygiene protocols is vital for hospital infection control staff. A new automated hand hygiene compliance system (HHCS) was trialed as an alternative to human observers in an intensive care unit and an intensive care stepdown unit at a hospital facility in the northeastern United States. Using a retrospective cohort design, researchers investigated whether implementation of the HHCS resulted in improved hand hygiene compliance and a reduction in common HAI rates. Pearson χ2 tests were used to assess changes in compliance, and incidence rate ratios were used to test for significant differences in infection rates. During the study period, the HHCS collected many more hand hygiene events compared with human observers (632,404 vs 480) and ensured that the hospital met its compliance goals (95%+). Although decreases in multidrug-resistant organisms, central line-associated bloodstream infections, and catheter-associated urinary tract infection rates were observed, they represented nonsignificant differences. Human hand hygiene observers may not report accurate measures of compliance. The HHCS is a promising new tool for fine-grained assessment of hand hygiene compliance. Further study is needed to examine the association between the HHCS and HAI rate reduction.


Transplantation of virally transduced cells into the dermis of immunocompetent and immunodeficient (SCID) mice to determine gene expression profile and differential donor cell survival.
Cell therapy and bioengineering hold great promise as therapeutic approaches using cells and cell-derived factors to treat various pathologic or trauma-induced states. One possible application is the transplantation of cells into wounded tissue to help regulate tissue repair. Cells engineered for optimal wound healing may help to minimize scarring following surgery or to enhance the rate of healing of chronic wounds. The purpose of the current study was to determine the effect of a viral insert, the LacZ-bearing, first generation adenovirus AdRGD, on the survival of dermally transplanted murine skin allogenic fibroblasts. The LacZ insert facilitated quantitation of both cell survival and gene expression and was used here to measure viable cell number. In addition to bearing the LacZ marker, the AdRGD vector is capable of carrying therapeutic gene inserts, so this study tested the feasibility of gene therapy for wound healing. Murine skeletal muscle PP6 (i.e., Pre-Plate 6) myogenic stem cells served as an alternate donor cell type. Cells were labeled with the LacZ-bearing AdRGD adenovirus vector and injected (50,000 cells/site) into the dorsal skin of adult normal, immunocompetent mice as well as in immunodeficient SCID mice. Skin biopsies were taken on days 0, 1, 2, 3, and 7 post-transplant, and assayed for LacZ expression. Soon after transplant (day 1), cell numbers underwent a transient decrease, but by day 2 post-transplant they were present in appreciable numbers. Between days 2-7 post-transplant, both allogenic fibroblasts and PP6 myogenic stem cells maintained survivability in similar numbers. Further, survival of transplanted cell types was similar in both normal, immunocompetent as well as SCID mice during this time period. There were no signs of acute inflammation or rejection in any of the samples. This study shows that AdRGD-transduced cells are not immunogenic in the mouse skin model and the cells show similar survival for the first 7 days post-transplantation independent of the cell type or immunocompetence of the host.


HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats.
Reactive oxygen species and proinflammatory cytokines contribute to cardiovascular diseases. Inhibition of downstream transcription factors and gene modifiers of these components are key mediators of hypertensive response. Histone acetylases/deacetylases can modulate the gene expression of these hypertrophic and hypertensive components. Therefore, we hypothesized that long-term inhibition of histone deacetylase with valproic acid might attenuate hypertrophic and hypertensive responses by modulating reactive oxygen species and proinflammatory cytokines in SHR rats. Seven-week-old SHR and WKY rats were used in this study. Following baseline blood pressure measurement, rats were administered valproic acid in drinking water (0.71% wt/vol) or vehicle, with pressure measured weekly thereafter. Another set of rats were treated with hydralazine (25 mg/kg per day orally) to determine the pressure-independent effects of HDAC inhibition on hypertension. Following 20 weeks of treatment, heart function was measured using echocardiography, rats were euthanized, and heart tissue was collected for measurement of total reactive oxygen species, as well as proinflammatory cytokine, cardiac hypertrophic, and oxidative stress gene and protein expressions. Blood pressure, proinflammatory cytokines, hypertrophic markers, and reactive oxygen species were increased in SHR versus WKY rats. These changes were decreased in valproic acid-treated SHR rats, whereas hydralazine treatment only reduced blood pressure. These data indicate that long-term histone deacetylase inhibition, independent of the blood pressure response, reduces hypertrophic, proinflammatory, and hypertensive responses by decreasing reactive oxygen species and angiotensin II type1 receptor expression in the heart, demonstrating the importance of uncontrolled histone deacetylase activity in hypertension.


Oxidative DNA damage from nanoparticle exposure and its application to workers' health: a literature review.
The use of nanoparticles (NPs) in industry is increasing, bringing with it a number of adverse health effects on workers. Like other chemical carcinogens, NPs can cause cancer via oxidative DNA damage. Of all the molecules vulnerable to oxidative modification by NPs, DNA has received the greatest attention, and biomarkers of exposure and effect are nearing validation. This review concentrates on studies published between 2000 and 2012 that attempted to detect oxidative DNA damage in humans, laboratory animals, and cell lines. It is important to review these studies to improve the current understanding of the oxidative DNA damage caused by NP exposure in the workplace. In addition to examining studies on oxidative damage, this review briefly describes NPs, giving some examples of their adverse effects, and reviews occupational exposure assessments and approaches to minimizing exposure (e.g., personal protective equipment and engineering controls such as fume hoods). Current recommendations to minimize exposure are largely based on common sense, analogy to ultrafine material toxicity, and general health and safety recommendations.


Recent advances in JAK inhibitors for the treatment of metabolic syndrome.
With an epidemic spread, metabolic syndrome represents an increasingly emerging risk for the population globally, and is currently recognized as a pathological entity. It is represented by a cluster of different conditions including increased blood pressure, high blood sugar, excess body fat around the waist and abnormal cholesterol or triglyceride levels. These conditions lead directly to several disorders, including obesity, dyslipidemia, hyperglycaemia, insulin resistance, impaired glucose tolerance and hypertension causing an increase in cardiovascular risk and in particular atherosclerotic disease. Despite efforts to promote healthier lifestyles through exercise, reduced caloric intake, and improved dietary choices, the incidence and prevalence of metabolic syndrome continue to rise worldwide. Recent research has highlighted the involvement of signaling pathways in chronic inflammatory conditions like obesity and type 2 diabetes mellitus, revealing the significance of the JAK/STAT pathway in atherosclerotic events. This pathway serves as a rapid membrane-to-nucleus signaling module that regulates the expression of critical mediators. Consequently, JAK inhibitors (JAKi) have emerged as potential therapeutic options for metabolic diseases, offering a promising avenue for intervention. The aim of this review is to shed light on the emerging indications of JAK inhibitors in metabolic syndrome, emphasizing their potential role in attenuating associated inflammatory processes, improving insulin sensitivity, and addressing cross-talk with the insulin pathway, with the intention of contributing to efforts in the field of inflammation pharmacology.


Cysteamine bitartrate delayed-release capsules control leukocyte cystine levels and promote statural growth and kidney health in an open-label study of treatment-naïve patients <6 years of age with nephropathic cystinosis.
Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disease that is characterized by accumulation of cysteine and formation of crystals within cells of different organs and tissues causing systemic manifestations in childhood that include poor linear growth, ocular involvement, hypothyroidism, and progressive kidney disease. This study was a long-term, prospective open-label evaluation of twice-daily delayed release (DR) cysteamine capsules in cystinosis patients <6 years of age who were naïve to any form of cysteamine treatment. Fifteen treatment-naïve patients <6 years old (mean age 2.2 ± 1.0 years, 53% male, 73% White) were enrolled and treated with DR-cysteamine capsules for up to 18 months. Patients had clinically meaningful decreases in WBC cysteine concentration during treatment (3.2 ± 3.0 nmol ½ cystine/mg protein at Day 1 to 0.8 ± 0.8 nmol ½ cystine/mg protein at study exit), and anthropometric data improvements were consistently observed in height, weight and body surface area. Additionally, estimated glomerular filtration rate increased from 55.93 ± 22.43 ml/min/1.73 m2 at baseline to 63.79 ± 21.44 ml/min/1.73 m2 at study exit. Pharmacokinetic/Pharmacodynamic results support the use of the same starting, escalation, and maintenance doses according to body surface for children aged <6 years that are currently recommended in adults and older children. All patients experienced ≥1 adverse event(s) with vomiting (80%) and upper respiratory tract infection (53%) most frequently reported. Based on our study, patients <6 years of age with nephropathic cystinosis without prior treatment can safely and effectively initiate treatment with DR-cysteamine, a delayed-release form of cysteamine bitartrate that can be given every 12 h.


Predicting kala-azar disease manifestations in asymptomatic patients with latent Leishmania donovani infection by detection of antibody against recombinant K39 antigen.
Clinically visceral leishmaniasis is suspected in only a fraction of infected persons, as the majority of these may not have clinical manifestations and remain asymptomatic. There is scanty information on diagnosing latent infections and predicting disease in asymptomatic persons. We therefore carried out a study on asymptomatic contacts of patients with visceral leishmaniasis and post-kala-azar dermal leishmaniasis by using methods for detection of antibody to recombinant K39 (rK39) antigen. A total of 240 patients with leishmaniasis and 150 asymptomatic contacts were tested for anti-rK39 immunoglobulin G (IgG) and IgA antibodies. Fifty-five asymptomatic persons were found to be seropositive. These individuals were monitored every 3 months for 1 year. On follow-up, 43.9% of the asymptomatic seropositive contacts developed kala-azar within the first 3 months, and a cumulative total of 69% developed kala-azar within 1 year. The rest remained asymptomatic and self-healed the infection. The sensitivity and specificity of rK39 enzyme-linked immunosorbent assay (ELISA) and dipstick tests were 100%, while an in-house-developed latex agglutination test had 80% sensitivity. The antibody profile showed that the IgG anti-rK39 antibodies reached a titer of up to 10(-6) within 6 months of infection, started declining thereafter, and completely disappeared in 2 to 3 years in successfully treated cases. Significant titers of IgA antibodies were detectable a little earlier than those of IgG antibodies and were undetectable after 6 months. The study showed that mass screening of family members and contacts by using anti-rK39 ELISA could be a highly reliable tool for early diagnosis and to plan prophylactic treatment of latently infected asymptomatic carriers to eradicate kala-azar.


Analysis of causes of death among brought-in-dead cases in a third-level Hospital in Lusaka, Republic of Zambia, using the tariff method 2.0 for verbal autopsy: a cross-sectional study.
Over one third of deaths in Zambian health facilities involve someone who has already died before arrival (i.e., Brough in Dead), and in most BiD cases, the CoD have not been fully analyzed. Therefore, this study was designed to evaluate the function of automated VA based on the Tariff Method 2.0 to identify the CoD among the BiD cases and the usefulness by comparing the data on the death notification form. The target site was one third-level hospital in the Republic of Zambia's capital city. All BiD cases who reached the target health facility from January to August 2017 were included. The deceased's closest relatives were interviewed using a structured VA questionnaire and the data were analyzed using the SmartVA to determine the CoD at the individual and population level. The CoD were compared with description on the death notification forms by using t-test and Cohen's kappa coefficient. One thousand three hundred seventy-eight and 209 cases were included for persons aged 13 years and older (Adult) and those aged 1 month to 13 years old (Child), respectively. The top CoD for Adults were infectious diseases followed by non-communicable diseases and that for Child were infectious diseases, followed by accidents. The proportion of cases with a determined CoD was significantly higher when using the SmartVA (75% for Adult and 67% for Child) than the death notification form (61%). A proportion (42.7% for Adult and 46% for Child) of the CoD-determined cases matched in both sources, with a low concordance rate for Adult (kappa coefficient = 0.1385) and a good for Child(kappa coefficient = 0.635). The CoD of the BiD cases were successfully analyzed using the SmartVA for the first time in Zambia. While there many erroneous descriptions on the death notification form, the SmartVA could determine the CoD among more BiD cases. Since the information on the death notification form is reflected in the national vital statistics, more accurate and complete CoD data are required. In order to strengthen the death registration system with accurate CoD, it will be useful to embed the SmartVA in Zambia's health information system.


Psychiatric disorder symptoms, substance use, and sexual risk behavior among African-American out of school youth.
To examine the association between symptoms of psychiatric disorder (i.e. depression, anxiety, and substance use) and sexual risk behavior in a sample of African-American adolescents and young adults in an employment training program. Baseline data were used from a pilot study of an intervention to reduce depressive symptoms among youth disconnected from school and the workforce. Participants were recruited from two employment training programs in East and West Baltimore (N=617; age 16-23 years). Data were collected through audio computer-assisted self-interview (ACASI). Mental health indicators were measured using the Center for Epidemiological Studies Depression Scale and Beck Anxiety Inventory. Multivariate logistic regression was used to determine the odds of sexual risk behavior for each mental health condition and combinations of conditions. Lack of condom use at last sex was significantly associated with elevated anxiety symptoms. Number of sexual partners was associated with elevated depression symptoms and substance use. Early sexual debut was associated with substance use in the past 30 days. Also, there were differences in the likelihood of engaging in sexual risk behavior comparing groups with different combinations of mental health problems to those with no symptoms of disorder or substance use. The results demonstrate the need for HIV prevention programs that target out-of-school youth, as they are likely to engage in risky sexual behavior. Our findings highlight the need to develop behavioral interventions that address disorder symptoms, substance use, and risky sexual behavior among youth in employment training programs.


Anti-FGF2 approaches as a strategy to compensate resistance to anti-VEGF therapy: long-pentraxin 3 as a novel antiangiogenic FGF2-antagonist.
Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, plays a pivotal role in tumor growth, progression and metastasis. Over the last 30 years, numerous pro- and antiangiogenic molecules, their ligands, and intracellular signaling pathways have been identified, and significant efforts have been undertaken to develop antiangiogenic strategies for cancer therapy. Agents that selectively target vascular endothelial growth factor (VEGF) and its receptors have shown promising activity in clinical trials and have been approved for use in selected cancer indications. However, patients may ultimately develop resistance to these drugs. One proposed mechanism of tumor escape from anti-VEGF therapy is the up-regulation of fibroblast growth factor-2 (FGF2). FGF2 is a pleiotropic, angiogenesis inducer belonging to the family of the heparin-binding FGF growth factors. FGF2 is expressed by numerous tumor types and exerts its proangiogenic activity by interacting with tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins expressed on the endothelial cell surface. Experimental evidence suggests that targeting FGF2, in addition to VEGF, might provide synergistic effects in the treatment of angiogenesis-related diseases, including cancer. Several FGF2 inhibitors, with different chemical structure and mechanism of action, have been identified. Recent observations have shown the ability of the soluble pattern recognition receptor long-pentraxin-3 (PTX3) to bind FGF2, thus acting as a FGF2 antagonist. PTX3 binds FGF2 with high affinity and specificity. This interaction prevents the binding of FGF2 to its cognate tyrosine kinase receptors, leading to inhibition of the angiogenic activity of the growth factor. Further, preliminary observations support the hypothesis that PTX3 may inhibit FGF2-mediated tumor angiogenesis and growth. The identification of the FGF2-binding domain in the unique N-terminal extension of PTX3 has allowed the design of PTX3-derived synthetic peptides endowed with significant antiangiogenic activity in vitro and in vivo. These findings may provide the basis for the development of novel antiangiogenic FGF2 antagonists, with potential implications for cancer therapy.


Bronchial responsiveness to histamine and allergen in patients with asthma, rhinitis, cough.
A standardized bronchial histamine challenge was performed in 423 patients presenting with 1) asthma, 2) rhinitis, 3) asthma and rhinitis 4) rhinitis with cough or 5) chronic cough alone. Each group was further subdivided into allergic and non-allergic subjects. Twenty healthy subjects served as a control group. Mean histamine thresholds (dose causing 15% decrease in FEV1) of all patient groups differed significantly from controls. There were also significant differences between groups: bronchial responsiveness was higher in allergic than in non-allergic subjects and more marked in asthmatics than in patients with rhinitis or cough. In contrast no differences in bronchial responsiveness to housedust mite or grass pollen could be demonstrated between different groups of allergic patients with asthma and/or rhinitis. Moreover correlations between thresholds for histamine and for these allergens were not significant. This lack of correlation suggests that separate mechanisms are responsible for non-specific and specific bronchial hyperresponsiveness. The presence of asthma in an allergic individual is essentially determined by a high degree of non-specific bronchial hyperresponsiveness.


Factors influencing consumers' selection of a primary care physician.
There is a growing body of literature regarding patient choice of health care plans, patient satisfaction, and patient evaluation of health care quality, but there is little information concerning the factors that influence the initial selection of a primary care physician (PCP). This exploratory study identifies and conceptualizes the physician selection dimensions which include: physician reputation/manner, physician record, physician search, consumer self-awareness, physician location, physician qualifications, physician demographics, office atmospherics, house calls/insurance, and valuing patient opinion. The study also develops and tests a scale for PCP selection using factor analysis which is demonstrated to be valid, and determines significant differences of variables, which include education level, gender, and age, using a summated scale. The study is of use to physicians in their targeting and communication strategies, and to researchers seeking to refine the scale.


Exercise induced increases in muscle fiber number.
The effect of weight-lifting, which induced muscular enlargement, on fiber number was tested in the flexor carpi radialis muscle by operantly conditioning 6 cats to flex their right wrist against increasing resistance for an average of 101 weeks. The left was used as a control. At the end of training, the cats were performing "one-arm" lifts with an average of 57% of their body weight. There was an 11% greater muscle weight (P less than 0.01) and 9% (P less than 0.02) more fibers in the exercised muscles from the right limb than in the left. This study using a different method, supports our earlier observations that prolonged weight-lifting exercise significantly increases the total number of muscle fibers.


The future of the public's health: vision, values, and strategies.
The expansive vision of modern public health, "healthy people in healthy communities," is politically charged. This paper offers a justification for this broad vision and offers concrete proposals. By pointing to the poor condition of public health agencies; urging a transition to an intersectoral public health system; promoting the adoption of bold changes in U.S. physical, social, and economic conditions; and endorsing a values shift to a commitment to collective interest in healthier communities, we hope to take a dramatic step toward achieving these aspirations for "healthy people in healthy communities."


[Effect of negative pressure on the lower half of the body (the Chibis suit) and of local negative pressure on central circulation in the healthy human].
Catheters were chronically implanted into pulmonary and radial arteries of 8 healthy volunteers to examine the effect of lower body negative pressure (LBNP in the Chibis suit) and local negative pressure on the leg on central circulation, oxidative metabolism and acid-base equilibrium in the blood. In 1-hour head-down tests (at -20 degrees) the effect of two regimens of LBNP (at -30 and -60 mm Hg) and local negative pressure (at -50 and -100 mm Hg) was studied, each exposure averaging 15-20 min. Both LBNP and local negative pressure induced changes in central circulation that were similar qualitatively and dissimilar quantitatively. The use of regimen I of both exposures caused more marked changes than that of regimen II.


Impact of Mandibular Advancement Therapy on Endothelial Function in Severe Obstructive Sleep Apnea.
Endothelial dysfunction, a major predictor of late cardiovascular events, is linked to the severity of obstructive sleep apnea (OSA). To determine whether treatment with mandibular advancement device, the main alternative to continuous positive airway pressure, improves endothelial function in patients with severe OSA. In this trial, we randomized patients with severe OSA and no overt cardiovascular disease to receive 2 months of treatment with either effective mandibular advancement device or a sham device. The primary outcome, change in reactive hyperemia index, a validated measurement of endothelial function, was assessed on an intention-to-treat basis. An embedded microsensor objectively measured treatment compliance. A total of 150 patients (86% males; mean [SD] age, 54 [10] yr; median [interquartile range] apnea-hypopnea index, 41 [35-53]; mean [SD] Epworth sleepiness scale, 9.3 [4.2]) were randomized to effective mandibular advancement device (n = 75) or sham device (n = 75). On intention-to-treat analysis, effective mandibular advancement device therapy was not associated with improvement of endothelial function compared with the sham device. Office and ambulatory blood pressure outcomes did not differ between the two groups. Effective mandibular advancement device therapy was associated with significant improvements in apnea-hypopnea index (P < 0.001); microarousal index (P = 0.008); and symptoms of snoring, fatigue, and sleepiness (P < 0.001). Mean (SD) objective compliance was 6.6 (1.4) h/night with the effective mandibular advancement device versus 5.6 (2.3) h/night with the sham device (P = 0.006). In moderately sleepy patients with severe OSA, mandibular advancement therapy reduced OSA severity and related symptoms but had no effect on endothelial function and blood pressure despite high treatment compliance. Clinical trial registered with www.clinicaltrials.gov (NCT 01426607).


Open label smoking cessation with varenicline is associated with decreased glutamate levels and functional changes in anterior cingulate cortex: preliminary findings.
Varenicline, the most effective single agent for smoking cessation, is a partial agonist at α4β2 nicotinic acetylcholine receptors. Increasing evidence implicates glutamate in the pathophysiology of addiction and one of the benefits of treatment for smoking cessation is the ability to regain cognitive control. To evaluate the effects of 12-week varenicline administration on glutamate levels in the dorsal anterior cingulate cortex (dACC) and functional changes within the cognitive control network. We used single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) in the dACC and functional MRI (fMRI) during performance of a Stroop color-naming task before and after smoking cessation with varenicline in 11 healthy smokers (open label design). Using the dACC as a seed region, we evaluated functional connectivity changes using a psychophysiological interaction (PPI) analysis. We observed a significant decrease in dACC glutamate + glutamine (Glx)/Cr levels as well as significant blood oxygen level-dependent signal (BOLD) decreases in the rostral ACC/medial orbitofrontal cortex and precuneus/posterior cingulate cortex. These BOLD changes are suggestive of alterations in default mode network (DMN) function and are further supported by the results of the PPI analysis that revealed changes in connectivity between the dACC and regions of the DMN. Baseline measures of nicotine dependence and craving positively correlated with baseline Glx/Cr levels. These results suggest possible mechanisms of action for varenicline such as reduction in Glx levels in dACC and shifts in BOLD connectivity between large scale brain networks. They also suggest a role for ACC Glx in the modulation of behavior. Due to the preliminary nature of this study (lack of control group and small sample size), future studies are needed to replicate these findings.


Breastfeeding duration and residential isolation amid aboriginal children in Western Australia.
To examine factors that impact on breastfeeding duration among Western Australian Aboriginal children. We hypothesised that Aboriginal children living in remote locations in Western Australia were breastfed for longer than those living in metropolitan locations. A population-based cross-sectional survey was conducted from 2000 to 2002 in urban, rural and remote settings across Western Australia. Cross-tabulations and multivariate logistic regression analyses were performed, using survey weights to produce unbiased estimates for the population of Aboriginal children. Data on demographic, maternal and infant characteristics were collected from 3932 Aboriginal birth mothers about their children aged 0-17 years (representing 22,100 Aboriginal children in Western Australia). 71% of Aboriginal children were breastfed for three months or more. Accounting for other factors, there was a strong gradient for breastfeeding duration by remoteness, with Aboriginal children living in areas of moderate isolation being 3.2 times more likely to be breastfed for three months or more (p < 0.001) compared to children in metropolitan Perth. Those in areas of extreme isolation were 8.6 times more likely to be breastfed for three months or longer (p < 0.001). Greater residential isolation a protective factor linked to longer breastfeeding duration for Aboriginal children in our West Australian cohort.


Age-related changes in the preattentional detection of visual change.
The ability to detect changes in the environment which occur outside the focus of current awareness is essential if the individual is to be able to divert attention to biologically salient stimuli. The preattentional mechanism underlying the automatic detection of stimulus change in the auditory modality has been extensively studied by recording an event-related potential known as the mismatch negativity. Recently a homologous response from the visual cortex has also been described. Ageing has been shown to affect the efficiency of preattentional processing in the auditory modality, a factor which may contribute to cognitive changes in the elderly. It is unclear whether a similar effect occurs in the visual system. To investigate this issue the visual mismatch negativity was recorded from 12 older adults and 24 younger adults. Whereas the younger adults displayed a robust visual MMN, that evoked in the older adults was significantly reduced in amplitude. The results are indicative of age-related deficits in automatic visual processing.