Prevascularization-free Primary Subcutaneous Transplantation of Xenogeneic Islets Coencapsulated With Hepatocyte Growth Factor.
Subcutaneous pouch is a potential site for islet transplantation. However, insufficient oxygen supply remains challenging. Pretreatment of neovascularization using basic fibroblast growth factor can solve this, but it needs 2× operations. We developed a device that contains rat islets in chitosan gel packed in a bag made of highly biocompatible ethylene vinyl alcohol copolymer porous membrane. This study investigated whether coencapsulation of hepatocyte growth factor (HGF) with islets in the device enables novel method of prevascularization-free primary subcutaneous transplantation. In vitro experiments examined slow release of HGF from the chitosan gel and islet-protection effect of HGF against hypoxia. In the latter, rat islets with/without HGF (200 ng/mL) was cultured in 1% oxygen. In in vivo experiment, fabricated device with/without HGF (10 μg/device) containing rat islets was primarily transplanted to streptozotocin-induced diabetic mice subcutaneously. In vitro experiments showed sustained release of HGF for 28 d and alleviating effect of HGF on cell death and glucose-responsive insulin release after hypoxic culture. Islet + HGF mice, but not islet-alone mice, showed decreased nonfasting blood glucose and regained body weight after transplantation. In intraperitoneal glucose tolerance test, islet + HGF mice exhibited decreased fasting blood glucose (200 ± 55 mg/dL) and good blood glucose disappearance rate (K value) (0.817 ± 0.101) comparing to normal mice (123 ± 28 mg/dL and 1.074 ± 0.374, respectively). However, in islet-alone mice, fasting blood glucose was high (365 ± 172 mg/dL) and K value was indeterminable. Serum insulin in islet + HGF mice (1.58 ± 0.94 μg/L) was close to normal mice (1.66 ± 0.55 μg/L), whereas those in islet-alone mice (0.279 ± 0.076 μg/L) and diabetic mice (0.165 ± 0.079 μg/L) were low. Immunohistochemical examination showed intact insulin- and glucagon-positive islets in retrieved devices with HGF, but no intact islet was found in the device without HGF. HGF could enhance islet survival in hypoxia and enhance in vivo function of encapsulated islets after primary subcutaneous transplantation.


Cross-sectional relationship of pedometer-determined ambulatory activity to indicators of health.
To describe the cross-sectional relationship between an objective measure of walking (pedometer-determined steps/day) and general indicators of health, a prior diagnosis of one or more components of the metabolic syndrome, and self-reported occupational activity in a generally sedentary working population. Steps/day were compared with previous diagnosis of one or more components of the metabolic syndrome (by self-administered questionnaire) and with general health indicators including BMI, waist circumference, resting heart rate, and blood pressure in 182 subjects in Prince Edward Island, Canada. Study participants were volunteer employees recruited from five workplaces where, in general, the job types were moderately or highly sedentary. Steps/day were 7230 +/- SD 3447 for women (n = 153) and 8265 +/- 2849 (n = 21) for men. Pedometer-determined steps/day were associated inversely with BMI (r = -0.4005, p < 0.0001) in all participants and waist circumference in females only (r = -0.4303, p < 0.0001). There was a low correlation between steps/day and diastolic blood pressure in the whole sample (r = -0.2140, p = 0.0383). Participants who reported a prior diagnosis of one or more components of the metabolic syndrome (hypertension, hypercholesterolemia, heart disease, or type 2 diabetes) took fewer steps/day than healthy participants (p = 0.0254). Pedometer-determined steps/day were positively associated with self-reported occupational activity (p = 0.0002). Fewer steps/day are associated with increased BMI, waist circumference, diastolic blood pressure, and components of the metabolic syndrome. Low occupational activity is a contributing factor to low total ambulatory activity.


Modelling the early growth of ductal carcinoma in situ of the breast.
The growth of a tumour in a rigid walled cylindrical duct is examined in order to model the initial stages of tumour cell expansion in ductal carcinoma in situ (DCIS) of the breast. A nutrient-limited growth model is formulated, in which cell movement is described by a Stokes flow constitutive relation. The effects on the shape of the tumour boundary of the material properties (i.e. the viscosity) and the extent to which the cells adhere to the duct wall are studied using numerical and asymptotic methods. It is shown how stable, non-planar, interface configurations result and that, during these initial stages, before the duct wall has been breached, few cells die and a nutrient-rich model is usually sufficient to capture the behaviour. Finally, we discuss the relevance of this approach to DCIS and suggest possible avenues for further work.


Impact of dynamic alignment, motion, and center of rotation on myelopathy grade and regional disability in cervical spondylotic myelopathy.
Cervical stenosis is a defining feature of cervical spondylotic myelopathy (CSM). Matsunaga et al. proposed that elements of stenosis are both static and dynamic, where the dynamic elements magnify the canal deformation of the static state. For the current study, the authors hypothesized that dynamic changes may be associated with myelopathy severity and neck disability. This goal of this study was to present novel methods of dynamic motion analysis in CSM. A post hoc analysis was performed of a prospective, multicenter database of patients with CSM from the AOSpine North American study. One hundred ten patients (34%) met inclusion criteria, which were symptomatic CSM, age over 18 years, baseline flexion/extension radiographs, and health-related quality of life (HRQOL) questionnaires (modified Japanese Orthopaedic Association [mJOA] score, Neck Disability Index [NDI], the 36-Item Short Form Health Survey Physical Component Score [SF-36 PCS], and Nurick grade). The mean age was 56.9 ± 12 years, and 42% of patients were women (n = 46). Correlations with HRQOL measures were analyzed for regional (cervical lordosis and cervical sagittal vertical axis) and focal parameters (kyphosis and spondylolisthesis between adjacent vertebrae) in flexion and extension. Baseline dynamic parameters (flexion/extension cone relative to a fixed C-7, center of rotation [COR], and range of motion arc relative to the COR) were also analyzed for correlations with HRQOL measures. At baseline, the mean HRQOL measures demonstrated disability and the mean radiographic parameters demonstrated sagittal malalignment. Among regional parameters, there was a significant correlation between decreased neck flexion (increased C2-7 angle in flexion) and worse Nurick grade (R = 0.189, p = 0.048), with no significant correlations in extension. Focal parameters, including increased C-7 sagittal translation overT-1 (slip), were significantly correlated with greater myelopathy severity (mJOA score, Flexion R = -0.377, p = 0.003; mJOA score, Extension R = -0.261, p = 0.027). Sagittal slip at C-2 and C-4 also correlated with worse HRQOL measures. Reduced flexion/extension motion cones, a more posterior COR, and smaller range of motion correlated with worse general health SF-36 PCS and Nurick grade. Dynamic motion analysis may play an important role in understanding CSM. Focal parameters demonstrated a significant correlation with worse HRQOL measures, especially increased C-7 sagittal slip in flexion and extension. Novel methods of motion analysis demonstrating reduced motion cones correlated with worse myelopathy grades. More posterior COR and smaller range of motion were both correlated with worse general health scores (SF-36 PCS and Nurick grade). To our knowledge, this is the first study to demonstrate correlation of dynamic motion and listhesis with disability and myelopathy in CSM.


Amyloid-binding compounds and their anti-prion potency.
Prion diseases, or transmissible spongiform encephalopathies, are characterized by abnormal prion protein accumulation in the brain. Abnormal prion proteins, having properties of amyloids when extracted from the brain, are observed as amyloid plaque deposits in the brain in some prion diseases such as variant Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome. This article reviews amyloid-binding compounds from the perspective of their usefulness for diagnosis and therapy of prion diseases. Styrylbenzoazole derivatives and phenylhydrazine derivatives are recently developed amyloid binding compounds that present benefits for prion-disease-related medicinal applications. For instance, styrylbenzoazole derivative BF-227, currently used as an amyloid imaging probe of positron emission tomography in Alzheimer disease, is useful also for the diagnosis of Gerstmann-Sträussler-Scheinker syndrome. A phenylhydrazine derivative, compB, has remarkable prophylactic effects on intracerebrally infected animals with certain prion strains, even when administered orally. These amyloid-binding compounds, however, are not applicable to prion strains or prion diseases of all types. For example, amyloid-binding compounds are ineffective for inhibiting prion strains such as 263K. They are not feasible for detecting abnormal prion protein accumulation in the brain for prion diseases having no amyloid plaques. To elucidate the limitations of amyloid-binding compounds, further investigation is necessary to clarify the binding mode of the compounds to abnormal prion protein structures at an atomic level.


Respiratory responses in reversible diaphragm paralysis.
The effects of diaphragm paralysis on respiratory activity were assessed in 13 anesthetized, spontaneously breathing dogs studied in the supine position. Transient diaphragmatic paralysis was induced by bilateral phrenic nerve cooling. Respiratory activity was assessed from measurements of ventilation and from the moving time averages of electrical activity recorded from the intercostal muscles and the central end of the fifth cervical root of the phrenic nerve. The degree of diaphragm paralysis was evaluated from changes in transdiaphragmatic pressure and reflected in rib cage and abdominal displacements. Animals were studied both before and after vagotomy breathing O2, 3.5% CO2 in O2, or 7% CO2 in O2. In dogs with intact vagi, both peak and rate of rise of phrenic and inspiratory intercostal electrical activity increased progressively as transdiaphragmatic pressure fell. Tidal volume decreased and breathing frequency increased as a result of a shortening in expiratory time. Inspiratory time and ventilation were unchanged by diaphragm paralysis. These findings were the same whether O2 or CO2 in O2 was breathed. After vagotomy, no significant change in phrenic or inspiratory intercostal activity occurred with diaphragm paralysis in spite of increased arterial CO2 partial pressure. Ventilation and tidal volume decreased significantly, and respiratory timing was unchanged. These results suggest that mechanisms mediated by the vagus nerves account for the compensatory increase in respiratory electrical activity during transient diaphragm paralysis. That inspiratory time is unchanged by diaphragm paralysis whereas the rate or rise of phrenic nerve activity increases suggest that reflexes other than the Hering-Breuer reflex contribute to the increased respiratory response.


Chronic anaemia, hyperbaric oxygen and tumour radiosensitivity.
Anaemia is an important factor in the response of some human tumours to radiotherapy. The outcome is also influenced by whether the treatment is given in air or high pressure oxygen (HPO). The present study examined the relationship between anaemia and tumour response to radiation given in air or HPO in C3H mice transplanted with a mammary adenocarcinoma using a growth delay assay to assess the radiation response. Chronic anaemia was induced by the use of a low iron diet and was characterized by a significant reduction in host haematocrit and whole blood viscosity. In addition, anaemia was associated with a right shift in the oxyhaemoglobin dissociation curve and an increase in the volume doubling time of the tumour; but there was no change in the concentration of 2,3-diphosphoglycerate in the red cells. Radiation studies with these anaemic mice demonstrated that the tumour radiosensitivity was decreased when treatment was given in air. HPO was successful in overcoming the increased radioresistance associated with anaemia. This result suggested that tumours grown in anaemic mice have a higher hypoxic fraction than those grown in control mice. Changes in host physiology with chronic anaemia may contribute to the benefit seen with HPO but such alterations per se may be inadequate to maintain tumour oxygenation when treatment is given in air.


Physicochemical and metabolic basis for the differing neurotoxicity of the pyrrolizidine alkaloids, trichodesmine and monocrotaline.
Monocrotaline and trichodesmine are structurally closely related pyrrolizidine alkaloids (PAs) exhibiting different extrahepatic toxicities, trichodesmine being neurotoxic (LD(50) 57 mu mol/kg) and monocrotaline pneumotoxic (LD(50) 335 mu mol/kg). We have compared certain physicochemical properties and metabolic activities of these two PAs in order to understand the quantitative and qualitative differences in toxicity. Both PAs were metabolized in the isolated, perfused rat liver to highly reactive pyrrolic dehydroalkaloids that appear to be responsible for the toxicity of PAs. More dehydrotrichodesmine (468 nmol/g liver) than dehydromonocrotaline (116 nmol/g liver) was released from liver into perfusate on perfusion for 1 hr with 0.5 mM of the parent PA. Dehydrotrichodesmine had a significantly longer aqueous half-life (5.4 sec) than that of dehydromonocrotaline (3.4 sec). In vivo, significantly higher levels of bound pyrroles were found in the brain 18 hr after injection of trichodesmine (25 mg/kg; i.p.) than were seen following either an equal dose (25 mg/kg; i.p.) or an equitoxic dose (90 mg/kg; i.p.) of monocrotaline. Trichodesmine had a higher partition coefficient than monocrotaline for both chloroform and heptane, indicating its greater lipophilicity. The pK(a) of trichodesmine (7.07) was only slightly higher than that of monocrotaline (pK(a¿ 6.83), suggesting that a difference in degree of ionization was not a major factor affecting the relative ability of the dehydroalkaloids to cross the blood-brain barrier. We conclude that the greater lethality and neurotoxicity of trichodesmine compared to monocrotaline is due to two structural characteristics: (i) steric hindrance at position 14 of dehydrotrichodesmine results in greater resistance to hydrolysis, allowing more to be released from the liver and to be delivered to the brain; (ii) the larger isopropyl substituent at position 14 of dehydrotrichodesmine renders the molecule more lipophilic, leading to greater penetration of the brain.


Next-generation text-mining mediated generation of chemical response-specific gene sets for interpretation of gene expression data.
Availability of chemical response-specific lists of genes (gene sets) for pharmacological and/or toxic effect prediction for compounds is limited. We hypothesize that more gene sets can be created by next-generation text mining (next-gen TM), and that these can be used with gene set analysis (GSA) methods for chemical treatment identification, for pharmacological mechanism elucidation, and for comparing compound toxicity profiles. We created 30,211 chemical response-specific gene sets for human and mouse by next-gen TM, and derived 1,189 (human) and 588 (mouse) gene sets from the Comparative Toxicogenomics Database (CTD). We tested for significant differential expression (SDE) (false discovery rate -corrected p-values < 0.05) of the next-gen TM-derived gene sets and the CTD-derived gene sets in gene expression (GE) data sets of five chemicals (from experimental models). We tested for SDE of gene sets for six fibrates in a peroxisome proliferator-activated receptor alpha (PPARA) knock-out GE dataset and compared to results from the Connectivity Map. We tested for SDE of 319 next-gen TM-derived gene sets for environmental toxicants in three GE data sets of triazoles, and tested for SDE of 442 gene sets associated with embryonic structures. We compared the gene sets to triazole effects seen in the Whole Embryo Culture (WEC), and used principal component analysis (PCA) to discriminate triazoles from other chemicals. Next-gen TM-derived gene sets matching the chemical treatment were significantly altered in three GE data sets, and the corresponding CTD-derived gene sets were significantly altered in five GE data sets. Six next-gen TM-derived and four CTD-derived fibrate gene sets were significantly altered in the PPARA knock-out GE dataset. None of the fibrate signatures in cMap scored significant against the PPARA GE signature. 33 environmental toxicant gene sets were significantly altered in the triazole GE data sets. 21 of these toxicants had a similar toxicity pattern as the triazoles. We confirmed embryotoxic effects, and discriminated triazoles from other chemicals. Gene set analysis with next-gen TM-derived chemical response-specific gene sets is a scalable method for identifying similarities in gene responses to other chemicals, from which one may infer potential mode of action and/or toxic effect.


Stereotactic ablative body radiotherapy in patients with prostate cancer.
Prostate is the most common non-cutaneous cancer diagnosed among men in North America. Fortunately most prostate cancers are screen detected and non-metastatic on diagnosis. Treatment options for men with localized prostate cancer include surgery ± postoperative radiation or radiation ± androgen deprivation therapy (ADT). Brachytherapy ± external beam radiation treatment (EBRT) appears to have superior long-term disease control over EBRT alone likely because of higher biologic effective dose delivered. Stereotactic ablative body radiation (SABR) is a novel, non-invasive, high-precision EBRT technique that allows safe delivery of biologic doses similar to brachytherapy with similar or lower side effects [measured using toxicity or quality of life (QOL) scales]. Efficacy for SABR appears to be similar to brachytherapy including positive biopsy rates 2-3 years post treatment, biochemical failure (BF) rates out to 10-year and incidence of metastases. SABR dose escalation reduces biopsy positivity and prostate-specific antigen (PSA) nadirs but increases genitourinary (GU) and gastrointestinal (GI) toxicity-no effect on BF has been realized yet. The overall treatment time (OTT) varies in many protocols. Phase 2 randomized data shows that QOL is better in the acute setting with a weekly course of treatment compared to an every other day treatment regimen with no difference in late setting. Follow-up data are immature and likely underpowered to determine efficacy differences. SABR is cheaper and uses less resource than any other radiation technique. Given the healthcare resource challenges (including financial resources), SABR would be a welcomed addition if studies show non-inferiority to other radiation techniques. For patients with de novo or metastatic disease on relapse, there is much enthusiasm regarding the use of SABR in the setting of oligometastatic prostate cancer. SABR appears to be feasible to deliver, well tolerated and may delay the next line of therapy. However, until adequately powered randomized studies confirm a benefit, such an approach cannot be considered standard of care treatment at this time. Enrollment of eligible prostate cancer patients onto SABR clinical trials should be encouraged.


Identifying Specific Combinations of Multimorbidity that Contribute to Health Care Resource Utilization: An Analytic Approach.
Multimorbidity affects the majority of elderly adults and is associated with higher health costs and utilization, but how specific patterns of morbidity influence resource use is less understood. The objective was to identify specific combinations of chronic conditions, functional limitations, and geriatric syndromes associated with direct medical costs and inpatient utilization. Retrospective cohort study using the Health and Retirement Study (2008-2010) linked to Medicare claims. Analysis used machine-learning techniques: classification and regression trees and random forest. A population-based sample of 5771 Medicare-enrolled adults aged 65 and older in the United States. Main covariates: self-reported chronic conditions (measured as none, mild, or severe), geriatric syndromes, and functional limitations. Secondary covariates: demographic, social, economic, behavioral, and health status measures. Medicare expenditures in the top quartile and inpatient utilization. Median annual expenditures were $4354, and 41% were hospitalized within 2 years. The tree model shows some notable combinations: 64% of those with self-rated poor health plus activities of daily living and instrumental activities of daily living disabilities had expenditures in the top quartile. Inpatient utilization was highest (70%) in those aged 77-83 with mild to severe heart disease plus mild to severe diabetes. Functional limitations were more important than many chronic diseases in explaining resource use. The multimorbid population is heterogeneous and there is considerable variation in how specific combinations of morbidity influence resource use. Modeling the conjoint effects of chronic conditions, functional limitations, and geriatric syndromes can advance understanding of groups at greatest risk and inform targeted tailored interventions aimed at cost containment.


Functional equivalence of morphologies enables morphological and ecological diversity.
Diversity in organismal forms among taxa is thought to reflect distinct selection pressures across environments. The central assumption underlying this expectation is that taxa experiencing similar selection have similar response to that selection. However, because selection acts on trait function, taxa similarity in selection response depends crucially on the relationship between function and morphology. Further, when a trait consists of multiple parts, changes in function in response to selection can result from modification of different parts, and adaptation to the same environment might result in functional but not morphological similarity. Here, we address the extent to which functional and morphological diversity in masticatory apparatus of soricid shrews reflects a shared ecological characteristic of their diet type. We examine the factors limiting morphological variation across shrew species by assessing the relative contribution of trait function (biomechanics of the jaw), ecology, and phylogeny to species similarity in mandibular traits. We found that species that shared diet type were functionally but not morphologically similar. The presence of multiple semi-independently varying traits enabled functional equivalence of composite foraging morphologies and resulted in variable response to selection exerted by similar diet. We show that functional equivalence of multiple morphologies enabled persistence of differences in habitat use (e.g., habitat moisture and coverage) among species that specialize on the same diet. We discuss the importance of developmental and functional integration among traits for evolutionary diversification of morphological structures that generate equivalent functions.


Autism spectrum disorders in relation to parental occupation in technical fields.
A previous study reported that fathers of children with autism spectrum disorders (ASD) were more likely to work as engineers, requiring "systemizing skills," and suggesting a distinct phenotype, but alternatively this may have been related to selection biases. We conducted a population-based study to explore whether fathers, or mothers, of children with ASD are over-represented in fields requiring highly technical skills. Subjects included 284 children with ASD and 659 gender-matched controls, born in 1994 in the San Francisco Bay Area. Parental occupation and industry were abstracted verbatim from birth certificates. Engineering, computer programming, and science were examined as highly technical occupations. To limit bias by parental socio-economic status, we selected a referent group of occupations that seemed professionally similar but of a less technical nature. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated by logistic regression, adjusting for parental age, education, and child race. Mothers of cases were somewhat more likely to work in hi-tech occupations (6.7%) than mothers of controls (4.0%, P=0.07), but little difference was observed among fathers, nor for engineering separately. Compared to parents in other "white collar" occupations, the adjusted OR for highly technical occupations among mothers was 2.5 (95% CI: 1.2-5.3) and among fathers was 1.3 (95% CI: 0.79-2.1), with no evidence of a joint effect observed. Our results regarding maternal occupation in technical fields being associated with ASD in offspring suggest further study to distinguish parental occupation as a phenotypic marker of genetic loading vs. other social or exposure factors.


Diagnostic potential of the NMDA receptor peptide assay for acute ischemic stroke.
The acute assessment of patients with suspected ischemic stroke remains challenging. The use of brain biomarker assays may improve the early diagnosis of ischemic stroke. The main goal of the study was to evaluate whether the NR2 peptide, a product of the proteolytic degradation of N-methyl-D-aspartate (NMDA) receptors, can differentiate acute ischemic stroke (IS) from stroke mimics and persons with vascular risk factors/healthy controls. A possible correlation between biomarker values and lesion sizes was investigated as the secondary objective. A total of 192 patients with suspected stroke who presented within 72 h of symptom onset were prospectively enrolled. The final diagnosis was determined based on clinical observations and radiological findings. Additionally gender- and age-matched healthy controls (n = 52) and persons with controlled vascular risk factors (n = 48) were recruited to compare NR2 peptide levels. Blinded plasma was assayed by rapid magnetic particles (MP) ELISA for NR2 peptide within 30 min and results for different groups compared using univariate and multivariate statistical analyses. There was a clinical diagnosis of IS in 101 of 192 (53%) and non-stroke in 91 (47%) subjects. The non-stroke group included presented with acute stroke symptoms who had no stroke (n = 71) and stroke mimics (n = 20). The highest NR2 peptide elevations where found in patients with IS that peaked at 12 h following symptom onset. When the biomarker cut off was set at 1.0 ug/L, this resulted in a sensitivity of 92% and a specificity of 96% to detect IS. A moderate correlation (r(s) = 0.73) between NR2 peptide values and acute ischemic cortical lesions (<200 mL) was found. This study suggests that the NR2 peptide may be a brain specific biomarker to diagnose acute IS and may allow the differentiation of IS from stroke mimics and controls. Additional larger scale clinical validation studies are required.


Goldfish brain and heart are well protected from Ni²⁺-induced oxidative stress.
After 96 h goldfish exposure to 10, 25 or 50 mg/L of Ni(2+) no Ni accumulation was found in the brain, but lipid peroxide concentration was by 44% elevated in the brain, whereas carbonyl protein content was by 45-45% decreased in the heart. High molecular mass thiol concentration was enhanced by 30% in the heart, while in the brain low molecular mass thiol concentration increased by 28-88%. Superoxide dismutase activity was by 27% and 35% increased in the brain and heart, respectively. Glutathione peroxidase activity was lowered to 38% and 62% of control values in both tissues, whereas catalase activity was increased in the heart by 15-45%, accompanied by 18-29% decreased glutathione reductase activity. The disturbances of free radical processes in the brain and heart might result from Ni-induced injuries to other organs with more prominent changes in the heart, because of close contact of this organ with blood, whereas the blood-brain barrier seems to protect the brain.


Burden of disease from road traffic and railway noise - a quantification of healthy life years lost in Sweden.
Objectives National quantifications of the health burden related to traffic noise are still rare. In this study, we use disability-adjusted life-years (DALY) measure to assess the burden of disease from road traffic and railway noise in Sweden. Methods The number of DALY was assessed for annoyance, sleep disturbance, hypertension, myocardial infarction (MI) and stroke using a method previously implemented by the World Health Organization (WHO). Population exposure to noise was obtained from the Swedish Environmental Protection Agency and the Swedish Transport Administration. Data on disease occurrence were gathered from registers held by the National Board of Health and Welfare and Statistics Sweden. Disability weights (DW) and duration were based on WHO definitions. Finally, we used research-based exposure-response functions or relative risks to estimate disease attributable to noise in each exposure category. Results The number of DALY attributed to traffic noise in Sweden was estimated to be 41 033 years; 36 711 (90%) related to road traffic and 4322 (10%) related to railway traffic. The most important contributor to the disease burden was sleep disturbances, accounting for 22 218 DALY (54%), followed by annoyance, 12 090 DALY (30%), and cardiovascular diseases, 6725 DALY (16%). Conclusions Road traffic and railway noise contribute significantly to the burden of disease in Sweden each year. The total number of DALY should, however, be interpreted with caution due to limitations in data quality.


RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders.
Genome-wide expression analysis using next generation sequencing (RNA-Seq) provides an opportunity for in-depth molecular profiling of fundamental biological processes, such as cellular differentiation and malignant transformation. Differentiating human neurons derived from induced pluripotent stem cells (iPSCs) provide an ideal system for RNA-Seq since defective neurogenesis caused by abnormalities in transcription factors, DNA methylation, and chromatin modifiers lie at the heart of some neuropsychiatric disorders. As a preliminary step towards applying next generation sequencing using neurons derived from patient-specific iPSCs, we have carried out an RNA-Seq analysis on control human neurons. Dramatic changes in the expression of coding genes, long non-coding RNAs (lncRNAs), pseudogenes, and splice isoforms were seen during the transition from pluripotent stem cells to early differentiating neurons. A number of genes that undergo radical changes in expression during this transition include candidates for schizophrenia (SZ), bipolar disorder (BD) and autism spectrum disorders (ASD) that function as transcription factors and chromatin modifiers, such as POU3F2 and ZNF804A, and genes coding for cell adhesion proteins implicated in these conditions including NRXN1 and NLGN1. In addition, a number of novel lncRNAs were found to undergo dramatic changes in expression, one of which is HOTAIRM1, a regulator of several HOXA genes during myelopoiesis. The increase we observed in differentiating neurons suggests a role in neurogenesis as well. Finally, several lncRNAs that map near SNPs associated with SZ in genome wide association studies also increase during neuronal differentiation, suggesting that these novel transcripts may be abnormally regulated in a subgroup of patients.


Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice.
CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondria-mediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.


Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis.
Monocyte chemoattractant protein 1 (MCP-1) level in plasma is described as a marker for joint inflammation in rheumatoid arthritis (RA). MCP-1 in plasma and synovial fluid (SF) was quantified by ELISA in 36 RA patients with synovitis of the knee at Day 1 and 30. Disease activity was assessed by the swollen joint count, Ritchie Articular Index (RAI), global assessment, pain on visual analog scale, Health Assessment Questionnaire, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). By linear regression analysis plasma MCP-1 levels correlated significantly with the swollen joint count (Day 1: R = 0.47, p = 0.005; Day 30: R = 0.53, p < 0.001) and the RAI (Day 1: R = 0.37, p = 0.03; Day 30: R = 0.41, p = 0.01). The correlations of swollen joint count and RAI with ESR and CRP were significant only on Day 30 for the ESR (R = 0.40, p = 0.02). No association was found between plasma MCP-1 levels and the ESR/CRP levels. MCP-1 levels in plasma in RA patients were elevated compared to controls (p < 0.001) and MCP-I levels in SF were higher than in plasma (p < 0.001). No correlation was found between SF MCP-1 levels and in vitro migration of mononuclear cells towards SF. MCP-1 appears to participate in the disease process in RA, and plasma MCP-1 may be useful in monitoring joint inflammation.


Geometrical optimisation of a biochip microchannel fluidic separator.
This article reports on the geometric optimisation of a T-shaped biochip microchannel fluidic separator aiming to maximise the separation efficiency of plasma from blood through the improvement of the unbalanced separation performance among different channel bifurcations. For this purpose, an algebraic analysis is firstly implemented to identify the key parameters affecting fluid separation. A numerical optimisation is then carried out to search the key parameters for improved separation performance of the biochip. Three parameters, the interval length between bifurcations, the main channel length from the outlet to the bifurcation region and the side channel geometry, are identified as the key characteristic sizes and defined as optimisation variables. A balanced flow rate ratio between the main and side channels, which is an indication of separation effectiveness, is defined as the objective. It is found that the degradation of the separation performance is caused by the unbalanced channel resistance ratio between the main and side channel routes from bifurcations to outlets. The effects of the three key parameters can be summarised as follows: (a) shortening the interval length between bifurcations moderately reduces the differences in the flow rate ratios; (b) extending the length of the main channel from the main outlet is effective for achieving a uniformity of flow rate ratio but ineffective in changing the velocity difference of the side channels and (c) decreasing the lengths of side channels from upstream to downstream is effective for both obtaining a uniform flow rate ratio and reducing the differences in the flow velocities between the side branch channels. An optimisation process combining the three parameters is suggested as this integration approach leads to fast convergent process and also offers flexible design options for satisfying different requirements.


Sequential expression of Trks A, B, and C in the regenerating olfactory neuroepithelium.
This study examines how the family of neurotrophin receptor tyrosine kinases (Trks) participates in the regeneration and replacement of olfactory neurons within the adult rat olfactory neuroepithelium. mRNA and protein products representing the high-affinity nerve growth factor (NGF) receptor Trk A, its family members Trk B and Trk C, and the low-affinity NGF receptor (INGFR) are all detected within both mature and regenerating olfactory neuroepithelium and within primary cultures of olfactory neurons. Cellular immunoreactivity for Trks A, B, and C and INGFR changes dramatically during the lifetime of an olfactory neuron and is demonstrated by inducing the epithelium into a coordinate rapid cycle of degeneration and regeneration in vivo by removal of the target organ, the olfactory bulb. Trk A-positive neuronal precursor basal cells undergo mitosis to produce Trk B-positive immature neurons that mature under the local influence of the olfactory neuroepithelium and the target-derived influence of the olfactory bulb to become a Trk C-positive mature neuron. Primary cultures of immature olfactory neurons demonstrate neurotrophin-induced phosphorylation of Trks A, B, and C and subsequent activation of the immediate early gene c-Fos, and they change their expression of differentiation stage-specific markers after treatment with individual and combinations of neurotrophins. This is the first population of neurons of a single lineage in which Trks A, B, and C and the INGFR have been demonstrated to be expressed sequentially during neuronal division, commitment, and differentiation and to be fully capable of transducing cellular signals causing phenotypic changes in differentiation state.


Knee Arthrodesis in a Patient with Charcot Neuroarthropathy Secondary to Familial Amyloid Polyneuropathy: A Case Report.
We report a rare case of severe Charcot neuroarthropathy of the knee secondary to familial amyloid polyneuropathy, which was treated surgically with a knee arthrodesis. This treatment allowed an early symptomatic and functional improvement and a short consolidation time without any major complications. Neuropathy is the earliest and most major burden in patients with familial amyloid polyneuropathy; it requires careful evaluation and adequate treatment aimed at preventing or slowing the progression of secondary damage, involving Charcot neuroarthropathy, that may occur. Surgical arthrodesis with antegrade intramedullary nailing may be appropriate in a patient with severe Charcot neuroarthropathy of the knee.


Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons.
Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca(2+)) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP(3)R) Ca(2+) release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP(3)R channel gated. Recordings of endogenous IP(3)R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed that they were more likely than IP(3)R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca(2+) signaling. These results indicate that exaggerated Ca(2+) signaling through IP(3)R-PS interaction is a disease-specific and robust proximal mechanism in FAD.


Nanoscale architecture of the Schizosaccharomyces pombe contractile ring.
The contractile ring is a complex molecular apparatus which physically divides many eukaryotic cells. Despite knowledge of its protein composition, the molecular architecture of the ring is not known. Here we have applied super-resolution microscopy and FRET to determine the nanoscale spatial organization of Schizosaccharomyces pombe contractile ring components relative to the plasma membrane. Similar to other membrane-tethered actin structures, we find proteins localize in specific layers relative to the membrane. The most membrane-proximal layer (0-80 nm) is composed of membrane-binding scaffolds, formin, and the tail of the essential myosin-II. An intermediate layer (80-160 nm) consists of a network of cytokinesis accessory proteins as well as multiple signaling components which influence cell division. Farthest from the membrane (160-350 nm) we find F-actin, the motor domains of myosins, and a major F-actin crosslinker. Circumferentially within the ring, multiple proteins proximal to the membrane form clusters of different sizes, while components farther from the membrane are uniformly distributed. This comprehensive organizational map provides a framework for understanding contractile ring function.


Lattice Microarchitecture for Bone Tissue Engineering from Calcium Phosphate Compared to Titanium.
Additive manufacturing of bone tissue engineering scaffolds will become a key element for personalized bone tissue engineering in the near future. Several additive manufacturing processes are based on extrusion where the deposition of the filament will result in a three-dimensional lattice structure. Recently, we studied diverse lattice structures for bone tissue engineering realized by laser sintering of titanium. In this work, we used lithography-based ceramic manufacturing of lattice structures to produce scaffolds from tricalcium phosphates (TCP) and compared them in vivo to congruent titanium scaffolds manufactured with the identical computer-aided design data to look for material-based differences in bony healing. The results show that, during a 4-week period in a noncritical-size defect in a rabbit calvarium, both scaffolds with the identical microarchitecture performed equally well in terms of bony regeneration and bony bridging of the defect. A significant increase in both parameters could only be achieved when the TCP-based scaffolds were doped with bone morphogenetic protein-2. In a critical-size defect in the calvarial bone of rabbits, however, the titanium scaffold performed significantly better than the TCP-based scaffold, most likely due to its higher mechanical stability. We conclude that titanium and TCP-based scaffolds of the same microarchitecture perform equally well in terms of bone regeneration, provided the microarchitecture meets the mechanical demand at the site of implantation.


Breast cancer in limited-resource countries: an overview of the Breast Health Global Initiative 2005 guidelines.
Breast cancer is the most common cause of cancer-related death among women worldwide, with case fatality rates highest in low-resource countries. Despite significant scientific advances in its management, most of the world faces resource constraints that limit the capacity to improve early detection, diagnosis, and treatment of the disease. The Breast Health Global Initiative (BHGI) strives to develop evidence-based, economically feasible, and culturally appropriate guidelines that can be used in nations with limited health care resources to improve breast cancer outcomes. Using an evidence-based consensus panel process, four BHGI expert panels addressed the areas of early detection and access to care, diagnosis and pathology, treatment and resource allocation, and health care systems and public policy as they relate to breast health care in limited-resource settings. To update and expand on the BHGI Guidelines published in 2003, the 2005 BHGI panels outlined a stepwise, systematic approach to health care improvement using a tiered system of resource allotment into four levels-basic, limited, enhanced, and maximal-based on the contribution of each resource toward improving clinical outcomes. Early breast cancer detection improves outcome in a cost-effective fashion assuming treatment is available, but requires public education to foster active patient participation in diagnosis and treatment. Clinical breast examination combined with diagnostic breast imaging (ultrasound +/- diagnostic mammography) can facilitate cost-effective tissue sampling techniques for cytologic or histologic diagnosis. Breast-conserving treatment with partial mastectomy and radiation therapy requires more health care resources and infrastructure than mastectomy, but can be provided in a thoughtfully designed limited-resource setting. The availability and administration of systemic therapies are critical to improving breast cancer survival. Estrogen receptor testing allows patient selection for hormonal treatments (tamoxifen, oophorectomy). Chemotherapy, which requires some allocation of resources and infrastructure, is needed to treat node-positive, locally advanced breast cancers, which represent the most common clinical presentation of disease in low-resource countries. When chemotherapy is not available, patients with locally advanced, hormone receptor-negative cancers can only receive palliative therapy. Future research is needed to better determine how these guidelines can best be implemented in limited-resource settings.


Association between anaphylaxis and anti-influenza drug use: An analysis of the Japanese Adverse Drug Event Report database.
We aimed to investigate the association between anaphylaxis and anti-influenza drug use using the Japanese Adverse Drug Event Report (JADER) database, a national spontaneous reporting database in Japan. We surveyed registered cases from the JADER database between April 2004 and November 2019. The target drugs were five anti-influenza drugs, namely oseltamivir, zanamivir, peramivir, laninamivir, and baloxavir. Adverse events associated with anaphylaxis, "anaphylactic reaction," "anaphylactic shock," "anaphylactoid reaction," and "anaphylactoid shock," were evaluated. The association between anaphylaxis and anti-influenza drug use was assessed by calculating the reporting odds ratio (ROR) and information component (IC) as a measure of disproportionality. Signals were considered positive if the lower limit of the 95% confidence interval (CI) of ROR was > 1, and that of IC was > 0. The number of anaphylaxis cases associated with anti-influenza drug use was 199 (0.9%). Signals were detected for inhaled laninamivir (ROR: 4.24 [95% CI: 3.06-5.88], IC: 1.83 [1.35-2.30]), intravenous peramivir (ROR: 2.97 [2.11-4.17], IC: 1.40 [0.90-1.89]), and oral baloxavir (ROR: 3.05 [2.22-4.18], IC: 1.44 [0.98-1.90]). Conversely, signals were not detected for oral oseltamivir or inhaled zanamivir. Although zanamivir and laninamivir were used as dry powder inhalers containing lactose as an additive, they differed in terms of signal detection. Our analysis indicated that the signal of anaphylaxis may varies based on the main component or dosage form of each anti-influenza drug. Appropriate use of these drugs is essential to prevent anaphylaxis and improve health status.


Unconventional microfluidics: expanding the discipline.
Since its inception, the discipline of microfluidics has been harnessed for innovations in the biomedicine/chemistry fields-and to great effect. This success has had the natural side-effect of stereotyping microfluidics as a platform for medical diagnostics and miniaturized lab processes. But microfluidics has more to offer. And very recently, some researchers have successfully applied microfluidics to fields outside its traditional domains. In this Focus article, we highlight notable examples of such "unconventional" microfluidics applications (e.g., robotics, electronics). It is our hope that these early successes in unconventional microfluidics prompt further creativity, and inspire readers to expand the microfluidics discipline.


Effects of insulin on human adipose tissue metabolism in vivo.
1. The metabolic effects of insulin on human adipose tissue were studied by combining the euglycaemic clamp technique with measurement of arteriovenous differences across the subcutaneous adipose tissue of the anterior abdominal wall. 2. Eight normal subjects were studied after an overnight fast, and for 120 min during infusion of insulin (mean arterialized plasma insulin 50-55 m-units/l). 3. During the insulin infusion, the arterialized and abdominal venous levels of both non-esterified fatty acids and glycerol fell, and the arteriovenous differences for the release of these substances narrowed. The fractional rate of re-esterification of fatty acids was around 20% in the fasting state and increased to almost 100% during hyperinsulinaemia. 4. In the fasting state the uptake of glucose and 3-hydroxybutyrate by adipose tissue could account for only 20% of the oxygen uptake. During insulin infusion, adipose tissue glucose uptake increased and could account for more than 100% of oxygen uptake, implying storage of glucose. 5. Net balances of different substrates across adipose tissue were examined by calculating fluxes in terms of microgram-atoms of carbon. In the fasting state adipose tissue was in marked negative carbon balance (because of the export of non-esterified fatty acids); during insulin infusion it just reached 'carbon balance'. These results were in contrast to those from a previous study of glucose ingestion, in which the adipose tissue showed marked positive carbon balance (net substrate deposition).


A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells.
Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over-expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism. Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression. Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-α. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R)-hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation. 12R-LOX is involved in MUC5AC expression. This occurs via ERK- and Sp1-signalling pathways.


Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse).
Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.


Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments.
Bone marrow derived cells (BMDCs) have been shown to contribute in the tumor development. In vivo animal models to investigate the role of BMDCs in tumor development are poorly explored. We established a novel chimeric mouse model using as low as 5 × 10(6) GFP+ BM cells in athymic nude mice, which resulted in >70% engraftment within 14 d. In addition, chimera was established in NOD-SCID mice, which displayed >70% with in 28 d. Since anti-angiogenic therapies (AAT) were used as an adjuvant against VEGF-VEGFR pathway to normalize blood vessels in glioblastoma (GBM), which resulted into marked hypoxia and recruited BMDCs to the tumor microenvironment (TME). We exploited chimeric mice in athymic nude background to develop orthotopic U251 tumor and tested receptor tyrosine kinase inhibitors and CXCR4 antagonist against GBM. We were able to track GFP+ BMDCs in the tumor brain using highly sensitive multispectral optical imaging instrument. Increased tumor growth associated with the infiltration of GFP+ BMDCs acquiring suppressive myeloid and endothelial phenotypes was seen in TME following treatments. Immunofluorescence study showed GFP+ cells accumulated at the site of VEGF, SDF1 and PDGF expression, and at the periphery of the tumors following treatments. In conclusion, we developed a preclinical chimeric model of GBM and phenotypes of tumor infiltrated BMDCs were investigated in context of AATs. Chimeric mouse model could be used to study detailed cellular and molecular mechanisms of interaction of BMDCs and TME in cancer.


A cytosolic copper storage protein provides a second level of copper tolerance in Streptomyces lividans.
Streptomyces lividans has a distinct dependence on the bioavailability of copper for its morphological development. A cytosolic copper resistance system is operative in S. lividans that serves to preclude deleterious copper levels. This system comprises of several CopZ-like copper chaperones and P1-type ATPases, predominantly under the transcriptional control of a metalloregulator from the copper sensitive operon repressor (CsoR) family. In the present study, we discover a new layer of cytosolic copper resistance in S. lividans that involves a protein belonging to the newly discovered family of copper storage proteins, which we have named Ccsp (cytosolic copper storage protein). From an evolutionary perspective, we find Ccsp homologues to be widespread in Bacteria and extend through into Archaea and Eukaryota. Under copper stress Ccsp is upregulated and consists of a homotetramer assembly capable of binding up to 80 cuprous ions (20 per protomer). X-ray crystallography reveals 18 cysteines, 3 histidines and 1 aspartate are involved in cuprous ion coordination. Loading of cuprous ions to Ccsp is a cooperative process with a Hill coefficient of 1.9 and a CopZ-like copper chaperone can transfer copper to Ccsp. A Δccsp mutant strain indicates that Ccsp is not required under initial copper stress in S. lividans, but as the CsoR/CopZ/ATPase efflux system becomes saturated, Ccsp facilitates a second level of copper tolerance.


User involvement in the planning and delivery of mental health services: a cross-sectional survey of service users and providers.
To identify methods for involving service users in the planning and delivery of psychiatric services and factors which may assist and impede this process. A cross-sectional postal survey of user groups and providers of psychiatric services throughout Greater London (UK). Seventeen (94%) service providers and 29 (48%) user groups responded to the survey. Service providers employed a wide variety of different methods for involving users but none met national standards for user involvement (UI). Service providers stated that the main obstacle to UI was that users who took part were not representative of local patients. User groups highlighted staff resistance as a major obstacle and 80% stated that they were not satisfied with current arrangements for UI. While users and providers of mental health services were able to identify changes resulting from UI the responsiveness of staff and the representativeness of service users may be impeding this process.


Synthetic isoflavones and doping: A novel class of aromatase inhibitors?
Anectodical information suggests that flavonoids may be widely used among athletes for their multiple biochemical and pharmacological effects. We have evaluated in vitro the effects of two synthetic isoflavones, methoxyisoflavone and ipriflavone, on the catalytic activity of human aromatase (CYP19), the enzyme catalyzing the conversion of androgens (ie, testosterone or androstenedione) to estrogens (ie, estradiol and estrone). The potential inhibitory effect was evaluated by measuring the rate of aromatization of testosterone, monitored by gas chromatography-mass spectrometry (GC-MS), both in the presence and in the absence of methoxyisoflavone or ipriflavone, comparing their effects with those of synthetic aromatase inhibitors (formestane, anastrozole, and aminoglutethimide) presently included in the list of prohibited substances and methods, and of natural flavonoids (chrysin, quercetin, and daidzein), that are known inhibitors of CYP19. The preliminary results of our in vitro study show that methoxyisoflavone and ipriflavone act as competitive inhibitors of aromatase, the degree of inhibition measured in vitro being of the same order of magnitude of that of the aromatase inhibitors commonly used in anti-estrogenic therapies. Our preliminary in vitro results indicate that, in principle, a sufficiently large intake of isoflavones could alter the kinetics of the dynamic equilibria between androgens and estrogens, suggesting their monitoring in doping control routine analysis.


The Feasibility and Acceptability of LISTEN for Loneliness.
The purpose of this paper is to present the initial feasibility and acceptability of LISTEN (Loneliness Intervention using Story Theory to Enhance Nursing-sensitive outcomes), a new intervention for loneliness. Loneliness is a significant stressor and known contributor to multiple chronic health conditions in varied populations. In addition, loneliness is reported as predictive of functional decline and mortality in large samples of older adults from multiple cultures. Currently, there are no standard therapies recommended as effective treatments for loneliness. The paucity of interventions has limited the ability of healthcare providers to translate what we know about the problem of loneliness to active planning of clinical care that results in diminished loneliness. LISTEN was developed using the process for complex intervention development suggested by the Medical Research Council (MRC) [1] [2]. Feasibility and acceptability of LISTEN were evaluated as the first objective of a longitudinal randomized trial which was set in a university based family medicine center in a rural southeastern community in Appalachia. Twenty-seven older adults [(24 women and 3 men, mean age: 75 (SD 7.50)] who were lonely, community-dwelling, and experiencing chronic illness, participated. Feasibility was evaluated by tracking recruitment efforts, enrollment, attendance to intervention sessions, attrition, and with feedback evaluations from study personnel. Acceptability was assessed using quantitative and qualitative evaluation data from participants. LISTEN was evaluated as feasible to deliver with no attrition and near perfect attendance. Participants ranked LISTEN as highly acceptable for diminishing loneliness with participants requesting a continuation of the program or development of additional sessions. LISTEN is feasible to deliver in a primary healthcare setting and has the potential to diminish loneliness which could result in improvement of the long-term negative known sequelae of loneliness such as hypertension, depression, functional decline, and mortality. Feedback from study participants is being used to inform future trials of LISTEN with consideration for developing additional sessions. Longitudinal randomized trials are needed in varied populations to assess long-term health and healthcare system benefits of diminishing loneliness, and to assess the potential scalability of LISTEN as a reimbursable treatment for loneliness.


Molecular mechanisms of normal iron homeostasis.
Humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Dietary iron absorption is regulated locally by hypoxia inducible factor (HIF) signaling and iron-regulatory proteins (IRPs) in enterocytes and systematically by hepatic hepcidin, the central iron regulatory hormone. Hepcidin not only controls the rate of iron absorption but also determines iron mobilization from stores through negatively modulating the function of ferroportin, the only identified cellular iron exporter to date. The regulation of hepatic hepcidin is accomplished by the coordinated activity of multiple proteins through different signaling pathways. Recent studies have greatly expanded the knowledge in the understanding of hepcidin expression and regulation by the bone morphogenetic protein (BMP) signaling, the erythroid factors, and inflammation. In this review, we mainly focus on the roles of recently identified proteins in the regulation of iron homeostasis.


Effect of common single-nucleotide polymorphisms in acetylsalicylic acid metabolic pathway genes on platelet reactivity in patients with diabetes.
Platelet reactivity in patients on acetylsalicylic acid (ASA) therapy can be influenced by physiological or pathological conditions affecting ASA pharmacokinetics or pharmacodynamics. The mechanism of such variability in the therapeutic response to ASA, particularly in diabetic patients, is poorly understood. The rate of elimination of ASA and its metabolite, salicylic acid (SA), is likely a major factor determining drug efficacy. The objective of this study was to investigate the effect of genetic polymorphisms in the selected candidate genes within the ASA metabolic pathway on the platelet reactivity and concentration of ASA and thromboxane A(2) (TxA(2)) metabolites in a population of patients with type 2 diabetes mellitus (T2DM). The study cohort consisted of 287 Caucasians with T2DM who had been taking ASA tablets at the dose of 75 mg per day for at least 3 months. Platelet reactivity analyses were performed using VerifyNow Aspirin and PFA-100 assays. The measured ASA metabolite included salicylic acid (ASA), and TxA(2) metabolites included serum TxB(2) and urinary 11-dh-TxB(2). Genotyping for the selected 18 single-nucleotide polymorphisms (SNPs) within 5 genes of the ASA metabolic pathway was performed using a Sequenom iPLEX platform. No statistically significant association was observed between the investigated SNPs genotypes, platelet reactivity, and measured metabolites in the investigated cohort of patients. The results of our study failed to confirm that the selected variants in the genes within the ASA metabolic pathway might contribute to platelet reactivity in a diabetic population treated with ASA.


Preparation and evaluation of spore-specific affinity-augmented bio-imprinted beads.
A novel, affinity-augmented, bacterial spore-imprinted, bead material was synthesized, based on a procedure developed for vegetative bacteria. The imprinted beads were intended as a front-end spore capture/concentration stage of an integrated biological detection system. Our approach involved embedding bead surfaces with Bacillus thuringiensis kurstaki (Bt) spores (as a surrogate for Bacillus anthracis) during synthesis. Subsequent steps involved lithographic deactivation using a perfluoroether; spore removal to create imprint sites; and coating imprints with the lectin, concanavalin A, to provide general affinity. The synthesis of the intended material with the desired imprints was verified by scanning electron and confocal laser-scanning microscopy. The material was evaluated using spore-binding assays with either Bt or Bacillus subtilis (Bs) spores. The binding assays indicated strong spore-binding capability and a robust imprinting effect that accounted for 25% additional binding over non-imprinted controls. The binding assay results also indicated that further refinement of the surface deactivation procedure would enhance the performance of the imprinted substrate.


Mental health nursing placement: A comparative study of non-traditional and traditional placement.
Professional placement experiences have been considered as an approach to improving nursing attitudes towards mental health nursing and selection of mental health nursing as a career. Mental health nursing placements are now occurring in less traditional settings, however, published research of these placements remains scarce. The aim of this non-experimental comparative study was to investigate the impact of nursing student participation in a non-traditional placement, compared to participation in traditional placement. Particular focus was on the attitudes of nursing students toward mental health nursing and career preferences. Participants of the intervention group attended the non-traditional placement, (n = 23). Participants of the comparison group attended traditional placement settings (n = 27), including placements in inpatient and community mental health. The study utilised The Preplacement Survey. Results showed significant differences in scores of the non-traditional placement Recovery Camp cohort related to reduced anxiety, reduced negative attitudes, and increased preparedness for mental health. These correlated with a comparatively increased desire to pursue a future career in mental health; albeit not a statistically significant increase. Considering mental health care, in any setting, is highly dependent on the training and ability of nurses to deliver effective service, the findings of the current study are important.


Impact of polyphenol antioxidants on cycling performance and cardiovascular function.
This investigation sought to determine if supplementation with polyphenol antioxidant (PA) improves exercise performance in the heat (31.5 °C, 55% RH) by altering the cardiovascular and thermoregulatory responses to exercise. Twelve endurance trained athletes ingested PA or placebo (PLAC) for 7 days. Consecutive days of exercise testing were performed at the end of the supplementation periods. Cardiovascular and thermoregulatory measures were made during exercise. Performance, as measured by a 10 min time trial (TT) following 50 min of moderate intensity cycling, was not different between treatments (PLAC: 292 ± 33 W and PA: 279 ± 38 W, p = 0.12). Gross efficiency, blood lactate, maximal neuromuscular power, and ratings of perceived exertion were also not different between treatments. Similarly, performance on the second day of testing, as assessed by time to fatigue at maximal oxygen consumption, was not different between treatments (PLAC; 377 ± 117 s vs. PA; 364 ± 128 s, p = 0.61). Cardiovascular and thermoregulatory responses to exercise were not different between treatments on either day of exercise testing. Polyphenol antioxidant supplementation had no impact on exercise performance and did not alter the cardiovascular or thermoregulatory responses to exercise in the heat.


Real-World Patterns of EGFR Testing and Treatment with Erlotinib for Non-Small Cell Lung Cancer in the United States.
Despite being the basis of one of the most effective interventions in lung cancer, little is known about the patterns of epidermal growth factor receptor (EGFR) mutation testing in the general population. We assessed the frequencies and determinants of EGFR testing and erlotinib treatment among a population-based sample. A random sample (n = 1,358) of patients diagnosed in 2010 with histologically-confirmed NSCLC, as reported to the Surveillance Epidemiology and End Results (SEER) program, had their medical records abstracted and treating physicians queried. Logistic regression was used to identify factors associated with EGFR testing and erlotinib treatment. Survival was examined using Cox proportional hazards regression. The frequency of EGFR testing was 16.8% overall and 22.6% for stage IV adenocarcinoma patients. Given an EGFR mutation, 33.6% of all patients and 48.3% of stage IV patients received erlotinib. Among stage IV patients, increased age, Medicaid/no/unknown insurance status, death within 2 months of diagnosis and comorbidity were inversely associated with EGFR testing; erlotinib treatment was less likely among smokers and patients with non-adenocarcinomas. EGFR-mutation was associated with improved survival, albeit only among stage IV adenocarcinomas. Less than a quarter of NSCLC patients diagnosed in 2010 received EGFR testing and less than half of the patients with EGFR-mutant stage IV tumors received erlotinib. Significant disparities were observed in EGFR mutation testing by health insurance status, comorbidity and age. A national strategy is imperative to ensure that resources and processes are in place to efficiently implement molecular testing of cancer.


β1 Integrin regulates adult lung alveolar epithelial cell inflammation.
Integrins, the extracellular matrix receptors that facilitate cell adhesion and migration, are necessary for organ morphogenesis; however, their role in maintaining adult tissue homeostasis is poorly understood. To define the functional importance of β1 integrin in adult mouse lung, we deleted it after completion of development in type 2 alveolar epithelial cells (AECs). Aged β1 integrin-deficient mice exhibited chronic obstructive pulmonary disease-like (COPD-like) pathology characterized by emphysema, lymphoid aggregates, and increased macrophage infiltration. These histopathological abnormalities were preceded by β1 integrin-deficient AEC dysfunction such as excessive ROS production and upregulation of NF-κB-dependent chemokines, including CCL2. Genetic deletion of the CCL2 receptor, Ccr2, in mice with β1 integrin-deficient type 2 AECs impaired recruitment of monocyte-derived macrophages and resulted in accelerated inflammation and severe premature emphysematous destruction. The lungs exhibited reduced AEC efferocytosis and excessive numbers of inflamed type 2 AECs, demonstrating the requirement for recruited monocytes/macrophages in limiting lung injury and remodeling in the setting of a chronically inflamed epithelium. These studies support a critical role for β1 integrin in alveolar homeostasis in the adult lung.


Regulation of male sexual behavior by progesterone receptor, sexual experience, and androgen.
Recent studies have demonstrated that physiological doses of progesterone may facilitate the androgen-dependent display of male sexual behavior in laboratory rats and three species of lizard. We used mice with a targeted disruption of the progesterone receptor to investigate whether such interactions exist in male mice and whether they may be modified by sexual experience. We found that naive intact male progesterone receptor knockout (PRKO) mice exhibit reduced mount frequencies compared to wild-type (WT) mice. Also unlike WT mice, sexually experienced PRKO males show profound losses in many measures of sexual behavior following castration. In a second experiment, we tested whether male mice heterozygous for a null mutation at the progesterone receptor locus were responsive to testosterone and progesterone treatment. We found that heterozygous males showed a reduced response to testosterone. The data are consistent with experiments indicating that the progesterone receptor is able to facilitate male-typical sex behaviors in other species and suggest novel mechanisms underlying the interaction of androgens and experience.


Functional genomics reveals diverse cellular processes that modulate tumor cell response to oxaliplatin.
Oxaliplatin is widely used to treat colorectal cancer, as both adjuvant therapy for resected disease and palliative treatment of metastatic disease. However, a significant number of patients experience serious side effects, including prolonged neurotoxicity, from oxaliplatin treatment creating an urgent need for biomarkers of oxaliplatin response or resistance to direct therapy to those most likely to benefit. As a first step to improve selection of patients for oxaliplatin-based chemotherapy, we have conducted an in vitro cell-based small interfering RNA (siRNA) screen of 500 genes aimed at identifying genes whose loss of expression alters tumor cell response to oxaliplatin. The siRNA screen identified twenty-seven genes, which when silenced, significantly altered colon tumor cell line sensitivity to oxaliplatin. Silencing of a group of putative resistance genes increased the extent of oxaliplatin-mediated DNA damage and inhibited cell-cycle progression in oxaliplatin-treated cells. The activity of several signaling nodes, including AKT1 and MEK1, was also altered. We used cDNA transfection to overexpress two genes (LTBR and TMEM30A) that were identified in the siRNA screen as mediators of oxaliplatin sensitivity. In both instances, overexpression conferred resistance to oxaliplatin. In summary, this study identified numerous putative predictive biomarkers of response to oxaliplatin that should be studied further in patient specimens for potential clinical application. Diverse gene networks seem to influence tumor survival in response to DNA damage by oxaliplatin. Finally, those genes whose loss of expression (or function) is related to oxaliplatin sensitivity may be promising therapeutic targets to increase patient response to oxaliplatin.


Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients.
Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.


Effects of organophosphate compounds on a soil protist, Colpoda inflata (Ciliophora, Colpodidae).
Many investigations on protists indicate that they play an important role in agricultural soils. We have tested the effects of three organophosphate (OP) pesticides, basudin, cidial, and fenix, on the soil ciliate Colpoda inflata, and examined its viability, fission rate, ability to excyst and extrude macronuclear chromatin into cytoplasm. Exposure to these OPs caused a dose-dependent effect on cell viability, and significantly reduced the mean fission rate at a concentration of 1/10(5) v/v. After exposure of resting cysts to 1/10(5) v/v or 1/10(6) v/v concentrations of basudin or cidial, the number of excysted cells was significantly lower than that of the controls. Conversely, exposure to a 1/10(5) v/v fenix concentration did not affect excystment and exposure to 1/10(6) v/v was found to promote excystment. Moreover, exposure to these OPs (1/10(4) v/v or 1/10(5) v/v) interferred with the ability to extrude macronuclear chromatin. The median lethal concentration in 60 min for each OPs tested was at least a hundred times lower than the doses recommended by the manufacturer. Finally, as the inhibition of cholinesterase (ChE) activity is the first target of OPs, the presence of ChE activity was checked in C. inflata. Three ChE activities were found, hydrolyzing the substrates acetyl-beta-methyl thiocholine iodide, propionyl thiocholine iodide and butyryl thiocholine iodide, that appeared to be very low and not inhibited by OP-exposure.


Reliable change in postconcussive symptoms and its functional consequences among children with mild traumatic brain injury.
OBJECTIVE To examine reliable change in postconcussive symptoms and its functional consequences among children with mild traumatic brain injury (TBI) over the first year postinjury as compared with children with orthopedic injuries. DESIGN Prospective, longitudinal cohort. SETTING Emergency departments at 2 children's hospitals. PARTICIPANTS Eight- to 15-year-old children with mild TBI (n = 186) or orthopedic injuries (n = 99). MAIN EXPOSURE Closed-head or orthopedic trauma. MAIN OUTCOME MEASURES Parents rated preinjury symptoms retrospectively shortly after injury and postconcussive symptoms at 2 weeks and 3 and 12 months postinjury. A regression-based approach was used to determine whether each child displayed reliable increases in postconcussive symptoms at each postinjury occasion. Health-related quality of life was assessed at 3 and 12 months postinjury. Information regarding children's educational programming was collected at the initial and 12-month assessments. RESULTS Children with mild TBI were significantly more likely than those with orthopedic injuries to show reliable increases in both cognitive and somatic symptoms. Group differences in the likelihood of reliable increases became less common with time for somatic symptoms but persisted to 12 months postinjury for cognitive symptoms. Among children with mild TBI, reliable increases in symptoms were more common among children with loss of consciousness or abnormalities on neuroimaging. Reliable increases in symptoms were associated with significant declines in health-related quality of life and an increased likelihood of educational intervention. CONCLUSION Many children with mild TBI show reliable increases in postconcussive symptoms that are associated with significant functional impairment in their daily lives.


Medical informatics: past, present, future.
To reflect about medical informatics as a discipline. To suggest significant future research directions with the purpose of stimulating further discussion. Exploring and discussing important developments in medical informatics from the past and in the present by way of examples. Reflecting on the role of IMIA, the International Medical Informatics Association, in influencing the discipline. Medical informatics as a discipline is still young. Today, as a cross-sectional discipline, it forms one of the bases for medicine and health care. As a consequence considerable responsibility rests on medical informatics for improving the health of people, through its contributions to high-quality, efficient health care and to innovative research in biomedicine and related health and computer sciences. Current major research fields can be grouped according to the organization, application, and evaluation of health information systems, to medical knowledge representation, and to the underlying signal and data analyses and interpretations. Yet, given the fluid nature of many of the driving forces behind progress in information processing methods and their technologies, progress in medicine and health care, and the rapidly changing needs, requirements and expectations of human societies, we can expect many changes in future medical informatics research. Future research fields might range from seamless interactivity with automated data capture and storage, via informatics diagnostics and therapeutics, to living labs with data analysis methodology, involving sensor-enhanced ambient environments. The role of IMIA, the International Medical Informatics Association, for building a cooperative, strongly connected, and research-driven medical informatics community worldwide can hardly be underestimated. Health care continuously changes as the underlying science and practice of health are in continuous transformation. Medical informatics as a discipline is strongly affected by these changes and is in a position to be a key, active contributor in these changes.


Multidimensional internal dynamics underlying the perception of motion.
When ambiguous visual stimuli are presented continuously, they often lead to oscillations between usually two perceptions. Because of these oscillations, it has been thought that the underlying neural dynamics also arises from a binary or two-state system. Contradicting the binary assumption, it has been shown recently that the perception of some ambiguous stimuli is governed by continuously varying internal states, measured as biases that differ considerably from one observer to the next and that can also evolve over time (Wexler, Duyck, & Mamassian, 2015). Here I study bias patterns in the motion quartet, an ambiguous apparent motion stimulus, as the quartet's orientation is varied. The bias patterns are robustly idiosyncratic, and are even more complex than those that have been described previously. There are two qualitatively different bias types: Some observers prefer a translation axis, while others show preference for a rotation direction. Each type also varies parametrically: the orientation of the preferred axis, and the direction of preferred rotation. There are also clear cases of combination of the two bias types. When measured repeatedly over 9 hr, the bias patterns usually remain stable, but also sometimes evolve both parametrically (e.g., change of preferred axis), as well as across bias type (change from axial to rotational bias). Control experiments revealed that the variety of bias patterns observed across subjects, and their changes over time, are not due to voluntary decisions. Overall, these results exhibit the multidimensional complexity of internal states underlying the perception of even simple stimuli.


Nonlinear sequence similarity between the Xist and Rsx long noncoding RNAs suggests shared functions of tandem repeat domains.
The marsupial inactive X chromosome expresses a long noncoding RNA (lncRNA) called Rsx that has been proposed to be the functional analog of eutherian Xist Despite the possibility that Xist and Rsx encode related functions, the two lncRNAs harbor no linear sequence similarity. However, both lncRNAs harbor domains of tandemly repeated sequence. In Xist, these repeat domains are known to be critical for function. Using k-mer based comparison, we show that the repeat domains of Xist and Rsx unexpectedly partition into two major clusters that each harbor substantial levels of nonlinear sequence similarity. Xist Repeats B, C, and D were most similar to each other and to Rsx Repeat 1, whereas Xist Repeats A and E were most similar to each other and to Rsx Repeats 2, 3, and 4. Similarities at the level of k-mers corresponded to domain-specific enrichment of protein-binding motifs. Within individual domains, protein-binding motifs were often enriched to extreme levels. Our data support the hypothesis that Xist and Rsx encode similar functions through different spatial arrangements of functionally analogous protein-binding domains. We propose that the two clusters of repeat domains in Xist and Rsx function in part to cooperatively recruit PRC1 and PRC2 to chromatin. The physical manner in which these domains engage with protein cofactors may be just as critical to the function of the domains as the protein cofactors themselves. The general approaches we outline in this report should prove useful in the study of any set of RNAs.


The fate of conference abstracts: systematic review and meta-analysis of surgical treatments for men with benign prostatic enlargement.
From the literature search for a government-commissioned systematic review on surgical treatments for benign prostatic enlargement (BPE), we identified the relevant conference abstracts of randomised controlled trials (RCTs) which failed to reach full publication and their data were not utilised. We aimed to ascertain, first, the reasons of failure to reach full publication and second, to estimate the impact of including the abstracts' data. A two-part study, consisting of a questionnaire survey and a sensitivity analysis of the above said review. An ad hoc questionnaire was sent to each author of the relevant abstracts, as to determine the reasons of failure to reach full publication. The data from the abstracts were then extracted and incorporated into sensitivity analysis of the review. Forty-seven questionnaires were completed for 47 abstracts. Of these abstracts, 32 of them were claimed to have reached full publication. A number of reasons of failure to reach full publication were identified, for example: 'being written up' and 'lack of time'. Utilizable, relevant data were obtained from eight of the 47 abstracts, and put into sensitivity analysis. There were small changes in effect sizes and directions for three of 14 reviews' secondary outcomes. Common reasons of failure to reach full publication were also identified in the context for the BPE review. Inclusion of abstract data did not affect primary outcome defined in the original review. Identification, summarisation of conference abstracts and other grey literature should form an essential exercise for any systematic review.


Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized.
This study is a prospective, controlled clinical and electrophysiologic trial examining the chronic course of posttraumatic sleep-wake disturbances (SWD). We screened 140 patients with acute, first-ever traumatic brain injury of any severity and included 60 patients for prospective follow-up examinations. Patients with prior brain trauma, other neurologic or systemic disease, drug abuse, or psychiatric comorbidities were excluded. Eighteen months after trauma, we performed detailed sleep assessment in 31 participants. As a control group, we enrolled healthy individuals without prior brain trauma matched for age, sex, and sleep satiation. In the chronic state after traumatic brain injury, sleep need per 24 hours was persistently increased in trauma patients (8.1 ± 0.5 hours) as compared to healthy controls (7.1 ± 0.7 hours). The prevalence of chronic objective excessive daytime sleepiness was 67% in patients with brain trauma compared to 19% in controls. Patients significantly underestimated excessive daytime sleepiness and sleep need, emphasizing the unreliability of self-assessments on SWD in trauma patients. This study provides prospective, controlled, and objective evidence for chronic persistence of posttraumatic SWD, which remain underestimated by patients. These results have clinical and medicolegal implications given that SWD can exacerbate other outcomes of traumatic brain injury, impair quality of life, and are associated with public safety hazards.


Prevalence of alcohol use in pregnant women with substance use disorder.
Prenatal care programs for women with opioid use disorder (OUD) often focus treatment/counseling plans around illicit substances, while concurrent use of alcohol might present an equal or greater risk to the fetus. This study evaluated self-reported prevalence of alcohol use in patients participating in a comprehensive prenatal care program for women with substance use disorder (SUD; n = 295), of which 95% are treated for OUD, and pregnant women being served through general obstetrical clinics at the University of New Mexico (n = 365). During the screening phase of a prospective study, patients were asked to report alcohol use in the periconceptional period, and between the last menstrual period and pregnancy recognition. The screening interview was conducted at 22.3 (median = 22; Q1 = 16; Q3 = 29) gestational weeks. Among patients screened at the SUD clinic, 28.8% and 24.1% reported at least one binge drinking episode in the periconceptional period and in early pregnancy, respectively. The prevalence of binge drinking was similar in the general obstetrics population (24.7% and 24.4%, respectively). Among those who reported drinking in early pregnancy, median number of binge drinking episodes was higher among patients screened at the SUD clinic (median = 3; Q1 = 1; Q3 = 10) compared to the general obstetrics group (median = 1; Q1 = 1; Q3 = 3; p < 0.001). This study demonstrates a high prevalence of prenatal alcohol use in early pregnancy in both groups, while patients with SUD/OUD consume more alcohol. These findings underscore the need for targeted screening and intervention for alcohol use in all pregnant women, especially those with SUD/OUD.


Angiogenesis: a marker for neoplastic transformation of mammary papillary hyperplasia.
Mouse mammary papillomas elicit new formation of vessels when transplanted onto the rabbit iris. This angiogenic capacity is a property of carcinomas but not of the resting mammary gland. In mouse papillary hyperplasias, however, this property appears much earlier than any morphological or clinical sign of carcinoma. A test for angiogenic capacity may reveal a step in the progression toward clinical malignancy and thus could be used to screen for neoplastic potential of hyperplastic epithelium in biopsy tissues.


Differences in circulating MMP-9 levels with regard to viral load and AST:ALT ratio between chronic hepatitis B and C patients.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the two major causes of chronic liver inflammation, fibrosis and cirrhosis. They have the ability to cause persistent infection in susceptible hosts and severely damage liver function. Matrix metalloproteinase-9 (MMP-9) is one of the gelatinases that may be important in liver fibrosis. This study aims to evaluate whether or not MMP-9 in relation to viral load is involved in the development of liver dysfunction in HBV and HCV Blood samples from 20 patients chronically infected with HBV and 30 with HCV, along with 15 healthy individuals as controls, were investigated. Viral load was assessed by real-time polymerase chain reaction (PCR). Serum MMP-9 levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Alanine transaminase and aspartate aminotransferase (ALT and AST) activities were measured spectrophotometrically. Levels of MMP-9 were significantly higher in HCV than in HBV patients (P < 0.01), and positively correlated with HBV viral load (r = 0.842, P < 0.01) and AST:ALT ratio (r = 0.614, P < 0.05). Conversely, MMP-9 levels did not correlate with HCV viral load but did correlate with AST:ALT ratio (r = 0.652, P < 0.01). Therefore, MMP-9 levels could reflect progressive liver damage in HBV and HCV infection. However, a distinction between the pathological mechanism of HCV and HBV is suggested, as HCV probably promotes hepatocyte damage and fibrosis through mechanisms other than replication. Continuous expression of the HBV genome through replication and secretion of viral antigens may contribute to the transcriptional regulation of MMP-9, thus promoting liver damage and fibrosis.


Gender differences in endurance performance by elite cross-country skiers are influenced by the contribution from poling.
Greater gender differences have been found in exercise modes where the upper body is involved. Therefore, the present study investigated the influence of poling on gender differences in endurance performance by elite cross-country skiers. Initially, the performance of eight male and eight female sprint skiers was compared during four different types of exercise involving different degrees of poling: double poling (DP), G3 skating, and diagonal stride (DIA) techniques during treadmill roller skiing, and treadmill running (RUN). Thereafter, DP was examined for physiological and kinematic parameters. The relative gender differences associated with the DP, G3, DIA and RUN performances were approximately 20%, 17%, 14%, and 12%, respectively. Thus, the type of exercise exerted an overall effect on the relative gender differences (P < 0.05). In connection with DP, the men achieved 63%, 16%, and 8% higher VO2peak than the women in absolute terms and with normalization for total and fat-free body mass (all P < 0.05). The DP VO2peak in percentage of VO2max in RUN was higher in men (P < 0.05). The gender difference in DP peak cycle length was 23% (P < 0.05). In conclusion, the present investigation demonstrates that the gender difference in performance by elite sprint skiers is enhanced when the contribution from poling increases.


Social Disadvantage, Severe Child Abuse, and Biological Profiles in Adulthood.
Guided by the stress process model and the life course perspective, we hypothesize: (1) that childhood abuse is concentrated, in terms of type and intensity, among socially disadvantaged individuals, and (2) that experiencing serious abuse contributes to poor biological profiles in multiple body systems in adulthood. Data came from the Biomarker subsample of Midlife in the United States (2004-2006). We used latent class analysis to identify distinct profiles of childhood abuse, each reflecting a combination of type and severity. Results indicate that disadvantaged groups, women, and those from disadvantaged families are at greater risk of experiencing more severe and multiple types of abuse. Those with more severe and multifaceted childhood abuse show greater physiological dysregulation. Childhood abuse experiences partially accounted for the social status differences in physiological profiles. Our findings underscore that differential exposure to serious childhood stressors plays a significant role in gender and class inequalities in adult health.


Reactive oxygen species-regulating proteins peroxiredoxin 2 and thioredoxin, and glyceraldehyde-3-phosphate dehydrogenase are differentially abundant in induced sputum from smokers with lung cancer or asbestos exposure.
Lung cancer is a deadly disease, typically caused by known risk factors, such as tobacco smoke and asbestos exposure. By triggering cellular oxidative stress and altering the antioxidant pathways eliminating reactive oxygen species (ROS), tobacco smoke and asbestos predispose to cancer. Despite easily recognizable high-risk individuals, lung cancer screening and its early detection are hampered by poor diagnostic tools including the absence of proper biomarkers. This study aimed to recognize potential lung cancer biomarkers using induced sputum noninvasively collected from the lungs of individuals in risk of contracting lung cancer. Study groups composed of current and former smokers, who either were significantly asbestos exposed, had lung cancer, or were unexposed and asymptomatic. Screening of potential biomarkers was performed with 52, and five differentially abundant proteins, peroxiredoxin 2 (PRDX2), thioredoxin (TXN), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), extracellular matrix protein 1 (ECM1), and protein S100 A8 (S100A8), were chosen to undergo validation, for their previously known connection with oxidative stress or cancer. Results from the validation in 123 sputa showed that PRDX2, TXN, and GAPDH were differentially abundant in sputa from individuals with lung cancer. TXN had a negative correlation with asbestos exposure, yet a positive correlation with smoking and lung cancer. Thus, tobacco smoking, asbestos exposure, and lung carcinogenesis may disturb the cellular redox state in different ways. A strong correlation was found among PRDX2, TXN, GAPDH, and S100A8, suggesting that these proteins may present a diagnostic biomarker panel to aid recognizing individuals at high risk of contracting lung cancer.