Incidence and Progression of Chorioretinal Folds During Long-Duration Spaceflight.
The primary contributing factor for development of chorioretinal folds during spaceflight is unknown. Characterizing fold types that develop and tracking their progression may provide insight into the pathophysiology of spaceflight-associated neuro-ocular syndrome and elucidate the risk of fold progression for future exploration-class missions exceeding 12 months in duration. To determine the incidence and presentation of chorioretinal folds in long-duration International Space Station crew members and objectively quantify the progression of choroidal folds during spaceflight. In this retrospective cohort study, optical coherence tomography scans of the optic nerve head and macula of crew members completing long-duration spaceflight missions were obtained on Earth prior to spaceflight and during flight. A panel of experts examined the scans for the qualitative presence of chorioretinal folds. Peripapillary total retinal thickness was calculated to identify eyes with optic disc edema, and choroidal folds were quantified based on surface roughness within macular and peripapillary regions of interest. Spaceflight missions ranging 6 to 12 months. Incidence of peripapillary wrinkles, retinal folds, and choroidal folds; peripapillary total retinal thickness; and Bruch membrane surface roughness. A total of 36 crew members were analyzed (mean [SD] age, 46 [6] years; 7 [19%] female). Chorioretinal folds were observed in 12 of 72 eyes (17%; 6 crew members). In eyes with early signs of disc edema, 10 of 42 (24%) had choroidal folds, 4 of 42 (10%) had inner retinal folds, and 2 of 42 (5%) had peripapillary wrinkles. Choroidal folds were observed in all eyes with retinal folds and peripapillary wrinkles. Macular choroidal folds developed in 7 of 12 eyes (4 of 6 crew members) with folds and progressed with mission duration; these folds extended into the fovea in 6 eyes. Circumpapillary choroidal folds developed predominantly superior, nasal, and inferior to the optic nerve head and increased in prevalence and severity with mission duration. Choroidal folds were the most common fold type to develop during spaceflight; this differs from reports in idiopathic intracranial hypertension, suggesting differences in the mechanisms underlying fold formation. Quantitative measures demonstrate the development and progression of choroidal folds during weightlessness, and these metrics may help to assess the efficacy of spaceflight-associated neuro-ocular syndrome countermeasures.


Improving Anemia Assessment in Clinical and Public Health Settings.
We aim to provide a practical approach to assess anemia and its primary causes, both in clinical settings and in the context of public health programs. Anemia remains a global challenge; thus, to achieve goals for anemia reduction and assess progress, standardized approaches are required for the assessment of anemia and its causes. We first provide a brief review of how to assess anemia, based on hemoglobin concentrations and cutoffs that correspond to age, sex, and physiologic status. Next, we discuss how to assess the likely causes of anemia in different settings. The causes of anemia are classified as non-nutritional (for example, because of infection, inflammation, blood loss, or genetic disorders) or nutrition-specific (for example, because of deficiencies of iron, vitamin A, riboflavin, vitamin B12, or folate). There is an important overlap between these 2 categories, such as the increased likelihood of iron deficiency in the context of inflammation. Given the multifaceted nature of anemia etiology, we introduce a framework for anemia assessment based on the "ecology of anemia," which recognizes its many overlapping causes. This conceptual framework is meant to inform what data on anemia causes may need to be collected in population surveys. The framework has a supporting table with information on the diagnostic tests, biomarkers and proposed cutoffs, characteristics, and feasibility of collecting the myriad information that can help elucidate the anemia etiology. We also provide examples of how this framework can be applied to interpret the anemia risk factor data from population-based surveys that can inform decisions about context-specific interventions. Finally, we present research gaps and priorities related to anemia assessment.


In situ survey of life cycle phases of the coccolithophore Emiliania huxleyi (Haptophyta).
The cosmopolitan coccolithophore Emiliania huxleyi is characterized by a strongly differentiated haplodiplontic life cycle consisting of a diploid phase, generally bearing coccoliths (calcified) but that can be also non-calcified, and a non-calcified biflagellated haploid phase. Given most studies have focused on the bloom-producing calcified phase, there is little-to-no information about non-calcified cells in nature. Using field mesocoms as experimental platforms, we quantitatively surveyed calcified and non-calcified cells using the combined calcareous detection fluorescent in situ hybridization (COD-FISH) method and qualitatively screened for haploid specific transcripts using reverse transcription-PCR during E. huxleyi bloom successions. Diploid, calcified cells formed dense blooms that were followed by the massive proliferation of E. huxleyi viruses (EhVs), which caused bloom demise. Non-calcified cells were also detected throughout the experiment, accounting for a minor fraction of the population but becoming progressively more abundant during mid-late bloom periods concomitant with EhV burst. Non-calcified cell growth also paralleled a distinct window of haploid-specific transcripts and the appearance of autotrophic flagellates morphologically similar to haploid cells, both of which are suggestive of meiosis and sexual life cycling during natural blooms of this prominent marine phytoplankton species.


Identification of rare cell populations in autofluorescence lifetime image data.
Drug-resistant cells and anti-inflammatory immune cells within tumor masses contribute to tumor aggression, invasion, and worse patient outcomes. These cells can be a small proportion (<10%) of the total cell population of the tumor. Due to their small quantity, the identification of rare cells is challenging with traditional assays. Single cell analysis of autofluorescence images provides a live-cell assay to quantify cellular heterogeneity. Fluorescence intensities and lifetimes of the metabolic coenzymes reduced nicotinamide adenine dinucleotide and oxidized flavin adenine dinucleotide allow quantification of cellular metabolism and provide features for classification of cells with different metabolic phenotypes. In this study, Gaussian distribution modeling and machine learning classification algorithms are used for the identification of rare cells within simulated autofluorescence lifetime image data of a large tumor comprised of tumor cells and T cells. A Random Forest machine learning algorithm achieved an overall accuracy of 95% for the identification of cell type from the simulated optical metabolic imaging data of a heterogeneous tumor of 20,000 cells consisting of 70% drug responsive breast cancer cells, 5% drug resistant breast cancer cells, 20% quiescent T cells and 5% activated T cells. High resolution imaging methods combined with single-cell quantitative analyses allows identification and quantification of rare populations of cells within heterogeneous cultures.


Patients' experiences of screening for type 2 diabetes: prospective qualitative study embedded in the ADDITION (Cambridge) randomised controlled trial.
To provide insight into factors that contribute to the anxiety reported in a quantitative study of the psychological effect of screening for type 2 diabetes. To explore expectations of and reactions to the screening experience of patients with positive, negative, and intermediate results. Prospective qualitative interview study of patients attending a screening programme for type 2 diabetes. Seven general practices in the ADDITION (Cambridge) trial in the east of England. 23 participants (aged 50-69) attending different stages in the screening process. Participants' perceptions changed as they progressed through the screening programme; the stepwise process seemed to help them adjust psychologically. The first screening test was typically considered unimportant and was attended with no thought about its implications. By the final diagnostic test, type 2 diabetes was considered a strong possibility, albeit a "mild" form. After diagnosis, people with screen detected type 2 diabetes tended to downplay its importance and talked confidently about their plans to control it. Participants with intermediate results seemed uncertain about their diagnosis, and those who screened negative were largely unaware of their remaining high risk. This study helps in understanding the limited psychological impact of screening for type 2 diabetes quantified previously, in particular by the quantitative substudy of ADDITION (Cambridge). The findings have implications for implementing such a screening programme in terms of timing and content.


A comparison of the effectiveness of problem solving training and of cognitive-emotional rehabilitation on neurocognition, social cognition and social functioning in people with schizophrenia.
Social cognition and Problem Solving (PS) impairments are common characteristics in patients with schizophrenia. Experimental neuropsychological findings support the hypothesis that schizophrenia is characterized by a broad range of heterogeneous cognitive impairments. Since that time Problem Solving Training has been employed as a core strategy in a wide variety of therapeutic settings. Renewed interest in cognitive functioning, including social Problem Solving skills and social cognition in schizophrenia, has led us to reconsider the potential value of metacognitive strategy as a rehabilitation strategy. The present study reports the results obtained by 24 persons with schizophrenia who were randomly assigned to one of two training session groups: Cognitive-Emotional Rehabilitation (REC) vs Problem Solving Training (PST). Both treatments were administered to small groups composed of subjects suffering from schizophrenic disorders over a 12 months period: primary measures of clinical, social outcomes and secondary measures of cognitive and Problem Solving functions were conducted at 0, and 12 months. Results showed that both training methods were found to be effective in psychopathological measures and in social functioning. On cognitive function improvements were specific to the rehabilitative approach. PST are mainly improved capacities for planning and memory, while the REC improved measures such as social cognition Theory of mind and emotion recognition. The results confirmed that it is no necessary to divide the rehabilitation training in treatments directed to specific domains. The conceptualization and applicability of PST and REC its implications for persons with schizophrenia, and future studies in this research area have also been discussed.


Incidence of Acute Kidney Injury among Patients Treated with Piperacillin-Tazobactam or Meropenem in Combination with Vancomycin.
Acute kidney injury (AKI) increases during empirical antimicrobial therapy with the combination of piperacillin-tazobactam (TZP) and vancomycin (VAN) compared to the number of incidences with monotherapy or the combination of cefepime and VAN. Limited data regarding the impact of meropenem (MEM) combined with VAN exist. This study examined the AKI incidence among patients treated with MEM plus VAN (MEM+VAN) or TZP+VAN. Data were collected from the University of Kentucky Center for Clinical and Translational Science Enterprise Data Trust from September 2007 through October 2015. Adults without previous renal disease who received MEM+VAN or TZP+VAN for at least 2 days were included. AKI was assessed using risk, injury, failure, loss, and end-stage (RIFLE) criteria. Inverse probability of treatment weighting was utilized to control for differences between groups. In total, 10,236 patients met inclusion criteria, with 9,898 receiving TZP+VAN and 338 receiving MEM+VAN. AKI occurred in 15.4% of MEM+VAN patients and in 27.4% of TZP+VAN patients (P < 0.001). TZP+VAN was associated with increased AKI compared to the level with MEM+VAN (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.82 to 3.52), after controlling for confounders. Use of MEM+VAN should be considered an appropriate alternative therapy to TZP+VAN if nephrotoxicity is a major concern. The results of this study demonstrate that judicial use of TZP+VAN for empirical coverage of infection is needed.


Nitration of the pollen allergen bet v 1.0101 enhances the presentation of bet v 1-derived peptides by HLA-DR on human dendritic cells.
Nitration of pollen derived allergens can occur by NO(2) and ozone in polluted air and it has already been shown that nitrated major birch (Betula verrucosa) pollen allergen Bet v 1.0101 (Bet v 1) exhibits an increased potency to trigger an immune response. However, the mechanisms by which nitration might contribute to the induction of allergy are still unknown. In this study, we assessed the effect of chemically induced nitration of Bet v 1 on the generation of HLA-DR associated peptides. Human dendritic cells were loaded with unmodified Bet v 1 or nitrated Bet v 1, and the naturally processed HLA-DR associated peptides were subsequently identified by liquid chromatography-mass spectrometry. Nitration of Bet v 1 resulted in enhanced presentation of allergen-derived HLA-DR-associated peptides. Both the copy number of Bet v 1 derived peptides as well as the number of nested clusters was increased. Our study shows that nitration of Bet v 1 alters antigen processing and presentation via HLA-DR, by enhancing both the quality and the quantity of the Bet v 1-specific peptide repertoire. These findings indicate that air pollution can contribute to allergic diseases and might also shed light on the analogous events concerning the nitration of self-proteins.


Virtual Planning, Control, and Machining for a Modular-Based Automated Factory Operation in an Augmented Reality Environment.
This study presents a modular-based implementation of augmented reality to provide an immersive experience in learning or teaching the planning phase, control system, and machining parameters of a fully automated work cell. The architecture of the system consists of three code modules that can operate independently or combined to create a complete system that is able to guide engineers from the layout planning phase to the prototyping of the final product. The layout planning module determines the best possible arrangement in a layout for the placement of various machines, in this case a conveyor belt for transportation, a robot arm for pick-and-place operations, and a computer numerical control milling machine to generate the final prototype. The robotic arm module simulates the pick-and-place operation offline from the conveyor belt to a computer numerical control (CNC) machine utilising collision detection and inverse kinematics. Finally, the CNC module performs virtual machining based on the Uniform Space Decomposition method and axis aligned bounding box collision detection. The conducted case study revealed that given the situation, a semi-circle shaped arrangement is desirable, whereas the pick-and-place system and the final generated G-code produced the highest deviation of 3.83 mm and 5.8 mm respectively.


Enhanced Care Units: Guidance on development and implementation within Acute Medicine.
The Society for Acute Medicine (SAM) and Intensive Care Society (ICS) have produced joint guidance on the standards of care and infrastructure required to deliver enhanced care within Acute Medicine. The cohort of patients this relates to are in the most part already being looked after on the AMU, but co-location and providing enhanced monitoring and nursing input will ensure safe, high-quality care can be delivered to them. We strongly support the development of enhanced care units, whilst clearly acknowledging that they are not a replacement for critical care where that is indicated. Enhanced care and critical care complement each other and will help foster the close working between the two specialties that modern acute care requires. This guidance draws on expertise and existing relevant guidance from the two societies, alongside that from the Faculty of Intensive Care Medicine (FICM), British Thoracic Society (BTS), National Institute for Health and Care Excellence (NICE) and NHS England / Improvement (NHSE/I). We recognise this is an area with limited evidence and so will aim to review it regularly as the knowledge and experience in this area increases.


Assembly and stoichiometry of the AMPA receptor and transmembrane AMPA receptor regulatory protein complex.
Glutamate is a major excitatory neurotransmitter in the vertebrate brain. AMPA-type glutamate receptors mediate fast excitatory transmission. AMPA receptors assemble with transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits and function as native ion channels. However, the assembly and stoichiometry of AMPA receptor and TARP complexes remain unclear. Here, we developed a novel strategy to determine the assembly and stoichiometry of this protein complex and found that functional AMPA receptors indeed assembled as a tetramer in a dimer-of-dimers structure. Furthermore, we found that the AMPA receptor auxiliary subunit, TARP, had a variable stoichiometry (1-4 TARP units) on AMPA receptors and that 1 TARP unit was sufficient to modulate AMPA receptor activity. In neurons, TARP had fixed and minimum stoichiometry on AMPA receptors. This fundamental composition of the AMPA receptor/TARP complex is important for the elucidation of the molecular machinery that underlies synaptic transmission.


From "one medicine" to "one health" and systemic approaches to health and well-being.
Faced with complex patterns of global change, the inextricable interconnection of humans, pet animals, livestock and wildlife and their social and ecological environment is evident and requires integrated approaches to human and animal health and their respective social and environmental contexts. The history of integrative thinking of human and animal health is briefly reviewed from early historical times, to the foundation of universities in Europe, up to the beginning of comparative medicine at the end of the 19th century. In the 20th century, Calvin Schwabe coined the concept of "one medicine". It recognises that there is no difference of paradigm between human and veterinary medicine and both disciplines can contribute to the development of each other. Considering a broader approach to health and well-being of societies, the original concept of "one medicine" was extended to "one health" through practical implementations and careful validations in different settings. Given the global health thinking in recent decades, ecosystem approaches to health have emerged. Based on complex ecological thinking that goes beyond humans and animals, these approaches consider inextricable linkages between ecosystems and health, known as "ecosystem health". Despite these integrative conceptual and methodological developments, large portions of human and animal health thinking and actions still remain in separate disciplinary silos. Evidence for added value of a coherent application of "one health" compared to separated sectorial thinking is, however, now growing. Integrative thinking is increasingly being considered in academic curricula, clinical practice, ministries of health and livestock/agriculture and international organizations. Challenges remain, focusing around key questions such as how does "one health" evolve and what are the elements of a modern theory of health? The close interdependence of humans and animals in their social and ecological context relates to the concept of "human-environmental systems", also called "social-ecological systems". The theory and practice of understanding and managing human activities in the context of social-ecological systems has been well-developed by members of The Resilience Alliance and was used extensively in the Millennium Ecosystem Assessment, including its work on human well-being outcomes. This in turn entails systems theory applied to human and animal health. Examples of successful systems approaches to public health show unexpected results. Analogous to "systems biology" which focuses mostly on the interplay of proteins and molecules at a sub-cellular level, a systemic approach to health in social-ecological systems (HSES) is an inter- and trans-disciplinary study of complex interactions in all health-related fields. HSES moves beyond "one health" and "eco-health", expecting to identify emerging properties and determinants of health that may arise from a systemic view ranging across scales from molecules to the ecological and socio-cultural context, as well from the comparison with different disease endemicities and health systems structures.


[Interferon-inducing and antiviral effects of inosiplex in combination with high-molecular interferon inducers].
It has been shown that the immunostimulant inosiplex (IP) is capable of inducing interferon production in mice and of stimulating interferon induction by high-molecular inducers. The combined use of IP and poly (G)-poly (C) or dsRNA (RFf2) leads to a longer interferon circulation in the blood. All the combination schemes ensuring the effect of interferon production prolongation were tested for anti-viral activity. The prophylactic administration of the drugs permitted the attainment in mice of the increased resistance to experimental influenza.


BMP Signaling Pathway in Dentin Development and Diseases.
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described.


How physicians allocate causation: a scenario study with factorial design.
Causation is a complex concept but important in suspected work-related disease. Physicians routinely make initial assessments of causation as part of their work, but the factors contributing to these assessments are not well understood. To determine which factors influence a family physician's assessment of causation when seeing patients with suspected work-related injury or illness. Four groups of family physicians with differing levels of prior reporting (zero, low, medium, high) to the Workers Compensation Board received a questionnaire including four randomly allocated case scenarios. For each scenario there were four versions with either strong or weak causal features suggesting work or non-work factors were important causes or contributors. Responses to questions were made on a series of visual analogue scales. The nature of the condition and scenario type (i.e. strength of the causal information about workplace and non-workplace factors) were associated with the physicians' opinion on work-relatedness. Understanding the nature of the patient's work, the timing of symptoms and the patients' opinion about work-relatedness were viewed by the physicians as important. A decision that a condition was not work related was influenced primarily by the strength of potential causes outside work. Prior reporting history of the physician was not associated with opinions on work-relatedness, nor the factors considered in reaching this decision. The characteristics of the case scenario were more important in determining a physician's opinion about work-relatedness than the characteristics of the physician.


'Omics Approaches to Explore the Breast Cancer Landscape.
Breast cancer incidence is increasing worldwide with more than 600,000 deaths reported in 2018 alone. In current practice treatment options for breast cancer patients consists of surgery, chemotherapy, radiotherapy or targeting of classical markers of breast cancer subtype: estrogen receptor (ER) and HER2. However, these treatments fail to prevent recurrence and metastasis. Improved understanding of breast cancer and metastasis biology will help uncover novel biomarkers and therapeutic opportunities to improve patient stratification and treatment. We will first provide an overview of current methods and models used to study breast cancer biology, focusing on 2D and 3D cell culture, including organoids, and on in vivo models such as the MMTV mouse model and patient-derived xenografts (PDX). Next, genomic, transcriptomic, and proteomic approaches and their integration will be considered in the context of breast cancer susceptibility, breast cancer drivers, and therapeutic response and resistance to treatment. Finally, we will discuss how 'Omics datasets in combination with traditional breast cancer models are useful for generating insights into breast cancer biology, for suggesting individual treatments in precision oncology, and for creating data repositories to undergo further meta-analysis. System biology has the potential to catalyze the next great leap forward in treatment options for breast cancer patients.


Spotlight on denosumab in postmenopausal osteoporosis.
Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.


State Level Firearm Concealed-Carry Legislation and Rates of Homicide and Other Violent Crime.
Over the last 30 years, public opinion and state level legislation regarding the concealed-carry of firearms have shifted dramatically. Previous studies of potential effects have yielded mixed results, making policy recommendations difficult. We investigated whether liberalization of state level concealed-carry legislation was associated with a change in the rates of homicide or other violent crime. Data on violent crime and homicide rates were collected from the US Department of Justice Uniform Crime Reporting Program (UCR) and the Centers for Disease Control and Prevention (CDC) over 30 years, from 1986 to 2015. State level concealed-carry legislation was evaluated each study year on a scale including "no carry," "may issue," "shall issue," and "unrestricted carry." Data were analyzed using general multiple linear regression models with the log event rate as the dependent variable, and an autoregressive correlation structure was assumed with generalized estimating equation (GEE) estimates for standard errors. During the study period, all states moved to adopt some form of concealed-carry legislation, with a trend toward less restrictive legislation. After adjusting for state and year, there was no significant association between shifts from restrictive to nonrestrictive carry legislation on violent crime and public health indicators. Adjusting further for poverty and unemployment did not significantly influence the results. This study demonstrated no statistically significant association between the liberalization of state level firearm carry legislation over the last 30 years and the rates of homicides or other violent crime. Policy efforts aimed at injury prevention and the reduction of firearm-related violence should likely investigate other targets for potential intervention.


Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.
Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.


Breastfeeding behavior among adolescents: initiation, duration, and exclusivity.
Despite a substantial amount of evidence on breastfeeding among non-adolescent mothers, research and strategies uniquely designed to target adolescent mothers are critical because their rates of breastfeeding are disproportionately low and their transition to parenthood is often unlike that of older mothers. Literature to date, however, offers limited evidence for designing effective interventions. Therefore, we aimed to fill this gap in the literature by examining breastfeeding behaviors among a cohort of female adolescents as they transition to parenthood. Data were derived from a longitudinal cohort of pregnant adolescent females (ages 14-21 years) and their male partners, observed from pregnancy through 6 months postpartum. Means and frequencies were used to describe breastfeeding experiences, breastfeeding behaviors, and sociodemographic characteristics. We used multivariate logistic regression and Cox proportional hazards models to identify factors independently associated with breastfeeding initiation, exclusive breastfeeding, and breastfeeding duration. Approximately 71% initiated breastfeeding. Intending to breastfeed, having had complications in labor and delivery, and lower social support were associated with greater odds of breastfeeding initiation. Of the adolescent mothers who initiated breastfeeding, 84% had stopped by 6 months postpartum; among those, average breastfeeding duration was 5 weeks. Participants who exclusively breastfed had longer breastfeeding duration, and participants who had experienced intimate partner violence had shorter breastfeeding duration. Obese women and women who had more difficulty breastfeeding had lower odds of exclusive breastfeeding. Enhanced clinical support and the promotion of exclusive breastfeeding should be considered when designing interventions to improve breastfeeding rates among adolescent mothers.


Correlation of cocaine hydrochloride samples seized in Brazil based on determination of residual solvents: an innovative chemometric method for determination of linkage thresholds.
Cocaine sample correlation provides important information in the identification of traffic networks. However, available methods for estimating if samples are linked or not require the use of previous police investigation and forensic expert knowledge regarding the number of classes and provide thresholds that are both static and data set specific. In this paper, a novel unsupervised linkage threshold method (ULT) based on chemometric analysis is described and applied to the analysis of headspace gas chromatography mass spectrometry (HS-GC/MS) data of more than 250 real cocaine hydrochloride samples seized by Brazilian Federal Police. The method is capable of establishing linkage thresholds that do not require any prior information about the number of classes or distribution of the samples and can be dynamically updated as the data set changes. It is envisaged that the ULT method may also be applied to other forensic expertise areas where limited population knowledge is available and data sets are continually modified with the inflow of new information.


[Retrospective analysis of health variables in a Reykjavík nursing home 1983-2002 (corrected)].
A municipal nursing home with 68 beds in Reykjavík, opened in mid-year 1982. To analyse changes in demographic, health and outcome variables over 20 years. Retrospective analyses of data from medical records of all diseased persons with cross-sectional comparison of five four-year intervals. Droplaugarstadir Nursing Home in Reykjavík. The nursing home is supervised by fully qualified nurses and provides maintenance rehabilitation. Medical services are delivered from a specialist geriatric hospital department. RESIDENTS: All residents who died 1983 to 2002 [corrected]. Demographic data, type of dwelling before admission, Nursing Home Pre-admission Assessment Score (NAPA), mobility- and cognitive score, drug usage and a list of medical diagnoses. All recorded health events during stay, falls and fractures, medical and specialist consultations. Advance directives, as recorded and end-of-life treatment, place of death, clinical diagnosis of cause of death and length of stay. The total number of medical records read numbered 385, including 279 females and 106 males. The mean age on admission was 85 (+/- 7) years. During the first 4 years the majority of residents came from their own private homes or residential settings but in the last four years, 60% were admitted directly from a hospital ward. The mortality rate was 17% per year in the first period and the majority died in a hospital. This ratio took a sharp turn as the mortality rate increased to 40%, and in the last period only 2 of 97 deaths took place in a hospital. Admission mobility- and cognitive scores showed increased disability with time. The most common diagnosis on admission was dementia (56%), ischemic heart disease (46%), fractures (35%) and strokes (27%). Parkinsonism and maturity onset diabetes had a low prevalence rate of 6%. A mean NHPA of 57 (+/- 17) points confirmed a high dependency selection. The mean number of drugs per patient was 5.3 (+/- 3), including 1.1 (+/- 1) for psychoactive drugs and sedatives. The most common health events during residents? stay were urinary and respiratory infections, heart failure, cardiac- and cerebral events and pulmonary disorders. Hip fractures occurred in 45 residents (12%) and other types of fractures in 47 during their stay in the nursing home. The number of medical visits and specialist referrals increased with time. Palliative care was the most common form of treatment at end of life. Pneumonia was most commonly recorded cause of death in medical notes. The yearly mortality rate was 29% and the mean length of stay was 3 (+/- 2,9) years for the whole period. Retrospective analyses have many inherent drawbacks and the information in medical records tend to be scanty. Analyses of disabilities, as described in the medical record, can only be descriptive and health events are likely to be underreported. Statistical methods have a less meaningful role for interpretation as only diseased persons were included and survivors excluded. However, the length of time, uniform medical care and turnover rate of residents generate useful information on the patterns of the nursing home service during a time of considerable change. This retrospective analysis indicates increasing frailty in nursing home patients admitted over a period of 20 years. With time the residents are more often admitted directly from a hospital rather than from an individual dwelling. Most deaths took place in the nursing home and were preceded with informal or formal palliative care directives, which was a significant change over time. The data indicates growing efficiency in the nursing home selection processes due to the NHPA and improvements in holistic geriatric care. This development is in keeping with the Icelandic health care policy for elderly people to stay longer in their own home with access to a nursing home placement when needed.


Ecogenomic perspectives on domains of unknown function: correlation-based exploration of marine metagenomes.
The proportion of conserved DNA sequences with no clear function is steadily growing in bioinformatics databases. Studies of sequence and structural homology have indicated that many uncharacterized protein domain sequences are variants of functionally described domains. If these variants promote an organism's ecological fitness, they are likely to be conserved in the genome of its progeny and the population at large. The genetic composition of microbial communities in their native ecosystems is accessible through metagenomics. We hypothesize the co-variation of protein domain sequences across metagenomes from similar ecosystems will provide insights into their potential roles and aid further investigation. We calculated the correlation of Pfam protein domain sequences across the Global Ocean Sampling metagenome collection, employing conservative detection and correlation thresholds to limit results to well-supported hits and associations. We then examined intercorrelations between domains of unknown function (DUFs) and domains involved in known metabolic pathways using network visualization and cluster-detection tools. We used a cautious "guilty-by-association" approach, referencing knowledge-level resources to identify and discuss associations that offer insight into DUF function. We observed numerous DUFs associated to photobiologically active domains and prevalent in the Cyanobacteria. Other clusters included DUFs associated with DNA maintenance and repair, inorganic nutrient metabolism, and sodium-translocating transport domains. We also observed a number of clusters reflecting known metabolic associations and cases that predicted functional reclassification of DUFs. Critically examining domain covariation across metagenomic datasets can grant new perspectives on the roles and associations of DUFs in an ecological setting. Targeted attempts at DUF characterization in the laboratory or in silico may draw from these insights and opportunities to discover new associations and corroborate existing ones will arise as more large-scale metagenomic datasets emerge.


The Role of Resting-State Network Functional Connectivity in Cognitive Aging.
Aging is associated with disruptions in the resting-state functional architecture of the brain. Previous studies have primarily focused on age-related declines in the default mode network (DMN) and its implications in Alzheimer's disease. However, due to mixed findings, it is unclear if changes in resting-state network functional connectivity are linked to cognitive decline in healthy older adults. In the present study, we evaluated the influence of intra-network coherence for four higher-order cognitive resting-state networks on a sensitive measure of cognitive aging (i.e., NIH Toolbox Fluid Cognition Battery) in 154 healthy older adults with a mean age of 71 and education ranging between 12 years and 21 years (mean = 16). Only coherence within the cingulo-opercular network (CON) was significantly related to Fluid Cognition Composite scores, explaining more variance in scores than age and education. Furthermore, we mapped CON connectivity onto fluid cognitive subdomains that typically decline in advanced age. Greater CON connectivity was associated with better performance on episodic memory, attention, and executive function tasks. Overall, the present study provides evidence to propose CON coherence as a potential novel neural marker for nonpathological cognitive aging.


[Analysis of ethical aspects on human experimentation included in the instructions for the authors in 139 Brazilian scientific journals].
The concern with ethical standards during research in human subjects has been improving in Brazil during the last decade. Analysis of the ethical recommendations in instructions to authors may contribute to understand Brazilian Scientific Journals policies. To evaluate the recommendations related to the ethics of investigation in human subjects in instructions to authors of Brazilian Scientific Journals. Instructions to authors of 139 Brazilian Scientific Journals in medicine, biomedicine, nursery, odontology and general sciences were analysed. In one hundred ten (79.1%) of the 139 journals no recommendations related to ethics were found; 17 (12.2%) required previous approval by the institutional committee; 3 (2.1%) the procedures should be in accordance with the Declaration of Helsinki; 1 (0.7%) recommends the application of the informed consent; 5 (3.5%) recommend the use of Uniform requirements for manuscripts submitted to biomedical journals and 3 (2.1%) follow no specified rules. Twenty nine journals ask for references in ethics standards: in 15 (51.7%) the information must be included in the text; in 2 (6.8%) the authors must send a letter informing how the ethics standards were followed; in 1 (3.4%) a copy of the approval by the institutional committee must be included; in 1 (3.4%) believed the authors followed the standards and in 10 (34.4%) no specific reference was made. These results indicated that the majority of Brazilian Scientific Journals have little concern related to ethical aspects of research in human subjects included in instructions to authors. Even journals that make references to the ethical aspects the recommendations are quite different.


Knee joint pain may be an indicator for a hip joint problem in children: a case report.
Knee joint pain is one of the most common complaints related to the skeletal system encountered by paediatricians. Knee joint pain generally occurs as the result of hypermobility and growing pains, though disorders manifesting as arthritis/arthralgia and orthopaedic problems should be considered in the differential diagnosis. A thorough and careful physical examination and laboratory and radiological findings are of importance for an accurate diagnosis. Although treatment should be based on the aetiology of the knee pain, non-steroid anti-inflammatory drugs can be used to alleviate the pain. A 7-year-old male patient presented with recurring pain in the left knee. Physical examination of the patient, laboratory tests, and radiological examination of the knee joint were normal; roentgenograms performed for a presumed hip joint problem revealed a focal cortical defect on the left femoral head and an increased effusion in the left hip joint space compared with the right counterpart. With this case report, we would like to highlight that paediatric health and diseases specialists (paediatricians) should consider hip joint pathologies when patients present with knee pain, particularly knee pain with an unidentified aetiology.


Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes.
The oxidized guanine lesion 7,8-dihydro-8-oxo-2'-deoxyguanosine (OG) is highly mutagenic, resulting in G:C to T:A transversion mutations in the absence of repair. The Escherichia coli adenine glycosylase MutY and its human homolog (hMYH) play an important role in the prevention of mutations associated with OG by removing misincorporated adenine residues from OG:A mismatches. Previously, biallelic mutations of hMYH have been identified in a British family (Family N) with symptoms characteristic of familial adenomatous polyposis (FAP), which is typically associated with mutations in the adenomatous polyposis coli (APC) gene. Afflicted members of this family were compound heterozygotes for two mutations in hMYH, Y165C and G382D. These positions are highly conserved in MutY across phylogeny. The current work reveals a reduced ability of the hMYH variants compared to wild-type (WT) hMYH to complement the activity of E.coli MutY in mutY((-)) E.coli. In vitro analysis of the corresponding mutations in E.coli MutY revealed a reduction in the adenine glycosylase activity of the enzymes. In addition, evaluation of substrate affinity using a substrate analog, 2'-deoxy-2'-fluoroadenosine (FA) revealed that both mutations severely diminish the ability to recognize FA, and discriminate between OG and G. Importantly, adenine removal with both the mutant and WT E.coli enzymes was observed to be less efficient from a mismatch in the sequence context observed to be predominantly mutated in tumors of Family N. Interestingly, the magnitude of the reduced activity of the E.coli mutant enzymes relative to the WT enzyme was magnified in the "hotspot" sequence context. If the corresponding mutations in hMYH cause similar sensitivity to sequence context, this effect may contribute to the specific targeting of the APC gene. The lack of complementation of the hMYH variants for MutY, and the reduced activity of the Y82C and G253D E.coli enzymes, provide additional circumstantial evidence that the somatic mutations in APC, and the occurrence of FAP in Family N, are due to a reduced ability of the Y165C and G382D hMYH enzymes to recognize and repair OG:A mismatches.


Impact of elevated CO2 background levels on the host-seeking behaviour of Aedes aegypti.
Mosquitoes rely on carbon dioxide (CO2) to detect and orient towards their blood hosts. However, the variable and rapid fluctuations of atmospheric CO2 concentrations may have an impact on the host-seeking behaviour of mosquitoes. In this study, we analysed the effect of transient elevated background levels of CO2 on the host-seeking behaviour and the physiological characteristics of the CO2-sensitive olfactory receptor neurones (ORNs) in female yellow fever mosquitoes, Aedes aegypti. We show that the take-off and source contact behaviour of A. aegypti is impeded at elevated background levels of CO2 as a result of masking of the stimulus signal. The mechanism underlying this masking during take-off behaviour is one of sensory constraint. We show that the net response of the CO2-ORNs regulates this CO2-related behaviour. Since these neurones themselves are not habituated or fatigued by the transient elevation of background CO2, we propose that habituation of second-order neurones in response to the elevated CO2-ORN activity could be one mechanism by which the net response is transduced by the olfactory system. The findings from this study may help to predict future shifts in mosquito-host interactions and consequently to predict vectorial capacity in the light of climate change.


Precise mapping of the brain alpha 2-adrenergic receptor gene within chromosome 4p16.
The gene encoding the brain alpha 2-adrenergic receptor (ADRA2C) is located on human chromosome 4. It has been circumstantially associated with a number of human disorders, including Parkinson disease, panic disorders, and Huntington disease (HD). Using somatic cell hybrids, we localized the gene to chromosome 4p16 distal to P8 (D4S62). To investigate this locus further, we isolated several cosmid clones covering the entire gene. The gene was found to be intronless. Two (GT)n repeats in close proximity to the ADRAC2 gene were analyzed and used to define its precise location. Linkage disequilibrium studies of one microsatellite in HD families showed strong nonrandom association to the HD mutation, indicating its tight linkage to the HD gene. The investigation of families carrying recombinant chromosomes, pulsed-field analysis, and genomic walking mapped the ADRA2C gene adjacent to D4S81, 500 kb proximal to the HD gene. The newly defined microsatellites at the ADRAC2 locus, its precise localization within 4p16, and the detailed PCR conditions facilitate the identification of any defect caused by this gene.


Cannabidiol (CBD) as a treatment of acute and chronic back pain: A case series and literature review.
Two patient case reports are presented describing the use of cannabidiol (CBD) for the symptomatic relief of a lumbar compression fracture and in the mitigation of thoracic discomfort and dysesthesia secondary to a surgically resected meningioma. CBD appears to have antisnociceptive and anti-inflammatory effects on opioid-naive patients with neuro-pathic and radicular pain. Of note, the patients in this case series used the same CBD cream: Baskin Essentials Body Wellness Cream (400 mg CBD per two oz.) Conclusion: Hemp-derived CBD in a transdermal cream provided significant symptom and pain relief for the patients described in this case series. Based on these results, we believe further investigation is warranted to see if CBD-containing products should have a more prominent role in the treatment of acute and chronic pain.


Trait anxiety impact on posterior activation asymmetries at rest and during evoked negative emotions: EEG investigation.
The main objective of the present investigation was to examine how high trait anxiety would influence cortical EEG asymmetries under non-emotional conditions and while experiencing negative emotions. The 62-channel EEG was recorded in control (n=21) and high anxiety (HA, n=18) non-patient individuals. Results showed that in HA subjects, the lowest level of arousal (eyes closed) was associated with stronger right-sided parieto-temporal theta-1 (4-6 Hz) and beta-1 (12-18 Hz) activity, whereas increased non-emotional arousal (eyes open, viewing neutral movie clip) was marked by persisting favored right hemisphere beta-1 activity. In turn, viewing aversive movie clip by the HA group led to significant lateralized decrease of the right parieto-temporal beta-1 power, which was initially higher in the emotionally neutral conditions. The EEG data suggests that asymmetrical parieto-temporal theta-1 and beta-1 EEG activity might be better interpreted in terms of Gray's BAS and BIS theory.


Connecting Health and Technology (CHAT): protocol of a randomized controlled trial to improve nutrition behaviours using mobile devices and tailored text messaging in young adults.
Increasing intakes of fruits and vegetables intake, in tandem with reducing consumption of energy-dense and nutrient poor foods and beverages are dietary priorities to prevent chronic disease. Although most adults do not eat enough fruit and vegetables, teenagers and young adults tend to have the lowest intakes. Young adults typically consume a diet which is inconsistent with the dietary recommendations. Yet little is known about the best approaches to improve dietary intakes and behaviours among this group. This randomised controlled trial aims to evaluate the effectiveness of using a mobile device to assess dietary intake, provide tailored dietary feedback and text messages to motivate changes in fruit, vegetable and junk food consumption among young adults. The CHAT project will involve the development of the mobile device food record (MDFR), and evaluation of dietary feedback and implementation of a 6-month intervention in young adults aged 18 to 30 years. The participants will be randomly assigned to one of three groups (1) Intervention Group 1: MDFR + Text Messages + Dietary Feedback; (2) Intervention Group 2: MDFR + Dietary Feedback; (3) Control Group 3: MDFR, no feedback. All groups will undertake a 3-day dietary record using the MDFR but only the Intervention Groups 1 and 2 will receive tailored dietary feedback at baseline and at 6-months which will consist of assessment of serves of fruits, vegetables and junk food in comparison to dietary recommendations. Tailored nutrition text messages will be sent to Intervention Group 1 over the 6 months. Data will be collected at baseline and again at the 6-month completion. This trial will test if applications running on mobile devices have potential to assess diet, provide tailored feedback and nutrition messages as an effective way of improving fruit and vegetable consumption and reducing energy-dense nutrient poor foods in young adults. The CHAT project will assess the impact of the intervention on behavioural intention to eat a more healthful diet. This innovative approach if successful may provide a means to deliver a low cost health promotion program that has the potential to reach large groups, particularly young adults. Australian and New Zealand Clinical Trials Registry ACTRN12612000250831.


Light Limitation within Southern New Zealand Kelp Forest Communities.
Light is the fundamental driver of primary productivity in the marine environment. Reduced light availability has the potential to alter the distribution, community composition, and productivity of key benthic primary producers, potentially reducing habitat and energy provision to coastal food webs. We compared the underwater light environment of macroalgal dominated shallow subtidal rocky reef habitats on a coastline modified by human activities with a coastline of forested catchments. Key metrics describing the availability of photosynthetically active radiation (PAR) were determined over 295 days and were related to macroalgal depth distribution, community composition, and standing biomass patterns, which were recorded seasonally. Light attenuation was more than twice as high in shallow subtidal zones along the modified coast. Macroalgal biomass was 2-5 times greater within forested sites, and even in shallow water (2m) a significant difference in biomass was observed. Long-term light dose provided the best explanation for differences in observed biomass between modified and forested coasts, with light availability over the study period differing by 60 and 90 mol photons m-2 at 2 and 10 metres, respectively. Higher biomass on the forested coast was driven by the presence of larger individuals rather than species diversity or density. This study suggests that commonly used metrics such as species diversity and density are not as sensitive as direct measures of biomass when detecting the effects of light limitation within macroalgal communities.


[Changes in renal and testicular veins in left-sided varicocele and choice of the surgical method in children and adolescents].
Selective phleborenotesticulography, ++tensiometry of the left iliac, right and left renal veins, vena cava inferior, duplex scanning of the left renal vein were performed in 356, 296 and 57 patients, respectively, of a total of 356 examinees aged 8-17 years with left-side varicocele. Among other tests were measurements of hormones in the blood from the left and right testes (n = 24), pO2, pCO2. Stenosis, aortomesenteric compression (AMC) of the left renal vein, left-side venous renotesticular hypertension (RTH) of the left renal vein were diagnosed in 12, 342 and 158 patients, respectively. Secondary genesis of left varicocele has been proved. The diagnosis of left-side phlebohypertensive nephropathy was made preoperatively. Estradiol content in the blood of the left testis was 1.7 times higher than from the right one. 4 groups of patients were formed: group 1 patients (n = 142) had stenosis, AMC, dilatation of the testicular vein (DTV) and RTH; group 2 patients (n = 18) had AMC, DTV, borderline high pressure; group 3 patients (n = 18) had AMC, RTH, multiple thin testicular veins; group 4 patients (n = 174) had moderate AMC without hypertension. 160 patients of group 1 and 2 have undergone two-direction venous testiculo-iliac anastomosis operation. 193 patients of groups 3 and 4 have undergone Ivanissevich's operation. After Ivanissevich's operation 2 patients with secondary varicocele of the third degree retained varicocele of the first degree. After establishment of anastomoses, neither varicocele recurrences nor anastomosis thrombosis were registered.


Pharmacologically distinct, pertussis toxin-resistant inward currents evoked by metabotropic glutamate receptor (mGluR) agonists in dorsolateral septal nucleus (DLSN) neurons.
We have reported previously that a selective metabotropic glutamate receptor (mGluR) agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), caused a slow membrane depolarization in rat dorsolateral septal nucleus (DLSN) neurons. Using single electrode voltage-clamp recording methods, we now investigate the pharmacological properties of the receptor that mediates ACPD-induced membrane currents in DLSN neurons recorded from pertussis toxin (PTX)-treated rats. Two pharmacologically distinct inward currents, that is, the ACPD current and Qm current, have been identified based on their agonist preference and sensitivity to various antagonists. The ACPD current is blocked by L-2-amino-4-phosphonobutyric acid (L-AP4), but is insensitive to L-aspartic acid-beta-hydroxamate (L-AA beta H), (+)-alpha-methyl-4-carboxyphenylglycine (+)-MCPG), or L-2-amino-3-phosphonopropionic acid (L-AP3). The Qm current is blocked by L-AA beta H and (+)-MCPG, but is insensitive to L-AP3 or L-AP4. These two inward currents distribute differentially within subpopulations of DLSN neurons. The ACPD current is the only current observed in most DLSN "burster" neurons, while the Qm current is observed more frequently in DLSN "nonburster" neurons. The pharmacological profiles of these currents suggest that the Qm current is likely mediated by mGluR1 or mGluR5, while the ACPD current is mediated by receptors that are pharmacologically distinct from any of the currently cloned mGluRs.


The Physical Activity-Related Barriers and Facilitators Perceived by Men Living in Rural Communities.
Men, especially those living in rural areas, experience chronic disease at higher rates than the general population. Physical activity is a well-established protective factor against many chronic diseases; however, only a small fraction of men are meeting national guidelines for physical activity. The purpose of this study was to examine the perceived physical activity-related barriers and facilitators experienced by men living in rural areas in Canada. Participants completed a paper-and-pencil or online survey and asked to select personally relevant physical activity-related barriers and facilitators from a list of 9 and 10 choices, respectively. A total of 149 men completed the survey (50.3% between the ages of 18 and 55 years; 43.0% older than 55 years). Participants were predominantly from rural areas and smaller communities. Overall, the response options "I'm too tired," "I don't have enough time," and "I think I get enough exercise as work" were the three most frequently cited barriers to regular physical activity. The response options "Personal motivation to be healthy," "I enjoy it," and "Support from family and/or friends" were the three most often cited facilitators to physical activity. Results are similar to those shown in other populations. Results can be used to inform the development of policies and programs that aim to increase the physical activity levels of men living in rural areas and small communities.


Playing the Fertility Game at Work: An Equilibrium Model of Peer Effects.
We study workplace peer effects in fertility decisions using a game theory model of strategic interactions among coworkers that allows for multiple equilibria. Using register-based data on fertile-aged women working in medium sized establishments in Denmark, we uncover negative average peer effects. Allowing for heterogeneous effects by worker type, we find that positive effects dominate across worker types defined by age or education. Negative effects dominate within age groups and among low-education types. Policy simulations show that these estimated effects make the distribution of where women work an important consideration, beyond simply if they work, in predicting population fertility.


Lymphatic muscle cells in rat mesenteric lymphatic vessels of various ages.
Recent studies on aging-associated changes in mesenteric lymph flow in situ demonstrated predominance of the severe negative chronotropic effect of aging on the contractility of aged mesenteric lymphatic vessels (MLV). At the same time, contraction amplitude of the aged vessels was only slightly diminished by aging and can be rapidly stimulated within 5-15 minutes. However, the detailed quantitative evaluation of potential aging-associated changes in muscle cells investiture in MLV has never been performed. In this study we, for the first time, performed detailed evaluation of muscle cells investiture in MLV in reference to the position of lymphatic valve in different zones of lymphangion within various age groups (3-mo, 9-mo and 24-mo Fischer-344 rats). Using visual and quantitative analyses of the images of MLV immunohistochemically labeled for actin, we confirmed that the zones located close upstream (pre-valve zones) and above lymphatic valves (valve zones) possess the lowest investiture of lymphatic muscle cells. Most of the high muscle cells investiture zones exist downstream to the lymphatic valve (post-valve zones). The muscle cells investiture of these zones is not affected by aging, while pre-valve and valve zones demonstrate significant aging-associated decrease in muscle cells investiture. The low muscle cells investiture zones in lymphatic vessels consist of predominantly longitudinally oriented muscle cells which are positioned in pre-valve and valve zones and connect adjacent lymphangions. These cells may provide important functional impact on the biomechanics of the lymphatic valve gating and electrical coupling between lymphangions, while their aging-associated changes may delimit adaptive reserves of aged lymphatic vessels.


Lack of association between the rs6920220 (G/A) polymorphism of the 6q23 region and biopsy-proven giant cell arteritis.
Recently, 2 independent studies have identified an association between several single-nucleotide polymorphisms (SNP) located in the 6q23 chromosomal region and rheumatoid arthritis (RA). Like RA, giant cell arteritis (GCA) is also a complex polygenic disease in which more than 1 genetic locus is likely to contribute to disease susceptibility and clinical expression. We analyzed the involvement of the rs6920220 (G/A) polymorphism from the 6q23/TNFAIP3 gene region in susceptibility to GCA. Two hundred twenty patients with biopsy-proven GCA and 490 matched controls were assessed. DNA from patients and controls was obtained from peripheral blood. Samples were geno-typed for the 6q23 region rs6920220 using a TaqMan allele discrimination assay and by polymerase chain reaction (PCR) amplification. After PCR, the genotype of each sample was attributed automatically by allelic-specific fluorescence using the ABI Prism 7900 sequence detection system. No significant differences in the genotype distribution between patients with GCA and controls for the rs6920220 (G/A) polymorphism were found. No significant differences were observed when patients with GCA were stratified according to the presence of specific clinical features of the disease such as polymyalgia rheumatica or severe ischemic manifestations or specific visual ischemic complications. Our results show no involvement of this 6q23/TNFAIP3 gene region SNP in the susceptibility to or clinical expression of GCA.


[Analysis of organic and inorganic components of Diesel engine exhaust absorbed on ore-mine aerosol particles].
The article proposes results of research into exhausts' major components absorption in accumulated and floating dusts in ore mines in which self-propelled diesel vehicles are predominantly used. It was established that ore-mine aerosol particles had a large specific surface and contained a high percentage of carbon-black (1,1-35.1%). Different results were received for both organic and non-organic substances' sorption indices. In the samples, in addition to 3,4-benzapyrene, 11 more polycyclic aromatic hydrocarbons were identified, with concentrations 10-15 times higher than those of 3,4-benzapyrene.


Regulation of antigen-presentation-I. IFN-gamma induces antigen-presenting properties on B cells.
B cells require activation to efficiently present Ag to T cells. In agreement with this earlier observation we show that live, mitomycin C-treated B cells, but not B cells fixed in paraformaldehyde, stimulated the growth of allogeneic T cells in the primary MLR. However, if B cells were cultured with anti-Ig antibodies and IFN-gamma before fixation they acquired excellent T cell stimulatory activity. Neither reagent alone conferred this novel co-stimulatory function on the B cell surface. The activity induced by both stimuli was not attributed to an increase expression of class II-MHC molecules or IL-1. IL-2 or IL-4, in combination with anti-Ig, also induced B cell stimulatory activity, but were less effective than IFN-gamma. TNF failed to stimulate B cells, but synergized with IFN-gamma in the induction of this activity. These studies therefore demonstrate an important role for lymphokines in modulating B cell Ag-presenting activity as well as the acquisition by B cells of a novel co-stimulatory surface activity.


Aging, disability, and frailty: implications for universal design.
Throughout the world all populations are seeing burgeoning numbers of "elders", defined as persons aged 65 year and older. In many countries, including Japan, the United States, Norway, Sweden and the United Kingdom, those aged over 65 are at or approaching 15% of the population. As their numbers have increased, so have their health care expenses, leading to extensive research on the health, well being, and life expectancy of these increasingly older elders. Today this group is further sub-divided: the young-old ages 65-74, the old-old ages 75-84, and the oldest-old ages 85+, for both health care and research purposes. However broad variation still characterizes even these groupings. Rates of frailty and disability increase with increasing age among these elders. For example, inabilities to complete at least one activity of daily living increased from about 5-7% at ages 65-69 years to about 28-36% at ages 85+ in 1987. Death rates continue to decline at all ages past 50 years and rates of disability seem to be doing the same. For the foreseeable future, we may expect increasing numbers of older, frail elders than in previous decades. Thus, people are not only living longer, they generally are healthier at advanced ages than were previous cohorts, thus "old age" disabilities of the 20th century will be put off to even older ages during the 21st century. As yet there is no clear way to assess senescent changes in humans, although activities of daily living, allostatic load, and frailty indices have all been suggested. One future need is greater development and use of universal and accessible design in all aspects of the built environment.


Autophagy Inhibition Increased Sensitivity of Pancreatic Cancer Cells to Carbon Ion Radiotherapy.
Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer. We performed carbon ion radiotherapy (CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy. To investigate the role of CIRT-induced autophagy, autophagy inhibitors were added to cells prior to CIRT. To evaluate tumor formation, we inoculated CIRT-treated murine pancreatic cancer cells on the flank of syngeneic mice and measured tumor weight. We immunohistochemically measured autophagy levels in surgical sections from patients with pancreatic cancer who received neoadjuvant chemotherapy (NAC) plus CIRT or NAC alone. CIRT reduced the survival fraction of pancreatic cancer cells and induced apoptotic and necrotic alterations, along with autophagy. Preincubation with an autophagy inhibitor accelerated cell death. Mice inoculated with control pancreatic cancer cells developed tumors, while those inoculated with CIRT/autophagy inhibitor-treated cells showed significant evasion. Surgical specimens of NAC-treated patients expressed autophagy comparable to control patients, while those in the NAC plus CIRT group expressed little autophagy and nuclear staining. CIRT effectively killed the pancreatic cancer cells by inhibiting their autophagy-inducing abilities.


Direct observation of the alkylation products of deoxyguanosine and DNA by fast atom bombardment mass spectrometry.
By the methods of fast atom bombardment (FAB) mass spectrometry, thin-layer chromatography and ultraviolet absorption spectroscopy adducts have been studied which are formed by an antitumour alkylating drug thiotepa both in a model system, containing only deoxyguanosine (dGuo), and in DNA. Analysis of the model reaction mixture (dGuo + thiotepa) by FAB mass spectrometry permitted observation of adducts dGuo thiotepa, 2dGuo thiotepa, and also the products of their further modification in solution, which occurs by hydrolysis of the glycosidic bond and also by opening of the imidazole ring. In the case of DNA FAB mass spectrometry made it possible to characterize adducts of thiotepa with guanosine (Gua) and adenosine (Ade) without their preliminary purification. The site of alkylation of Gua in both dGuo and DNA is N7, and that of Ade in DNA is N3. The application of the results to the study of the molecular mechanism of the antitumour action of thiotepa is discussed.


[Puerperal infection. Analysis of 618 cases].
From September 1993 to March 1995 a prospective, descriptive study was performed at Obstetrical Department of the General Hospital 2A the Mexican Institute of Social Security. An attempt to know the real puerperal infection incidence in our own hospital to be able to make hypothesis and take specific measures in puerperal infection control. Dairy account of interesting data of cases under inclusion criteria. Entering data in personal computer. Graphics and analysis were accomplished using Lotus 123, Statgraphics, EPI-6 of CDC and Freelance computational programs. Search of central tendency measures were performed, (media, median, mode, standard deviation). Odds ratio and relative risk were calculated, including hospitalization time and its temporary variation to data cross. X square and pi were including hospitalization time and its temporary variation to data cross. X square and pi were determined to statistic validates. The cumulated rate of general puerperal infection were 1.2%. By stratification, the cumulated rate of infection after cesarean section, vaginal delivery and miscarriage were 5.4%, 0.8% and 0.3%, respectively. There was predominance of infection after cesarean section, over infection after vaginal delivery and after miscarriage. (monthly media of 24.6, 7.3 and 0.47, respectively). The puerperal infection was present principally in primiparous and in patients with one previous cesarean section. The patients in which the termination of pregnancy was by cesarean section, (0.015 infection cumulated incidence), had an infection risk 5.76 and 18.66 times greater than the patients with vaginal delivery and miscarriage. (Relative risk of 6.76 and 19.66) The site of puerperal infection was implicated in combinations or isolated, under nine clinical situation. The five most frequent clinical situation, between these nine, in incidence order from major to minor were the following: Endometritis alone, Endometritis combined with wound abscess. Endometritis with urinary infection, complicated endometritis, (sub vesical abscess, parametritis, peritonitis, salpingitis), and wound abscess alone). The greater hospitalization time was present in cases of complicated endometritis followed by wound abscess alone or combined. Complicated endometritis, (incidence 0.0010), compel us to hysterectomy in 15 cases. No death was registered among the patients with puerperal infection studied.


The relationship between Jim Crow laws and social capital from 1997-2014: A 3-level multilevel hierarchical analysis across time, county and state.
Jim Crow laws in the United States promoted racial prejudice, which may have reduced social capital. Our study tests the relationship between Jim Crow laws and social capital. We conducted 3-level multilevel hierarchical modeling to study differences in the stock of social capital for 1997, 2005, 2009 in Jim Crow states compared to states without Jim Crow laws. We examined the moderation effects of county level median income, percent Black and percent with high school education and Jim Crow laws on social capital. Jim Crow laws significantly reduced stock of social capital across 1997, 2005, 2009. The model was robust to the inclusion of random county, states, time and fixed county and state level covariates for median income, percent Black and percent with high school education. The largest percent of between state variations explained for fixed variables was from the addition of Jim Crow laws with 2.86%. These results demonstrate that although Jim Crow laws were abolished in 1965, the effects of racial segregation appear to persist through lower social connectiveness, community and trust. A positive moderation effect was seen for median income and percent Black with Jim Crow laws on social capital. Our study supports a negative association between Jim Crow laws and reduction in the stock of social capital. This may be attributed to the fracturing of trust, reciprocity and collective action produced by legal racial segregation. Findings from this study offer insight on the potential impacts of historical policies on the social structure of a community. Future research is necessary to further identify the mechanistic pathways and develop interventions to improve social capital.


THE INFLUENCE OF AMMONIUM SALTS ON CELL REACTION.
1. It may be shown by means of cells of the flowers of a hybrid Rhododendron which contain a natural indicator, by means of starfish eggs stained with neutral red, and by means of an "artificial cell" in which living frog's skin is employed that increased intracellular alkalinity may be brought about by solutions of a decidedly acid reaction which contain ammonium salts. 2. These results are analogous to those previously obtained with the CO(2)-bicarbonate system, and depend on the facts: (a) that NH(4)OH is sufficiently weak as a base to permit a certain degree of hydrolysis of its salts; and (b) that living cells are freely permeable to NH(4)OH (or NH(3)?) and not to mineral and many organic acids, and presumably not at least to the same extent to ammonium salts as such.


Urease-positive thermophilic Campylobacter (Campylobacter laridis variant) isolated from an appendix and from human feces.
Urease-positive thermophilic campylobacters were isolated for the first time from the feces of two adults with diarrheal disease and from the appendix of a child with appendicitis. They were identified as Campylobacter laridis by a hybridization dot blot assay. Urease testing should be included in the tests used for the identification of campylobacters at the species level, even for those strains which are not of gastric origin.


Bone mineral density is reduced in patients with Crohn's disease but not in patients with ulcerative colitis: a population based study.
Patients with inflammatory bowel disease are at risk of developing metabolic bone disease. To compare bone mineral density in patients with Crohn's disease with patients with ulcerative colitis and healthy subjects, and to evaluate possible risk factors for bone loss in inflammatory bowel disease. 60 patients with Crohn's disease, 60 with ulcerative colitis, and 60 healthy subjects were investigated. Each group consisted of 24 men and 36 women. Lumbar spine, femoral neck, and total body bone mineral density were measured by dual x ray absorptiometry (DXA), and Z scores were obtained by comparison with age and sex matched normal values. Mean Z scores were significantly lower in patients with Crohn's disease compared with patients with ulcerative colitis and healthy subjects. Patients with ulcerative colitis had bone mineral densities similar to healthy subjects. Use of corticosteroids, body mass index (BMI), and sex were significant predictor variables for bone mineral density in Crohn's disease. In ulcerative colitis only body mass index and sex were of significant importance. Disease localisation and small bowel resections had no influence on bone mineral density in patients with Crohn's disease. Patients with Crohn's disease have reduced bone mineral density. Several factors are probably involved, but the reduction is associated with corticosteroid therapy. When studying skeletal effects of inflammatory bowel disease, patients with Crohn's disease and those with ulcerative colitis should be evaluated separately.


The back pain of bus drivers. Prevalence in an urban area of California.
A stratified random sample of 195 subjects was selected from the membership of an urban transit union in California, two thirds consisting of motor coach operators and one third serving as a nondriving comparison group. Based on an orthopaedic medical history and physical examination, 80.5% of drivers were found to be experiencing back or neck pain at the time of examination, in contrast with 50.7 percent of nondrivers, itself a sizable percentage. For both groups, most pain was mild, (53.9 and 29.9%, respectively). The amount of severe pain was essentially the same in the two groups (10.2% and 9.0%). Both groups were most subject to low back pain. Drivers were most distinctive for movement-related pain in the cervical spine. They were also more subject in any part of the spine to postural pain. The latter finding suggests the need to introduce ergonomic and scheduling changes in the work of operating a motor coach. Drivers more than nondrivers struggled against their pain by doing exercise, seeking professional treatment, and taking medications, indicating that spinal disorders constitute a prominent health concern for workers in this occupation.


Compliance and concordance during domiciliary medication review involving pharmacists and older people.
Medication review is an advanced service registered pharmacists can now offer patients in the UK. This in-depth study of pharmacist-older patient communication during domiciliary medication review encounters examines how the interactions are constructed by participants and the influence of the compliance paradigm on the interaction. Twenty-nine observed, taped and transcribed consultations were analysed using discourse analysis. Ethnographic-style interviews in the field with pharmacists, follow-up interviews with patients and feedback workshops with pharmacists allowed interpretations to be tested and strengthened. The findings presented here use discourse analysis to look at the task-driven nature of the medication review encounters. The analysis explores the interactional format of three over-lapping phases of the consultations: (i) introductions and agenda setting; (ii) screening and testing patients' ability to comply; and, (iii) investigating over-the-counter medicines. Analysis suggests that a dominant compliance paradigm encourages pharmacist-led encounters with patients failing to engage in the medication review process. Little evidence of two-way reciprocated discussion or concordance was evident. The strategic nature of the discourse of compliance heard in these medication review encounters and its effect on older patients are discussed. The paper concludes with a consideration of the implications for pharmacy practice and policy development.


Isolation and characterization of polymorphic microsatellite markers in Tetranychus urticae and cross amplification in other Tetranychidae and Phytoseiidae species of economic importance.
Tetranychus urticae Koch is a cosmopolitan phytophagous mite considered as the most polyphagous species among spider mites. Population genetic studies using molecular markers such as microsatellites have proven to be extremely informative to address questions about population structure, phylogeography and host preferences. The aim of this study was to increase the available molecular tools to gain insight into the genetic structure of T. urticae populations of citrus orchards, which might help in their management. Five microsatellite DNA libraries were developed using probes with the motifs CT, CTT, GT and CAC following the FIASCO protocol. Positive clones, those that included the insert with the microsatellite, were detected using the PIMA-PCR technique. Combinations of primers were designed on 22 out of 32 new microsatellites loci and their polymorphism was tested in four populations sampled along the eastern coast of Spain. Eleven successful amplifications were obtained. Cross amplification was tested in the tetranychids Aphlonobia histricina, Eutetranychus banksi, E. orientalis, Oligonychus perseae, Panonychus citri, Tetranychus evansi, T. okinawanus and T. turkestani, and the phytoseiids Amblyseius swirskii, A. cucumeris, A. andersoni, Euseius stipulatus, Neoseiulus barkeri, N. californicus, Phytoseiulus persimilis and Typhlodromus phialatus. Eight successful cross amplifications were obtained.


Bacteremia caused by extended-spectrum-β-lactamase-producing Escherichia coli sequence type ST131 and non-ST131 clones: comparison of demographic data, clinical features, and mortality.
Escherichia coli producing the highly virulent, multidrug-resistant, CTX-M-15 extended-spectrum β-lactamase (ESBL), sequence type 131 (ST131), has emerged on three continents since the late 2000s. We described the molecular epidemiology, clinical features, and outcome of ESBL-producing E. coli bacteremia in Taiwan from 2005 to 2010. This study aims to determine whether the risk factors, clinical features, and outcomes of the ST131 isolate differ from those of non-ST131 isolates. From 2005 to 2010, we collected 122 nonduplicated, consecutive, ESBL-producing E. coli isolates from bloodstream infections in a 1,200-bed hospital in Taiwan. Isolates were characterized using multilocus sequence typing. Demographic data, clinical features, and outcomes were collected from medical chart records. Thirty-six (29.5%) patients with bacteremia with ESBL-producing E. coli ST131 were identified. Patients with clone ST131 were more likely to have secondary bacteremia and noncatheterized urinary tract infections (P < 0.05). Secondary bacteremia (odds ratio [OR], 5.05; 95% confidence interval [CI], 1.08 to 23.56) and urinary catheter nonuse (OR, 3.77; 95% CI, 1.17 to 12.18) were independent risk factors for the ST131 clone after adjustment. Mortality rates at day 28 were similar in ST131 and non-ST131 populations. Independent risk factors predicting mortality at day 28 included malignancy, shock, and hospital-acquired bacteremia. In ESBL-producing E. coli bloodstream infections, the ST131 clone was not associated with health-care-associated risk factors, such as urinary catheter use or antibiotic exposure. Although highly virulent and multidrug resistant, the ST131 clone was not associated with higher mortality than non-ST131 clones.


Cold plasma application to fresh green leafy vegetables: Impact on microbiology and product quality.
Fresh green leafy vegetables (FGLVs) are consumed either garden-fresh or by going through very few simple processing steps. For this reason, foodborne diseases that come with the consumption of fresh products in many countries have prioritized the development of new and reliable technologies to reduce food-related epidemics. Cold plasma (CP) is considered one of the sustainable and green processing approaches that inactivate target microorganisms without causing a significant temperature increase during processing. This review presents an overview of recent developments regarding the commercialization potential of CP-treated FGLVs, focusing on specific areas such as microbial inactivation and the influence of CP on product quality. The effect of CP differs according to the power of the plasma, frequency, gas flow rate, application time, ionizing gases composition, the distance between the electrodes and pressure, as well as the characteristics of the product. As well as microbial decontamination, CP offers significant potential for increasing the shelf life of perishable and short-shelf-life products. In addition, organizations actively involved in CP research and development and patent applications (2016-2022) have also been analyzed.


Research on the Construction of a Nursing Education Management Model Based on a Small Data-Driven Model and Its Application.
Based on the concept of responsible holistic nursing care, a whole-process dual-tutor nursing practice model is established and its application effects are explored. This paper firstly reviews the research progress of nursing workload prediction methods at home and abroad, in order to provide a reference for clinical nursing workers in China to choose a scientific, reasonable, and easy-to-use nursing workload prediction method. It is proposed to construct a nursing education management model based on small data to provide ideas and references for nursing education management to effectively predict the evolutionary trend of students' behaviour and improve the level of accurate services. The experimental group adopted a dual-tutor responsibility system for the whole-process nursing practice model, including a complete three-level supervision system: a dual-tutor teaching system, a PDCA responsibility system for continuous improvement, and a multichannel teacher-student interaction platform; the control group adopted the traditional nursing practice model.


NADH dehydrogenase subunit genes in the mitochondrial DNA of yeasts.
The genes encoding the NADH dehydrogenase subunits of respiratory complex I have not been identified so far in the mitochondrial DNA (mtDNA) of yeasts. In the linear mtDNA of Candida parapsilosis, we found six new open reading frames whose sequences were unambiguously homologous to those of the genes known to code for NADH dehydrogenase subunit proteins of different organisms, i.e., ND1, ND2, ND3, ND4L, ND5, and ND6. The gene for ND4 also appears to be present, as judged from hybridization experiments with a Podospora gene probe. Specific transcripts from these open reading frames (ND genes) could be detected in the mitochondria. Hybridization experiments using C. parapsilosis genes as probes suggested that ND genes are present in the mtDNAs of a wide range of yeast species including Candida catenulata, Pichia guilliermondii, Clavispora lusitaniae, Debaryomyces hansenii, Hansenula polymorpha, and others.


Say it audiovisually to physicians, patients, and the public.
The Department of Pathology at the Medical College of Wisconsin has, in addition to the medical school's central TV facility, its own closed circuit TV equipment. Here, the authors recall the initial reaction of laboratory personnel to the system, and they explain the many ways in which the equipment has been used since its installation.


Ultrasonic backscatter of the carotid wall in young and older athletes.
The aim of this study was to evaluate the effects of habitual exercise on the age-related changes of carotid wall composition defining its acoustic reflectivity by the quantitative approach of integrated backscatter (IBS) analysis. Cross-sectional study. University Hospital. Fifty-four competitive long-distance runners (males, age range 22-72 years) and 50 healthy sedentary controls. All the subjects underwent both 2-D conventional ultrasonography and IBS analysis. IBS values were sampled from a region of interest (ROI) placed within five consecutive regions of the common carotid intima-media, and then corrected (C-IBS) for the IBS value of the adventitia. Athletes showed a lower C-IBS (-27.07 +/- 2.9 dB vs. -24.57 +/- 4 dB, P < 0.0001) and a smaller intima-media thickness (IMT: 0.64 +/- 0.16 mm vs. 0.78 +/- 0.21 mm, P < 0.001) respect to sedentary controls. By selecting the lowest (<30 years of age) and the highest (>60 years of age) tertile of age, we assess the influence of age on IMT and IBS. Sedentary older individuals exhibited an IMT higher respect to young controls and to the both trained subgroups (P < 0.0001). C-IBS was lower in both subgroups of athletes, independently of age, and lower in sedentary young people respect to sedentary older subgroup (P < 0.0001). Endurance chronic exercise blunted the difference of C-IBS observed between young and older sedentary individuals. Moreover, C-IBS was positively related to age (r = 0.77, P < 0.0001) and IMT (r = 0.52, P < 0.0001). The age-related changes of the arterial wall are attenuated by physical training. These modifications can be quantitatively discriminated by ultrasonic backscatter method.


Molecular genetics of gastrointestinal non-Hodgkin's lymphomas: unusual prevalence and pattern of c-myc rearrangements in aggressive lymphomas.
Thirty-two extranodal lymphomas of the gastrointestinal (GI) tract underwent molecular genetic analysis by Southern blotting using probes for the immunoglobulin genes and the bcl-1, bcl-2, and c-myc loci, commonly involved in lymphomagenesis. No bcl-1 rearrangements were found. There was only one large-cell lymphoma with a bcl-2 rearrangement. A rearrangement of the c-myc gene was found in six of eight Burkittlike lymphomas of the intestine. In five of these six cases, a chromosomal translocation t(8;14) with an unusual breakpoint was demonstrated by comigration of the rearranged c-myc and a rearranged JH sequence. This pattern of rearrangement has not been previously associated with a specific group of non-Hodgkin's lymphomas. In contrast to all six low-grade lymphomas, c-myc rearrangements were found in 6 of 12 large-cell or high-grade mucosa-associated lymphomas of the stomach. No comigration of c-myc and immunoglobulin heavy-chain gene sequences were found. We conclude that primary GI lymphomas have different molecular genetic characteristics compared with node-based follicle center-cell lymphoma and as a group are not related to these lymphomas. In addition, the prevalence and patterns of c-myc rearrangements in the gastric large-cell lymphomas and ileocecal Burkittlike lymphomas are noteworthy and suggest a different and distinct pathogenesis for these tumors.


MicroRNAs miR-30b, miR-30d, and miR-494 regulate human endometrial receptivity.
MicroRNAs (miRNAs) act as important epigenetic posttranscriptional regulators of gene expression. We aimed to gain more understanding of the complex gene expression regulation of endometrial receptivity by analyzing miRNA signatures of fertile human endometria. We set up to analyze miRNA signatures of receptive (LH + 7, n = 4) versus prereceptive (LH + 2, n = 5) endometrium from healthy fertile women. We found hsa-miR-30b and hsa-miR-30d to be significantly upregulated, and hsa-miR-494 and hsa-miR-923 to be downregulated in receptive endometrium. Three algorithms (miRanda, PicTar, and TargetScan) were used for target gene prediction. Functional analyses of the targets using Ingenuity Pathways Analysis and The Database for Annotation, Visualization and Integrated Discovery indicated roles in transcription, cell proliferation and apoptosis, and significant involvement in several relevant pathways, such as axon guidance, Wnt/β-catenin, ERK/MAPK, transforming growth factor β (TGF-β), p53 and leukocyte extravasation. Comparison of predicted miRNA target genes and our previous messenger RNA microarray data resulted in a list of 12 genes, including CAST, CFTR, FGFR2, and LIF that could serve as a panel of genes important for endometrial receptivity. In conclusion, we suggest that a subset of miRNAs and their target genes may play important roles in endometrial receptivity.


Perihospitalization hemoglobin-epoetin associations in U.S. hemodialysis patients, 1998 to 2003.
While hospitalization is common for hemodialysis patients, perihospitalization associations between hemoglobin levels and epoetin doses are not well characterized. U.S. Medicare claims were used to identify 71,360 hemodialysis patients hospitalized from 1998 to 2003. Hemoglobin levels, epoetin doses, and epoetin responsiveness index (ERI) were compared by calendar year. In the prehospitalization month, the mean hemoglobin levels increased from 10.96 g/dL in 1998 to 11.76 in 2003 and the mean epoetin doses from 63,715 to 75,012 U; corresponding values in the hospitalization month were 10.53 and 11.19 g/dL, and 66,623 and 80,569 U. In each year, prehospitalization hemoglobin levels were achieved within 2 months, but ERI declined to prehospitalization levels within 12 months only in 2000. With mixed models, hemoglobin declines in the 3 prehospitalization months grew between 1998 (-0.1362 g/dL/month) and 2003 (-0.2003 g/dL/month). Epoetin responsiveness index slopes were J-shaped, with values of 287.9, 221.1, and 356.5U/month per g/dL in 1998, 2000, and 2003. In the 3 postadmission months, a modest increase in the rapidity of hemoglobin recovery was seen (+0.2538 g/dL/month in 1998, +0.2743 in 2003), with increasing rates of ERI change (+8.7 U/month/g/dL in 1998, +146.8 in 2003). While time to recovery of prehospitalization hemoglobin levels remained constant year to year, epoetin doses and ERI did not, suggesting that optimum perihospitalization anemia management practices have yet to be determined.


An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors.
This study tested the hypothesis that the number of CA single sequence repeat (CA-SSR) in the intron 1 of the epidermal growth factor receptor (egfr) gene, which affects transcription efficiency of the gene, is associated with the response to EGFR inhibitors. To this end, we determined the number of CA dinucleotides in the intron 1 of the egfr gene in a panel of 12 head and neck cancer cell lines that lack egfr gene amplification and measured the expression of EGFR (mRNA and protein), as well as response to EGFR inhibition. Cells with lower number of CA dinucleotides in the CA-SSR had higher expression of the EGFR gene and protein and were more sensitive to the inhibitory effects of erlotinib, a small molecule inhibitor of the EGFR tyrosine-kinase. Phenotypic modification by silencing EGFR mRNA expression in a susceptible cell line induced resistance to the drug. The number of CA dinucleotide was equivalent in genomic and tumor DNA obtained from 30 patients with head and neck cancer. In a clinical study in colorectal cancer, subjects with lower number of CA dinucleotide frequently developed skin toxicity, a feature that is related to the antitumor activity of this class of drugs. These results suggest that polymorphic variations in the intron 1 of the egfr gene is associated with response to EGFR inhibitors and may provide an explanation as to why the development of skin toxicity is associated with a favorable outcome in patients treated with these agents.


Verification of chaotic behavior in an experimental loudspeaker.
The dynamics of an experimental electrodynamic loudspeaker is studied by using the tools of chaos theory and time series analysis. Delay time, embedding dimension, fractal dimension, and other empirical quantities are determined from experimental data. Particular attention is paid to issues of stationarity in a system in order to identify sources of uncertainty. Lyapunov exponents and fractal dimension are measured using several independent techniques. Results are compared in order to establish independent confirmation of low dimensional dynamics and a positive dominant Lyapunov exponent. We thus show that the loudspeaker may function as a chaotic system suitable for low dimensional modeling and the application of chaos control techniques.