Serum coding and non-coding RNAs as biomarkers of NAFLD and fibrosis severity.
In patients with non-alcoholic fatty liver disease (NAFLD), liver biopsy is the gold standard to detect non-alcoholic steatohepatitis (NASH) and stage liver fibrosis. We aimed to identify differentially expressed mRNAs and non-coding RNAs in serum samples of biopsy-diagnosed mild and severe NAFLD patients with respect to controls and to each other. We first performed a whole transcriptome analysis through microarray (n = 12: four Control: CTRL; four mild NAFLD: NAS ≤ 4 F0; four severe NAFLD NAS ≥ 5 F3), followed by validation of selected transcripts through real-time PCRs in an independent internal cohort of 88 subjects (63 NAFLD, 25 CTRL) and in an external cohort of 50 NAFLD patients. A similar analysis was also performed on liver biopsies and HepG2 cells exposed to oleate:palmitate or only palmitate (cellular model of NAFL/NASH) at intracellular/extracellular levels. Transcript correlation with histological/clinical data was also analysed. We identified several differentially expressed coding/non-coding RNAs in each group of the study cohort. We validated the up-regulation of UBE2V1, BNIP3L mRNAs, RP11-128N14.5 lncRNA, TGFB2/TGFB2-OT1 coding/lncRNA in patients with NAS ≥ 5 (vs NAS ≤ 4) and the up-regulation of HBA2 mRNA, TGFB2/TGFB2-OT1 coding/lncRNA in patients with Fibrosis stages = 3-4 (vs F = 0-2). In in vitro models: UBE2V1, RP11-128N14.5 and TGFB2/TGFB2-OT1 had an increasing expression trend ranging from CTRL to oleate:palmitate or only palmitate-treated cells both at intracellular and extracellular level, while BNIP3L was up-regulated only at extracellular level. UBE2V1, RP11-128N14.5, TGFB2/TGFB2-OT1 and HBA2 up-regulation was also observed at histological level. UBE2V1, RP11-128N14.5, BNIP3L and TGFB2/TGFB2-OT1 correlated with histological/biochemical data. Combinations of TGFB2/TGFB2-OT1 + Fibrosis Index based on the four factors (FIB-4) showed an Area Under the Curve (AUC) of 0.891 (P = 3.00E-06) or TGFB2/TGFB2-OT1 + Fibroscan (AUC = 0.892, P = 2.00E-06) improved the detection of F = 3-4 with respect to F = 0-2 fibrosis stages. We identified specific serum coding/non-coding RNA profiles in severe and mild NAFLD patients that possibly mirror the molecular mechanisms underlying NAFLD progression towards NASH/fibrosis. TGFB2/TGFB2-OT1 detection improves FIB-4/Fibroscan diagnostic performance for advanced fibrosis discrimination.


Measurements of human breast cancer using magnetic resonance spectroscopy: a review of clinical measurements and a report of localized 31P measurements of response to treatment.
A review of the literature has shown that in human breast tumours, large signals from phosphomonoesters (PME) and phosphodiesters (PDE) are evident. In serial measurements in 19 patients with breast cancer, a decrease in PME was significantly associated with a stable or responding disease (p = 0.017), and an increase in PME was associated with disease progression. Extract studies have shown PME to comprise of phosphoethanolamine (PEth) and phosphocholine (PCho), with the PEth to PCho ratio ranging from 1.3 to 12. The PCho content of high grade tumours was found to be higher than low grade tumours. In some animal models, changes in PCho have been shown to correlate with indices of cellular proliferation, and spheroid studies have shown a decrease in PCho content in spheroids with smaller growth fractions. A serial study of 25 patients with advanced primary breast tumours undergoing hormone, chemotherapy or radiotherapy treatments, showed that in this heterogenous group there were significant changes in metabolites that were seen during the first 3 weeks (range 2-4 weeks) of treatment, that correlated with volume change over this period, employed here as a measure of response. Changes in PME (p = 0.003), total phosphate (TP) (p = 0.008) and total nucleoside tri-phosphate (TNTP) (p = 0.02) over 3 (+/-1) weeks were significantly associated with response, as were the levels of PME (p<0.001), PDE (p = 0.01), TP (p = 0.001) and TNTP (p = 0.007) at week 3 (+/-1). PME at week 3 (+/-1) was also significantly associated with the best volume response to treatment (p = 0.03). A reproducibility analysis of results from the observation of normal breast metabolism in four volunteers showed a mean coefficient of variation of 25%, after correcting for changes resulting from the menstrual cycle. Reproducibility studies in four patients with breast cancer showed a mean coefficient of variation of 33%, with the reproducibility being better in patients measured on different days (difference in TP was -6%) compared with those measured on the same day (difference in TP was -29%).


Reproducible evaluation of classification methods in Alzheimer's disease: Framework and application to MRI and PET data.
A large number of papers have introduced novel machine learning and feature extraction methods for automatic classification of Alzheimer's disease (AD). However, while the vast majority of these works use the public dataset ADNI for evaluation, they are difficult to reproduce because different key components of the validation are often not readily available. These components include selected participants and input data, image preprocessing and cross-validation procedures. The performance of the different approaches is also difficult to compare objectively. In particular, it is often difficult to assess which part of the method (e.g. preprocessing, feature extraction or classification algorithms) provides a real improvement, if any. In the present paper, we propose a framework for reproducible and objective classification experiments in AD using three publicly available datasets (ADNI, AIBL and OASIS). The framework comprises: i) automatic conversion of the three datasets into a standard format (BIDS); ii) a modular set of preprocessing pipelines, feature extraction and classification methods, together with an evaluation framework, that provide a baseline for benchmarking the different components. We demonstrate the use of the framework for a large-scale evaluation on 1960 participants using T1 MRI and FDG PET data. In this evaluation, we assess the influence of different modalities, preprocessing, feature types (regional or voxel-based features), classifiers, training set sizes and datasets. Performances were in line with the state-of-the-art. FDG PET outperformed T1 MRI for all classification tasks. No difference in performance was found for the use of different atlases, image smoothing, partial volume correction of FDG PET images, or feature type. Linear SVM and L2-logistic regression resulted in similar performance and both outperformed random forests. The classification performance increased along with the number of subjects used for training. Classifiers trained on ADNI generalized well to AIBL and OASIS. All the code of the framework and the experiments is publicly available: general-purpose tools have been integrated into the Clinica software (www.clinica.run) and the paper-specific code is available at: https://gitlab.icm-institute.org/aramislab/AD-ML.


Neurofilament-tubulin binding site peptide NFL-TBS.40-63 increases the differentiation of oligodendrocytes in vitro and partially prevents them from lysophosphatidyl choline toxiciy.
During multiple sclerosis (MS), the main axon cystoskeleton proteins, neurofilaments (NF), are altered, and their release into the cerebrospinal fluid correlates with disease severity. The role of NF in the extraaxonal location is unknown. Therefore, we tested whether synthetic peptides corresponding to the tubulin-binding site (TBS) sequence identified on light NF chain (NFL-TBS.40-63) and keratin (KER-TBS.1-24), which could be released during MS, modulate remyelination in vitro. Biotinylated NFL-TBS.40-63, NFL-Scramble2, and KER-TBS.1-54 (1-100 μM, 24 hr) were added to rat oligodendrocyte (OL) and astrocyte (AS) cultures, grown in chemically defined medium. Proliferation and differentiation were characterized by using specific antibodies (A2B5, CNP, MBP, GFAP) and compared with untreated cultures. Lysophosphatidyl choline (LPC; 2 × 10(-5) M) was used to induce OL death and to test the effects of TBS peptides under these conditions. NFL-TBS.40-63 significantly increased OL differentiation and maturation, with more CNP(+) and MBP(+) cells characterized by numerous ramified processes, along with myelin balls. When OL were challenged with LPC, concomitant treatment with NFL-TBS.40-63 rescued more than 50% of OL compared with cultures treated with LPC only. Proliferation of OL progenitors was not affected, nor were AS proliferation and differentiation. NFL-TBS.40-63 peptide induces specific effects in vitro, increasing OL differentiation and maturation without altering AS fate. In addition, it partially protects OL from demyelinating injury. Thus release of NFL-TBS.40-63 caused by axonal damage in vivo could improve repair through increased OL differentiation, which is a prerequisite for remyelination.


[Mathematical modeling of protein loss during prolonged blood loss].
The dependence of protein losses on the initial condition and experimental conditions were studied in dogs on a model of repeated bloodletting. Various animals have an intensive increase in this value in the beginning and a gradual decrease at later stages. Four mathematical models adequately describing changes in losses depending on the number of bloodlettings and duration of arterial pressure compensation phase have been suggested.


The effects of sodium butyrate on lymphokine production.
The effect of sodium butyrate on lymphokine production in WEHI-3, LBRM-33, and JURKAT cells, as well as an IL-2-dependent T cell line (I) was studied. Constitutive production of IL-3 by WEHI-3 cells was enhanced by sodium butyrate and was accompanied by the growth arrest of WEHI-3 cells in the G1 phase of the cell cycle. Treatment of I cells with ConA and sodium butyrate led to an increase in IL-3 production and the initiation of IL-2 production. In contrast, the synthesis of IL-2 and IL-3 by the ConA-activated T lymphoma line LBRM-33 was coordinately inhibited by sodium butyrate. Similarly, the synthesis of IL-2 by the human T cell lymphoma JURKAT was inhibited by sodium butyrate. No cell cycle-specific effects of sodium butyrate were observed in LBRM-33 or JURKAT cells.


The Relationship between Body Mass Index and Risk of Failure following Meniscus Repair.
It is unknown whether body mass index (BMI) influences outcomes of meniscus repair. We hypothesized that increased BMI would be associated with increased risk of failure. A retrospective study was performed involving patients who had undergone meniscus repair between 2008 and 2012. Chart review and phone interviews were conducted to determine which patients required additional surgery. Patients were categorized as normal BMI (<25) or increased BMI (≥25). Of the 305 patients who met study criteria, 216 (70.8%) were available for follow-up at a mean of 19 months postoperatively. A total of 100 patients (46.3%) had a BMI <25 and 116 (53.7%) patients had a BMI ≥25. BMI was less than 35 in 90% of patients. Thirty-four patients (15.7%) required further surgery for a repair failure. Failure occurred in 20 patients (20%) in the normal BMI group and 14 patients (12%) in the increased BMI group (p = 0.14). Logistic regression revealed a trend toward decreased odds of repair failure in the increased BMI group (odds ratio: 0.46; 95% confidence interval: 0.20-1.05; p = 0.065). Patients with a BMI ≥25 did not have a higher risk of meniscus repair failure relative to those with a BMI <25. Given these findings, surgeons should not consider moderately increased BMI as a contraindication to meniscal repair. The effect of BMI greater than 35 on outcomes of meniscal repair remains unclear and warrants further study.


Investigating the Relationship Between Blood Pressure and Serum FGF23 Level in Patients Undergoing Hemodialysis in Guilan Province, A Cross Sectional Study.
The aim of current study is investigation of theimpact of serum FGF23 levels on blood pressure of patients withend-stage renal disease (ESRD) undergoing hemodialysis. Based on registry, 68 patients who underwent hemodialysis(HD) in the dialysis center of Shahid Beheshti hospital, Anzali,north of Iran, from April 2016 to May 2017 were enrolled. Enzyme-Linked ImmunoSorbent Assay (ELISA) was used to determineserum FGF23 levels. 24 hours blood pressure monitoring method,AMBB, was used to monitor the mean arterial pressure of patients.Spearman related analysis method was used to statistically analyzethe correlation of serum FGF23 level with mean arterial pressure,age, HD duration, kt/v, URR weight gaining, cause of ESRD, andthe mentioned laboratory parameters. Serum FGF23 levels of ESRD patients were not significantlyrelated to age, time of HD and gaining weight. Furthermore,these parameters were not related to blood pressure. However,FGF23 expression levels in serum were positively correlated withphosphorous and calcium- phosphorous. The mentioned laboratoryparameters had no significant correlation with 24 hours bloodpressure changes. Meanwhile, the minimum diastolic pressureand intact parathyroid hormone (iPTH) level showed a significantdirect linear correlation. We suggest that understanding relationship betweenphosphate, FGF23 and cardiovascular disease can be applied intargeted phosphate-based treatment. Kidney failure and the nondippercondition may be highly related to one another and leadto ESRD. Therefore, a special investment in controlling bloodpressure and examining it with a tool such as ABPM can greatlyhelp patients to progress effectively.


Rattle-type Fe(3)O(4)@SiO(2) hollow mesoporous spheres as carriers for drug delivery.
Rattle-type Fe(3)O(4)@SiO(2) hollow mesoporous spheres with different particle sizes, different mesoporous shell thicknesses, and different levels of Fe(3)O(4) content are prepared by using carbon spheres as templates. The effects of particle size and concentration of Fe(3)O(4)@SiO(2) hollow mesoporous spheres on cell uptake and their in vitro cytotoxicity to HeLa cells are evaluated. The spheres exhibit relatively fast cell uptake. Concentrations of up to 150 microg mL(-1) show no cytotoxicity, whereas a concentration of 200 microg mL(-1) shows a small amount of cytotoxicity after 48 h of incubation. Doxorubicin hydrochloride (DOX), an anticancer drug, is loaded into the Fe(3)O(4)@SiO(2) hollow mesoporous spheres, and the DOX-loaded spheres exhibit a somewhat higher cytotoxicity than free DOX. These results indicate the potential of Fe(3)O(4)@SiO(2) hollow mesoporous spheres for drug loading and delivery into cancer cells to induce cell death.


Two adenine nucleotide translocase paralogues involved in cell proliferation and spermatogenesis in the silkworm Bombyx mori.
Mitochondrial adenine nucleotide translocase (ANT) specifically acts in ADP/ATP exchange through the mitochondrial inner membrane. This transporter protein thereby plays a significant role in energy metabolism in eukaryotic cells. Most mammals have four paralogous ANT genes (ANT1-4) and utilize these paralogues in different types of cells. The fourth paralogue of ANT (ANT4) is present only in mammals and reptiles and is exclusively expressed in testicular germ cells where it is required for meiotic progression in the spermatocytes. Here, we report that silkworms harbor two ANT paralogues, the homeostatic paralogue (BmANTI1) and the testis-specific paralogue (BmANTI2). The BmANTI2 protein has an N-terminal extension in which the positions of lysine residues in the amino acid sequence are distributed as in human ANT4. An expression analysis showed that BmANTI2 transcripts were restricted to the testis, suggesting the protein has a role in the progression of spermatogenesis. By contrast, BmANTI1 was expressed in all tissues tested, suggesting it has an important role in homeostasis. We also observed that cultured silkworm cells required BmANTI1 for proliferation. The ANTI1 protein of the lepidopteran Plutella xylostella (PxANTI1), but not those of other insect species (or PxANTI2), restored cell proliferation in BmANTI1-knockdown cells suggesting that ANTI1 has similar energy metabolism functions across the Lepidoptera. Our results suggest that BmANTI2 is evolutionarily divergent from BmANTI1 and has developed a specific role in spermatogenesis similar to that of mammalian ANT4.


A knowledge-based method for protein structure refinement and prediction.
The native conformation of a protein, in a given environment, is determined entirely by the various interatomic interactions dictated by the amino acid sequence (1-3). We describe here a knowledge-based approach for protein structure assessment and prediction. Using a well-defined set of high-resolution protein structures, we have derived statistical potentials, in the form of atom-pairwise distance probability density functions. These provide a description of pairwise interatomic interactions of native proteins. When applied to highly randomized and noisy structures of proteins distinct from the basis set, native-like structures were obtained to very high precision (< or = 2A). The examples tested include proteins of all sizes (from 38 up to 461 amino acids long) and diverse topological structures (alpha, beta and alpha-beta classes). The potentials appear to be sensitive enough to recognize subtle distortions from a native packing structure and in optimization of structures drive them consistently to a higher probability. Therefore they provide a powerful tool for refinement of X-ray and NMR derived structures at arbitrary degrees of initial precision.


Cinnamon improves glucose and lipids of people with type 2 diabetes.
The objective of this study was to determine whether cinnamon improves blood glucose, triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels in people with type 2 diabetes. A total of 60 people with type 2 diabetes, 30 men and 30 women aged 52.2 +/- 6.32 years, were divided randomly into six groups. Groups 1, 2, and 3 consumed 1, 3, or 6 g of cinnamon daily, respectively, and groups 4, 5, and 6 were given placebo capsules corresponding to the number of capsules consumed for the three levels of cinnamon. The cinnamon was consumed for 40 days followed by a 20-day washout period. After 40 days, all three levels of cinnamon reduced the mean fasting serum glucose (18-29%), triglyceride (23-30%), LDL cholesterol (7-27%), and total cholesterol (12-26%) levels; no significant changes were noted in the placebo groups. Changes in HDL cholesterol were not significant. The results of this study demonstrate that intake of 1, 3, or 6 g of cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type 2 diabetes and suggest that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases.


Comparison between provocative test-based and long-term intraocular pressure parameters in patients with stable open-angle glaucoma.
To compare provocative test-based and long-term intraocular pressure variation parameters in patients with stable open-angle glaucoma. A prospective observational study was carried out in which stable open-angle glaucoma patients (⩾3 years of follow-up without any changes on current medical regimen) were consecutively enrolled. All patients were submitted to a water-drinking test. Long-term intraocular pressure parameters were obtained from isolated intraocular pressure measurements from each visit (⩾5 visits). We investigated the correlation and agreement between the following water-drinking test and long-term intraocular pressure parameters: mean, peak, and fluctuation. In addition, the percentage of eyes with significant intraocular pressure peaks during the water-drinking test (defined as a difference ⩾25% between water-drinking test intraocular pressure peak and mean long-term intraocular pressure) was assessed. Sixty-three eyes from 63 open-angle glaucoma patients (mean age, 60.7 ± 11.8 years) were included. Mean and water-drinking test intraocular pressure peak correlated significantly with mean (r = 0.67) and maximum long-term intraocular pressure (r = 0.52), respectively (p < 0.01). The correlation between water-drinking test intraocular pressure fluctuation and long-term intraocular pressure fluctuation was not significant (p = 0.45). Limits of agreement from Bland-Altman plots exceeded the maximum allowed difference between methods (3 mm Hg) for all the intraocular pressure parameters analyzed, suggesting poor agreement between water-drinking test-derived and long-term intraocular pressure values. Overall, significant water-drinking test intraocular pressure peaks were observed in 39.7% of these eyes with stable open-angle glaucoma. Although some water-drinking test-based and long-term intraocular pressure parameters correlate significantly, water-drinking test results may not reflect the long-term intraocular pressure profile of stable open-angle glaucoma patients, as their agreement is poor. Many of these patients may experience significant water-drinking test intraocular pressure peaks, despite long-standing stable disease and unchanged medical regimen.


Clinical relevance of dual-energy X-ray absorptiometry (DXA) as a simultaneous evaluation of fatty liver disease and atherosclerosis in patients with type 2 diabetes.
Whole body dual-energy X-ray absorptiometry (DXA) can simultaneously measure both regional fat and non-fat mass. Android-to-gynoid (A/G) ratio measured by DXA has been reported to be associated with cardiovascular risks and visceral adiposity; however, little is known regarding its relationship with fatty liver disease and atherosclerosis among patients with diabetes. This study was designed to investigate the association of android and gynoid fat mass measured by DXA with fatty liver disease and atherosclerosis in patients with type 2 diabetes. This is a cross-sectional study of 259 patients with type 2 diabetes (mean age 64 ± 13 years; 40.2 % female). Android and gynoid fat mass (kg) were measured by DXA. Skeletal muscle index (SMI) was calculated as appendicular non-fat mass (kg) divided by height (m(2)). Visceral fat area (VFA, cm(2)), subcutaneous fat area (SFA, cm(2)), and liver attenuation index (LAI) were assessed by abdominal computed tomography. Intima media thickness (IMT, mm) in common carotid arteries was determined by carotid ultrasonography. A/G ratio was significantly correlated with VFA (r = 0.72, p < 0.001), SFA (r = 0.32, p < 0.001) and LAI (r = -0.26, p < 0.001). A/G ratio (standardized β -0.223, p = 0.002) as well as VFA (standardized β -0.226, p = 0.001) were significantly associated with LAI in the univariate model. A/G ratio remained to be significantly associated with LAI (standardized β -0.224, p = 0.005) after adjusting for covariates including body mass index and transaminases. Among patients with low SMI (SMI < 7.0 in male and < 5.4 in female), A/G ratio was significantly associated with carotid IMT in the multivariate model (standardized β 0.408, p = 0.014). DXA can be used to simultaneously estimate the risks for both fatty liver disease and atherosclerosis in patients with type 2 diabetes.


Cardiac radiation dose distribution, cardiac events and mortality in early-stage lung cancer treated with stereotactic body radiation therapy (SBRT).
The impact of radiation dose to the heart in early-stage lung cancer patients treated with definitive stereotactic body radiation therapy (SBRT) is not well known. We, therefore, analyzed whether higher radiation dose to the heart would lead to an increase in cardiac toxicity and overall mortality. Seventy-four patients with 75 tumors treated definitively with SBRT for early-stage non-small cell lung cancer (NSCLC) and two cases of limited-stage small cell lung cancer (SCLC) with an average follow-up of 35 months (range, 1-130 months) were retrospectively analyzed. The whole heart and cardiac substructures including atria, ventricles, heart valves, atrioventricular (AV) node and four major coronary artery branches were contoured using commercial treatment planning software. For each structure, multiple dose-volume parameters were recorded. The relation between radiation doses to the heart, tumor location, and preexisting medical conditions with the development of cardiac events and mortality was assessed. Overall, there was large variability in dose to cardiac substructures: mean heart dose (MHD) averaged 1.90 Gy (range, 0.04-11.00 Gy) equivalent 2 Gy dose (EQD2) and average max dose to the left anterior descending artery (LAD) was 5.67 Gy (range, 0.04-48.60 Gy) EQD2. Patients with tumor location in the upper lobes received higher cardiac radiation dose compared to other lobes (P<0.0001). There was no difference in MHD between central and peripheral tumor locations. The distance between heart and tumor was negatively associated with MHD (r=-0.61, P<0.0001). Eighteen patients developed cardiac complications including the need for defibrillator placement, arrhythmia development and worsening heart failure. Preexisting cardiac disease was associated with an increased number of cardiac events after radiotherapy (P=0.039). However, neither radiation dose to the whole heart or the cardiac substructures, nor comorbidities such as diabetes, hypercholesterolemia, hypertension or COPD were associated with the number of cardiac events or overall mortality. Radiation doses to the heart and its substructures show large variability. Cardiac events occurred more frequently in patients with a history of heart problems. At present, the effect of radiation dose on cardiac toxicity is unclear in patients undergoing SBRT for early-stage lung cancer. Longer follow-up and a larger cohort are needed to assess for late cardiac sequelae.


Effect of Sapthaparna (Alstonia scholaris Linn) in modulating the benzo(a)pyrene-induced forestomach carcinogenesis in mice.
The chemopreventive effect of various doses of hydroalcoholic extract of Alstonia scholaris (ASE) was studied on the benzo(a)pyrene (BaP) induced forestomach carcinoma in female mice. The treatment of mice with different doses, i.e. 1, 2 and 4 mg/ml ASE in drinking water before, during and after the treatment with carcinogen, exhibited chemopreventive activity. The highest activity was observed for 4 mg/ml ASE, where the tumor incidence (93.33%) was reduced by 6.67%. Similarly, the tumor multiplicity reduced (61.29%) significantly (P<0.02) at 4 mg/ml in the pre-post-ASE treated group. However, the pre or post-treatment of mice with 4 mg/ml ASE did not show chemopreventive activity. These findings are corroborated by micronucleus assay, where treatment of mice with ASE before, during and after carcinogen treatment reduced the frequency of micronuclei (MN) in the splenocytes in a dose dependent manner. The MN frequency reached a nadir at 4 mg/ml ASE, the highest drug dose which showed maximum chemopreventive action. The ASE treatment not only reduced the frequency of splenocytes bearing one MN but also cells bearing multiple MN indicating the efficacy of ASE in inhibiting mutagenic changes induced by BaP. The pre or post-treatment of mice with 4 mg/ml ASE also significantly reduced the frequency of BaP-induced MN in the splenocytes of treated animals.


Hereditary hemochromatosis: implications for South Dakota physicians.
Hereditary Hemochromatosis (HH) still causes debate among health professionals regarding appropriateness of diagnostic and screening tools. The Hemochromatosis gene (HFE) was discovered in 1996 and is now recognized to cause the majority of HH cases. A C282Y missense mutation in the HFE gene causes up to 90 percent of HH cases. In northern European populations, prevalence of heterozygosity is estimated to be as high as 10 percent, with symptomatic iron overload developing in as many as one in 200 to 300. Many guidelines regarding population screening have been proposed. It is especially important to strike a balance between allocation of healthcare resources and patient well-being in areas such as South Dakota with a large northern European and high proportion of Medicare and Medicaid patient population. This article outlines a reasonable approach to diagnosis and management for primary care physicians in South Dakota centered on a prototypical case review.


Delineating the cytogenomic and epigenomic landscapes of glioma stem cell lines.
Glioblastoma multiforme (GBM), the most common and malignant type of glioma, is characterized by a poor prognosis and the lack of an effective treatment, which are due to a small sub-population of cells with stem-like properties, termed glioma stem cells (GSCs). The term "multiforme" describes the histological features of this tumor, that is, the cellular and morphological heterogeneity. At the molecular level multiple layers of alterations may reflect this heterogeneity providing together the driving force for tumor initiation and development. In order to decipher the common "signature" of the ancestral GSC population, we examined six already characterized GSC lines evaluating their cytogenomic and epigenomic profiles through a multilevel approach (conventional cytogenetic, FISH, aCGH, MeDIP-Chip and functional bioinformatic analysis). We found several canonical cytogenetic alterations associated with GBM and a common minimal deleted region (MDR) at 1p36.31, including CAMTA1 gene, a putative tumor suppressor gene, specific for the GSC population. Therefore, on one hand our data confirm a role of driver mutations for copy number alterations (CNAs) included in the GBM genomic-signature (gain of chromosome 7- EGFR gene, loss of chromosome 13- RB1 gene, loss of chromosome 10-PTEN gene); on the other, it is not obvious that the new identified CNAs are passenger mutations, as they may be necessary for tumor progression specific for the individual patient. Through our approach, we were able to demonstrate that not only individual genes into a pathway can be perturbed through multiple mechanisms and at different levels, but also that different combinations of perturbed genes can incapacitate functional modules within a cellular networks. Therefore, beyond the differences that can create apparent heterogeneity of alterations among GSC lines, there's a sort of selective force acting on them in order to converge towards the impairment of cell development and differentiation processes. This new overview could have a huge importance in therapy.


[Quality and availability of care for people with mental disorders – assessment of health care providers].
The aim of this study was to identify the opinions of mental health care providers on the quality of their services. The study was based on the opinions of mental health care providers. The study included facilities of the West Pomeranian province in Poland. A diagnostic survey was chosen as the research method. The questionnaire -based interview was carried out in facilities located in Szczecin. In other facilities the survey was carried out and the questionnaire was sent by post after prior calls. The study used a specially designed questionnaire which was based on quality categories proposed by Maxwell. In all categories of quality respondents most frequently indicated "high" and "average" scores. The "low" score was rarely reported. The best rated category of quality is justice in access to services. As many as 93.3% of respondents gave the highest rating to this category, and 6.7% rated it as average. The second best assessed category was the competence of personnel. As many as 80.0% of respondents representing health care centres rated personnel competence as high. The third top -rated category of quality was the effectiveness of services, or the provision of services in accordance with current knowledge and current scienti􀏐ic reports. As many as 76.7% of respondents rated the effectiveness of their services as high. The lowest rated category of quality was the adaptation of buildings to the needs of patients, and the safety of procedures. 1. Representatives of psychiatric care facilities highly rated the quality of services provided by their facility. 2. Top -rated quality categories were justice in access to services, personnel competence, and ef􀏐iciency of the services. 3. The lowest rated categories were the adaptation of facilities to the needs of patients, and the safety of procedures.


Grain, sugar and biomass accumulation in photoperiod-sensitive sorghums. II. Biochemical processes at internode level and interaction with phenology.
Sugar accumulation in sorghum (Sorghum bicolor (L.) Moench) stems is a complex trait that is particularly plastic in response to photoperiod. This study investigated sucrose accumulation in a sterile (no grain filling) and fertile near-isogenic line of the photoperiod-sensitive cultivar IS2848 in two greenhouse experiments. Variable phenology was induced by applying a short (12-h PP) and a long (13-h PP) photoperiod. Dynamics of plant growth, phenology, sugar accumulation and related enzyme activities in internodes were investigated. Under 13-h PP, plants flowered 28 days later and attained threefold higher sucrose concentration at anthesis compared with those under 12-h PP. Sucrose accumulation in individual internodes was driven by organ physiological age, not by plant phenology. Competition with grain filling was marginal but greater under 12-h PP (i.e. when sucrose accumulation in internodes occurred after flowering). Enzyme activities showed marked developmental patterns but contributed little to explaining differences between treatments and genotypes. The study demonstrates that sucrose storage physiology in sweet sorghum resembles that of sugarcane (Saccharum spp.) but is more complex due to photoperiod effects on phenology. It confirms the field results on 14 sorghum genotypes contrasting for phenology and photoperiod sensitivity presented in a companion paper. Perspectives for developing sorghum ideotype concepts for food and fuel crops are discussed.


Nicotine dependence in women.
Cigarette smoking is the most preventable cause of death in the United States, accounting for the deaths of approximately 140,000 women annually. Despite the known health risks, women continue to begin and continue smoking at high rates. Like other addictive drugs, nicotine becomes reinforcing with repeated use, induces euphoric sensations, and is self-administered. Tolerance to nicotine's effects develops rapidly and leads to increased use. Reducing or suppressing tobacco consumption produces a withdrawal syndrome characterized by irritability, difficulty concentrating, cognitive impairments, and weight gain. These withdrawal symptoms, along with other factors, lead to relapse rates comparable to those following cessation from other addictive drugs. This review article discusses the pathogenesis of nicotine addiction compared to other addictive substances such as cocaine and heroin with an effort to provide comparative data for men and women.


Gastric residual volume measurement in British neonatal intensive care units: a survey of practice.
Despite little evidence, the practice of routine gastric residual volume (GRV) measurement to guide enteral feeding in neonatal units is widespread. Due to increased interest in this practice, and to examine trial feasibility, we aimed to determine enteral feeding and GRV measurement practices in British neonatal units. An online survey was distributed via email to all neonatal units and networks in England, Scotland and Wales. A clinical nurse, senior doctor and dietitian were invited to collaboratively complete the survey and submit a copy of relevant guidelines. 95/184 (51.6%) approached units completed the survey, 81/95 (85.3%) reported having feeding guidelines and 28 guidelines were submitted for review. The majority of units used intermittent (90/95) gastric feeds as their primary feeding method. 42/95 units reported specific guidance for measuring and interpreting GRV. 20/90 units measured GRV before every feed, 39/90 at regular time intervals (most commonly four to six hourly 35/39) and 26/90 when felt to be clinically indicated. Most units reported uncertainty on the utility of aspirate volume for guiding feeding decisions; 13/90 reported that aspirate volume affected decisions 'very much'. In contrast, aspirate colour was reported to affect decisions 'very much' by 37/90 of responding units. Almost half, 44/90, routinely returned aspirates to the stomach. Routine GRV measurement is part of standard practice in British neonatal units, although there was inconsistency in how frequently to measure or how to interpret the aspirate. Volume was considered less important than colour of the aspirate.


Demands of professional cycling races: Influence of race category and result.
This study analyses the influence of race category and result on the demands of professional cycling races. In total, 2920 race files were collected from 20 male professional cyclists, within a variety of race categories: Single-day (1.WT) and multi-day (2.WT) World Tour races, single-day (1.HC) and multi-day (2.HC) Hors Catégorie races and single-day (1.1) and multi-day (2.1) category 1 races. Additionally, the five cycling "monuments" were analysed separately. Maximal mean power outputs (MMP) were measured across a broad range of durations. Volume and load were large to very largely (d = 1.30-4.80) higher in monuments compared to other single-day race categories. Trivial to small differences were observed for most intensity measures between different single-day race categories, with only RPE and sRPE·km-1 being moderately (d = 0.70-1.50) higher in the monuments. Distance and duration were small to moderately (d = 0.20-0.80) higher in 2.WT races compared to 2.HC and 2.1 multi-day race categories with only small differences in terms of load and intensity. Generally, higher ranked races (i.e. Monuments, 2.WT and GT) tend to present with lower shorter-duration MMPs (e.g. 5-120 sec) compared to races of "lower rank" (with less differences and/or mixed results being present over longer durations), potentially caused by a "blunting" effect of the higher race duration and load of higher ranked races on short duration MMPs. MMP were small to largely higher over shorter durations (<5 min) for a top-10 result compared to no top-10, within the same category.


[Influence of industrial and traffic pollution on reproduction of spermatophytes].
A review of studies conducted, primarily, in Europe in last 30 years that deal with influence of anthropogenic environmental pollution on functioning of reproductive and, by comparison, vegetative organs of spermatophytes is presented. In the papers considered the impacts of typical industrial and traffic pollutants (compounds of iron, zinc, copper, lead, chromium, cadmium, as well as sulfur dioxide, ozone, polycyclic aromatic hydrocarbons) on plants via soil, water, air, and precipitation have been studied. Special attention is paid to effects of heavy metals on embryological structures and processes in staminate and pistillate reproductive spheres of plants (archesporium, meiosis, sporogenesis, gametophytogenesis, morphology and functioning of gametophyte, endospermogenesis, embryogenesis). Detrimental effects of anthropogenic pollution on reproductive sphere of spermatophytes are manifested through disorder in processes of cells fission and differentiation, abnormality in structures development at early stages of morphogenesis, broadening of anomalies spectrum, decrease in pollen fertility, derangement of seed-bearing and germination.


[Clinical efficacy of the drug enerion in the treatment of patients with psychogenic (functional) erectile dysfunction].
Twenty patients with psychogenic erectile dysfunction received the drug enerion (Hungary). After a 30-day course of enerion erectile function improved in 16 of the above patients. A mean value of the international index of erectile function (IIEF) increased in them from 17.5 to 24.8 points. Improvement of cavernous arterial blood flow after the treatment was seen in 3 of 6 patients with arterial disorders. As shown by electromyographic examinations, cavernous electric activity normalized in 8 patients. Thus, psychogenic erectile dysfunction can be effectively treated with enerion.


[Use of antibiotic-resistant Bifidobacterium in treating ulcerative-necrotic enterocolitis in young children].
Ulceronecrotic colitis in premature children is accompanied by the development of pronounced intestinal dysbacteriosis characterized by a sharp increase in the number of Escherichia, enterococci, staphylococci and the appearance of opportunistic enterobacteria (Klebsiella, Serratia, Citrobacter, Proteus) in large amounts. Clinical convalescence was observed in 2 weeks in children receiving antibiotic-resistant bifidobacteria with antibiotics and in 3-4 weeks in children receiving commercial bifidobacteria with antibiotics, while children treated only with antibiotics showed no signs of clinical convalescence during the whole course of treatment. After the course of treatment the most effective recovery of the intestinal microflora was observed in the group of patients who had received antibiotics in combination with antibiotic-resistant bifidobacteria. It was manifested by a decrease in the number of Escherichia, Klebsiella, Proteus, Serratia, staphylococci and enterococci simultaneously with an increase in the number of endogenous lactobacilli and bifidobacteria. In those children who had received commercial bifidobacteria in combination with antibiotics or had been treated only with antibiotics the process of the recovery of the intestinal microflora was considerably less pronounced than in the patients of the first group; a decrease in the number of Escherichia, Klebsiella, Proteus and Serratia occurred to a lesser extent, and at the same time an essential increase in the number of enterococci and staphylococci was observed. The level of endogenous lactobacilli and bifidobacteria was considerably reduced. Antibiotic-resistant bifidobacteria actively took in the intestine of the patients. On day 5 after the course of treatment was over their level was (4.3 +/- 0.4) X 10(4) cells/g feces.


Adverse childhood experiences and suicidal behavior of adolescent psychiatric inpatients.
The present study examines the association of adverse childhood experiences (ACEs) to suicidal behavior and mortality in 508 Finnish adolescents (aged 12-17 years) who required acute psychiatric hospitalization between April 2001 and March 2006. The Schedule for Affective Disorder and Schizophrenia for School-Age Children Present and Lifetime (K-SADS-PL) and the European Addiction Severity Index (EuropASI) were used to obtain information about ACEs, adolescents' suicidal behavior and psychiatric diagnoses. The cases of death were obtained from Statistics Finland. The results of our study indicated that, among girls, exposure to sexual abuse statistically significantly increased the risk of non-suicidal self-injury (NSSI) (OR, 1.8; 95 % CI, 1.0-3.2) and suicide attempts (OR, 2.3; 95 % CI, 1.0-4.5). The cumulative number of ACEs was also associated with an increased risk of NSSI (OR, 1.2; 95 % CI, 1.0- 1.4) and suicide attempts (OR, 1.2; 95 % CI, 1.0-1.4) in girls. Among all deceased adolescents, ACEs were most notable among those who had died due to accidents and injuries. Gender differences in the types of ACEs were noted and discussed.


Absence of Missense Variant Detection in Inherited Dysfibrinogenemia May Result from a Poor Raw Data Analysis Algorithm or Mosaicism.
Variant identification underlying inherited dysfibrinogenemia quite exceptionally fails. We report on two dysfibrinogenemia cases whose underlying DNA variant could not be identified by Sanger analysis. These failures result from two distinct mechanisms. The first case involved raw signal overcorrection by a built-in software, and the second constituted the first description of mosaicism for one of the fibrinogen genes. This mosaicism was subsequently identified by next-generation sequencing reanalysis of the sample.


Interspecific variation in functional traits in relation to species climatic niche optima in Andean Polylepis (Rosaceae) tree species: evidence for climatic adaptations.
Plant functional traits can be genetically determined or phenotypically plastic. We assessed the degree of genetic determinism in the functional traits of Andean Polylepis tree species among 14 important traits that enable the species to withstand cold and dry conditions. We conducted a common garden experiment and related the species-specific means of the functional traits to the variables of climatic niche optima of the species (mean annual temperature and annual precipitation), deducing that if the interspecific variation in the functional trait is related to the species climatic niche optima according to the theoretically-expected pattern of climate-trait relationship, the variation of the trait must be genetically determined. In general, the traits were related either to species temperature or precipitation optima. For example, leaf size, maximum photosynthesis rate and root tip abundance were related to temperature, whereas light compensation and light saturation points were related to precipitation. Only leaf size showed a significant phylogenetic signal, indicating that most of the manifested climate-trait relationships are not caused purely by phylogeny, but are mainly a result of species specialisation along an environmental gradient. However, in many cases the relationships were rather weak. This suggests that important functional traits of Polylepis species involve both genetic and phenotypic components aiming to maximise the overall fitness of the species at high elevations.


Role of natural killer cells in the mechanism of the antitumor effect of interferon on Moloney sarcoma virus-transformed cells.
The growth of tumors induced by inoculation of cells transformed by Moloney sarcoma virus can be inhibited by in situ administration of interferon (IFN) beginning one day after tumor challenge and continuing for 2 or 3 additional days. Inhibition of tumor growth by IFN was associated with a marked augmentation of natural killer (NK) cell activity, both in the spleen and at the site of tumor challenge, by day 5 after tumor challenge. However, using optimal conditions for IFN treatment, depletion of NK cells by in vivo treatment with anti-asialo GM1 prior to tumor challenge had no significant effect on inhibition of tumor growth by IFN. When the tumor load was greater or when IFN treatment was shorter, treatment with anti-asialo-GM1 partially abrogated the inhibition of tumor growth by IFN. In vitro assays gave no evidence of IFN enhancement of specific T-cell or activated macrophage antitumor effect. These results suggest that under optimal treatment conditions, the mechanism of the antitumor effect of IFN was independent of augmentation of NK activity, but under suboptimal conditions NK cells play a role in the mechanism of the antitumor effect of IFN.


How to perform meaningful estimates of genetic effects.
Although the genotype-phenotype map plays a central role both in Quantitative and Evolutionary Genetics, the formalization of a completely general and satisfactory model of genetic effects, particularly accounting for epistasis, remains a theoretical challenge. Here, we use a two-locus genetic system in simulated populations with epistasis to show the convenience of using a recently developed model, NOIA, to perform estimates of genetic effects and the decomposition of the genetic variance that are orthogonal even under deviations from the Hardy-Weinberg proportions. We develop the theory for how to use this model in interval mapping of quantitative trait loci using Halley-Knott regressions, and we analyze a real data set to illustrate the advantage of using this approach in practice. In this example, we show that departures from the Hardy-Weinberg proportions that are expected by sampling alone substantially alter the orthogonal estimates of genetic effects when other statistical models, like F2 or G2A, are used instead of NOIA. Finally, for the first time from real data, we provide estimates of functional genetic effects as sets of effects of natural allele substitutions in a particular genotype, which enriches the debate on the interpretation of genetic effects as implemented both in functional and in statistical models. We also discuss further implementations leading to a completely general genotype-phenotype map.


Changes in Perceived Accessibility to Healthcare from the Elderly between 2005 and 2014 in China: An Oaxaca-Blinder Decomposition Analysis.
Elderly people are characterized with high needs for healthcare, accompanied by high barriers in access to healthcare. This study aimed to identify temporal changes in access to healthcare and determinants of such changes from the elderly in China, over the period between 2005 and 2014. Two waves (2005 and 2014) of data were extracted from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), measuring changes in perceived accessibility to healthcare when needed by the elderly (≥65 years). The effects of the explanatory variables (need, predisposing and enabling factors) on the changes were divided into two components using the Oaxaca-Blinder decomposition method: (1) the endowment portion as a result of distribution differences of the explanatory variables and (2) the coefficient portion as a result of differential responses of the dependent variable to the explanatory variables. Perceived accessibility to healthcare from the elderly increased from 89.6% in 2005 to 96.7% in 2014. The coefficient portion (82%) contributed more to the change than the endowment portion (63%) after adjustments for a negative interaction effect (-45%) between the two. Lower perceived accessibility was associated with older age, lower income, lower affordability of daily expenses and lower insurance coverage. But the coefficient effects suggested that their impacts on perceived accessibility to healthcare declined over time. By contrast, the impacts of gender and out-of-pocket payment ratio for medical care on perceived accessibility to healthcare increased over time. Perceived accessibility to healthcare from the elderly improved between 2005 and 2014. Gender gaps are closing. But the increased effect of out-of-pocket medical payments on perceived accessibility to healthcare deserves further investigation and policy interventions.


[A perinatal diagnostic problem: patients serologically negative but infected with HIV].
Comprehensive HIV diagnosis of 142 patients was done by ELISA, IgG immunoblot, IgA immunoblot (in patients under 24 months), plasma antigen determination, viral isolation by culture and genome detection by polymerase chain reaction (PCR) amplification. Results showed that 14 patients (10%) with negative or indefinite results for anti-HIV-1 IgG antibody were in fact infected by the virus. Eleven of these patients were between 2 and 24 months of age, two between 4 and 6.5 years and one was 30 years old. Diagnosis was obtained by antigen positivity in four of them; by PCR amplification of peripheral mononuclear cells of proviral DNA in five of them; by PCR and immunofluorescence (IF) of cultured cells in four cases, and the last diagnosis was made by IgG immunoblot and IF of the viral culture. These cases pose a problem because of false negative HIV serology, particularly in patients under 24 months of age.


Axonal transport in the motor neurons of rats with neuropathy induced by p-bromophenylacetylurea.
Axonal transport was studied in sciatic motor neurons of rats with neuropathy induced by p-bromophenylacetylurea (BPAU) in dimethylsulfoxide solution. Control rats were treated with the vehicle alone. To label rapidly transported proteins, the rats received an injection of 35S-methionine into the ventral horn of the spinal cord at the L1 vertebral level. Radiolabeled protein was collected at ligatures applied on the sciatic nerve at intervals thereafter. In animals with severe motor weakness owing to treatment with BPAU, 400 mg/kg, there was evidence of increased delivery of labeled protein into the axon during the early period after isotope injection, but reduced delivery later. A dose-dependent decrease in the amount of labeled protein recirculated by retrograde axonal transport was also noted. A significant reduction in the amount of protein transported retrogradely was also detected during the latent subclinical phase of the neuropathy. The velocity of rapid anterograde transport, examined in unligated sciatic nerves, was unaffected by BPAU treatment. However, the lag time between precursor injection and the onset of transport was shorter in BPAU-treated rats than in controls. This effect was not explainable on the basis of fluctuations in core body temperature. The results are consistent with the view that disturbances of rapid anterograde and retrograde transport play a role in the peripheral neurotoxicity of BPAU. Attention is directed to the possibility that the transport disturbances and the subsequent neuropathy are related to alterations in the processing of rapidly transported membrane-limited organelles in the nerve cell bodies.


Luminescent S-doped carbon dots: an emergent architecture for multimodal applications.
A facile route has been developed to synthesise and isolate sulphur doped fluorescent carbon dots for the first time. Such carbogenic quantum dots exhibit a wide band gap of 4.43 eV with a high open circuit voltage (VOC) of 617 mV along with a fill factor (FF) as high as 37%, using phenyl-C60-butyric acid methyl ester (PCBM) as the electron transporting layer. Besides the wide band gap, which is useful in the fabrication of solar cells, sulphur modified carbon dots also exhibit a high fluorescence quantum yield of 11.8% without any additional surface passivation, producing a unique fluorescent probe for further applications. In addition, the particles have a strong tendency to interact with the surface of gold nanoparticles and produce a thin fluorescent layer over their surfaces. Moreover, as they are completely biocompatible in nature, the highly fluorescent S-doped carbon dots have a strong potential for use in bioimaging applications. Interestingly, owing to the presence of oxygen and sulphur functionality, the highly negatively charged particles can easily bind with positively charged DNA-PEI complexes, simply by mixing them, and after interaction with DNA, bright blue fluorescence has been observed under an excitation wavelength of 405 nm .


Gene expression is altered in the lateral hypothalamus upon activation of the mu opioid receptor.
The lateral hypothalamus (LH) is a brain structure that controls hedonic properties of both natural rewards and drugs of abuse. Mu opioid receptors are known to mediate drug reward, but whether overstimulation of these receptors impacts on LH function has not been studied. Here we have used a genome-wide microarray approach to identify LH responses to chronic mu opioid receptor activation at the transcriptional level. We have subjected wild-type and mu opioid receptor knockout mice to an escalating morphine regimen, which produces severe physical dependence in wild-type but not mutant animals. We have analyzed gene profiles in LH samples using the 430A.2 Affymetrix array and identified a set of 25 genes whose expression is altered by morphine in wild-type mice only. The regulation was confirmed for a subset of these genes using real-time quantitative PCR on samples from independent treatments. Altered expression of aquaporin 4, apolipoprotein D, and prostaglandin synthase is indicative of modified LH physiology. The regulation of two signaling genes (the serum glucocorticoid kinase and the regulator of G protein signaling 4) suggests that neurotransmission is altered in LH circuitry. Finally, the downregulation of apelin may indicate a potential role for this neuropeptide in opioid signaling and hedonic homeostasis. Altogether, our study shows that chronic mu opioid receptor stimulation induces gene expression plasticity in the LH and provides a unique collection of mu opioid receptor-dependent genes that potentially contribute to alter reward processes in addictive diseases.


Rac1 and AMPK Account for the Majority of Muscle Glucose Uptake Stimulated by Ex Vivo Contraction but Not In Vivo Exercise.
Exercise bypasses insulin resistance to increase glucose uptake in skeletal muscle and therefore represents an important alternative to stimulate glucose uptake in insulin-resistant muscle. Both Rac1 and AMPK have been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transport is unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transport in isolated muscles with AMPK loss of function combined with either pharmacological inhibition or genetic deletion of Rac1.Muscle-specific knockout (mKO) of Rac1, a kinase-dead α2 AMPK (α2KD), and double knockout (KO) of β1 and β2 AMPK subunits (β1β2 KO) each partially decreased contraction-stimulated glucose transport in mouse soleus and extensor digitorum longus (EDL) muscle. Interestingly, when pharmacological Rac1 inhibition was combined with either AMPK β1β2 KO or α2KD, contraction-stimulated glucose transport was almost completely inhibited. Importantly, α2KD+Rac1 mKO double-transgenic mice also displayed severely impaired contraction-stimulated glucose transport, whereas exercise-stimulated glucose uptake in vivo was only partially reduced by Rac1 mKO with no additive effect of α2KD. It is concluded that Rac1 and AMPK together account for almost the entire ex vivo contraction response in muscle glucose transport, whereas only Rac1, but not α2 AMPK, regulates muscle glucose uptake during submaximal exercise in vivo.


A quantum chemical approach to the design of chiral negative index materials.
This paper presents methodology developed for the computational modeling and design of negative refractive index materials (NIMs) based on molecular chirality. An application of the methodology is illustrated by ab initio computations on two organometallic molecules which constitute the monomer units of a chiral polymer. Comparisons with experimental data for the polymer are made. Even though the resulting chirality parameter for the pristine material is small, it is shown that negative index can be achieved by introducing sharp plasmonic resonances with metal nanoparticle inclusions.


Utilization of multiple-dilution fluorescence fingerprint facilitates prediction of chemical attributes in spice extracts.
Fluorescence Fingerprint (FF) is a powerful tool for rapid quality assessment of various foods and plant-derived products. However, the conventional utilization of FFs measured at a single dilution level (DL) to substitute chemical analyses is extremely challenging, especially for multicomponent materials like spice extracts because fluorescence intensity and concentration widely differ between components, with complex phenomena like inner filter effects. Here, we proposed a new strategy to use the meta-data comprised of FFs measured at multiple DLs with machine learning to estimate common chemical attributes including total polyphenol and flavonoid contents, and antioxidant abilities. This strategy achieved more consistently satisfactory performance in estimation of all chemical attributes of spice extracts compared to using a single DL. Hence, the workflow employed in this study is expected to serve as an alternative method to quickly evaluate the chemical quality of spice extracts, as well as other plant products and food materials.


Lipid droplet accumulation occurs early following Salmonella infection and contributes to intracellular bacterial survival and replication.
Salmonellosis is a public health problem caused by Salmonella sp., a highly adapted facultative intracellular pathogen. After internalization, Salmonella sp. Manipulates several host processes, mainly through the activation of the type III secretion system (T3SS), including modification of host lipid metabolism and lipid droplet (LD) accumulation. LDs are dynamic and complex lipid-rich organelles involved in several cellular processes. The present study investigated the mechanism involved in LD biogenesis in Salmonella-infected macrophages and its role in bacterial pathogenicity. Here, we reported that S. Typhimurium induced a rapid time-dependent increase of LD formation in macrophages. The LD biogenesis was demonstrated to depend on Salmonella's viability and SPI1-related T3SS activity, with the participation of Toll-Like Receptor (TLR) signaling. We also observed that LD accumulation occurs through TLR2-dependent signaling and is counter-regulated by TLR4. Last, the pharmacologic modulation of LD formation by inhibiting diacylglycerol O-acyltransferase 1 (DGAT1) and cytosolic phospholipase A2 (cPLA2) significantly reduced the intracellular bacterial proliferation and impaired the prostaglandin E2 (PGE2 ) synthesis. Collectively, our data suggest the role of LDs on S. typhimurium intracellular survival and replication in macrophages. This data set provides new perspectives for future investigations about LDs in host-pathogen interaction.


Salt tolerance of the halophyte Limonium delicatulum is more associated with antioxidant enzyme activities than phenolic compounds.
In this work we studied the effect of salinity (ranging from 50 to 500mM NaCl) on the physiological and the antioxidant responses of the local halophyte Limonium delicatulum Kuntze. We based our analysis on 12 biochemical assays that are commonly used to measure the antioxidant responses under stress such as oxidative stress markers, enzymes activities and polyphenolic compounds. Our aim was to study parameters that are strongly correlated with the growth response to salinity. Results showed two different growth responses depending on the concentration of NaCl in the medium. Under 50 to 200mM, the growth was stimulated before it decreased significantly at 300-500mM. L. delicatulum revealed a good aptitude to maintain photosynthetic machinery by increasing the concentrations of photosynthetic pigments, which is essential for the stabilisation of photosystems and the photosynthesis process under optimal NaCl concentration. Their breakdown at higher salinity decreased the photosynthetic performance of plants resulting in growth inhibition. Moreover, to reduce the damaging effect of oxidative stress and to tolerate the accumulation of salt ions, L. delicatulum induced the activities of their antioxidant enzymes more than their contents in polyphenolic compounds.


Low concentrations of selenium in stream food webs of eastern Canada.
Herbivorous and predatory invertebrates and two species of fish (brook trout and blacknose dace) were collected from 49 streams in New Brunswick, Canada to determine whether concentrations of selenium (Se) in the biota were affected by a point source (a coal-fired power plant), and stream water chemistry (pH, sulphate, conductivity, and total organic carbon), and to determine the trophic transfer of Se through these food webs. Total Se concentrations in the biota were generally low (0.2 to 4.8 μg g(-1) dry weight) across sites and there was no relationship between distance from the coal-fired power plant and Se concentrations in invertebrates or fishes. Water chemistry was an equally poor predictor of Se concentrations in invertebrates and fish. Trophic position (determined using δ(15)N) was a significant predictor of Se concentrations in only five of the stream food webs, and two of these had negative slopes, indicating little or no trophic magnification across most systems; many fishes had lower concentrations than their invertebrate prey and trophic transfer was higher at sites with low invertebrate Se concentrations. Variability in Se concentrations in fishes was explained more by site of capture than microhabitat use within the site (as measured with δ(13)C), suggesting among-site differences in geological sources of Se. Because concentrations were below known toxicity thresholds for fish and other consumers, these results suggest that Se is not an environmental issue in New Brunswick streams that do not receive direct inputs from mining activities.


Attention-based deep clustering method for scRNA-seq cell type identification.
Single-cell sequencing (scRNA-seq) technology provides higher resolution of cellular differences than bulk RNA sequencing and reveals the heterogeneity in biological research. The analysis of scRNA-seq datasets is premised on the subpopulation assignment. When an appropriate reference is not available, such as specific marker genes and single-cell reference atlas, unsupervised clustering approaches become the predominant option. However, the inherent sparsity and high-dimensionality of scRNA-seq datasets pose specific analytical challenges to traditional clustering methods. Therefore, a various deep learning-based methods have been proposed to address these challenges. As each method improves partially, a comprehensive method needs to be proposed. In this article, we propose a novel scRNA-seq data clustering method named AttentionAE-sc (Attention fusion AutoEncoder for single-cell). Two different scRNA-seq clustering strategies are combined through an attention mechanism, that include zero-inflated negative binomial (ZINB)-based methods dealing with the impact of dropout events and graph autoencoder (GAE)-based methods relying on information from neighbors to guide the dimension reduction. Based on an iterative fusion between denoising and topological embeddings, AttentionAE-sc can easily acquire clustering-friendly cell representations that similar cells are closer in the hidden embedding. Compared with several state-of-art baseline methods, AttentionAE-sc demonstrated excellent clustering performance on 16 real scRNA-seq datasets without the need to specify the number of groups. Additionally, AttentionAE-sc learned improved cell representations and exhibited enhanced stability and robustness. Furthermore, AttentionAE-sc achieved remarkable identification in a breast cancer single-cell atlas dataset and provided valuable insights into the heterogeneity among different cell subtypes.


Helicobacter pylori eradication: a randomized prospective study of triple therapy versus triple therapy plus lactoferrin and probiotics.
Helicobacter pylori is causally associated with gastritis and peptic ulcer diseases. Recent data (meta-analysis) have demonstrated that triple therapy with amoxicillin, clarithromycin, and a proton pump inhibitor has an eradication rate of only 74-76% and new therapeutic protocols may be necessary. The aim of this study was to examine whether adding bovine lactoferrin (bLf) and probiotics (Pbs) to the standard triple therapy for H. pylori infection could improve the eradication rate and reduce side effects. H. pylori infection was diagnosed in 206 patients: in 107 based on an upper endoscopy exam and a rapid urease test, and in 99 by means of the H. pylori stool antigen-test and the C(13) urea breath test (C(13) UBT). The patients were randomized into two groups: 101 patients (group A) underwent standard triple eradication therapy (esomeprazole, clarithromycin, amoxicillin), while 105 patients (group B) underwent a modified eradication therapy (standard triple eradication therapy plus bLf and Pb). Successful eradication therapy was defined as a negative C(13) UBT 8 wk after completion of the treatment. Results were evaluated by intention-to-treat (ITT) and per-protocol (PP) analysis. Data were evaluated and considered positive when P<0.05. At the end of the study 175/206 patients showed negative C(13) UBT results. According to intention-to-treat analysis, the infection was eradicated in 73/101 patients from Group A and in 93/105 from Group B. PP analysis showed 73/96 patients from Group A and 93/101 from Group B to have been successfully treated. More patients from group A than from group B reported side effects from their treatment (P<0.05). The results of our study suggest that the addition of bLf and Pbs could improve the standard eradication therapy for H. pylori infection--bLf serving to increase the eradication rate and Pbs to reduce the side effects of antibiotic therapy.


Hand specific representations in language comprehension.
Theories of embodied cognition argue that language comprehension involves sensory-motor re-enactments of the actions described. However, the degree of specificity of these re-enactments as well as the relationship between action and language remains a matter of debate. Here we investigate these issues by examining how hand-specific information (left or right hand) is recruited in language comprehension and action execution. An fMRI study tested self-reported right-handed participants in two separate tasks that were designed to be as similar as possible to increase sensitivity of the comparison across task: an action execution go/no-go task where participants performed right or left hand actions, and a language task where participants read sentences describing the same left or right handed actions as in the execution task. We found that language-induced activity did not match the hand-specific patterns of activity found for action execution in primary somatosensory and motor cortex, but it overlapped with pre-motor and parietal regions associated with action planning. Within these pre-motor regions, both right hand actions and sentences elicited stronger activity than left hand actions and sentences-a dominant hand effect. Importantly, both dorsal and ventral sections of the left pre-central gyrus were recruited by both tasks, suggesting different action features being recruited. These results suggest that (a) language comprehension elicits motor representations that are hand-specific and akin to multimodal action plans, rather than full action re-enactments; and (b) language comprehension and action execution share schematic hand-specific representations that are richer for the dominant hand, and thus linked to previous motor experience.


The antibacterial effect of 2-octyl cyanoacrylate (Dermabond®) skin adhesive.
Dermabond® is a tissue adhesive commonly used for wound or surgical incision closure. Its use has previously been associated with a reduction in wound infection, and it has been thought to act as a physical barrier to bacteria accessing the wound. This study aimed to establish whether the Dermabond® adhesive demonstrated any intrinsic antimicrobial properties. Solidified pellets of Dermabond® were placed on standardised Agar plates cultured with a variety of pathogens. Inhibition of growth was demonstrated against Gram-positive bacteria. Culture swabs taken from the inhibition rings demonstrated no growth, suggesting that Dermabond has a bactericidal mechanism of action. Based on the design of this study, the results suggest that Dermabond® demonstrates bactericidal properties against Gram-positive bacteria. Its use for wound closure following surgical intervention may reduce postoperative wound infection by Gram-positive organisms.


Daily Caffeine Consumption Does Not Influence Acupuncture Analgesia in Healthy Individuals: A Preliminary Study.
Animal studies suggest that caffeine may interfere with acupuncture analgesia. This study investigated the modulation effect of daily caffeine intake on acupuncture analgesia in 27 healthy subjects using a crossover design. We found that real acupuncture increased pain thresholds compared to sham acupuncture. Further, there was no association between caffeine intake measurements of daily caffeine use, duration of caffeine consumption, or their interaction and preacupuncture and postacupuncture pain threshold changes. Our findings suggest that daily caffeine intake may not influence acupuncture analgesia in the cohort of healthy subjects who participated in study.


The function of CUX1 in oxidative DNA damage repair is needed to prevent premature senescence of mouse embryo fibroblasts.
Despite having long telomeres, mouse embryo fibroblasts (MEFs) senesce more rapidly than human diploid fibroblasts because of the accumulation of oxidative DNA damage. The CUX1 homeodomain protein was recently found to prevent senescence in RAS-driven cancer cells that produce elevated levels of reactive-oxygen species. Here we show that Cux1-/- MEFs are unable to proliferate in atmospheric (20%) oxygen although they can proliferate normally in physiological (3%) oxygen levels. CUX1 contains three domains called Cut repeats. Structure/function analysis established that a single Cut repeat domain can stimulate the DNA binding, Schiff-base formation, glycosylase and AP-lyase activities of 8-oxoguanine DNA glycosylase 1, OGG1. Strikingly and in contrast to previous reports, OGG1 exhibits efficient AP-lyase activity in the presence of a Cut repeat. Repair of oxidative DNA damage and proliferation in 20% oxygen were both rescued in Cux1-/- MEFs by ectopic expression of CUX1 or of a recombinant Cut repeat protein that stimulates OGG1 but is devoid of transcription activation potential. These findings reinforce the causal link between oxidative DNA damage and cellular senescence and suggest that the role of CUX1 as an accessory factor in DNA repair will be critical in physiological situations that generate higher levels of reactive oxygen species.


Phase Velocity Estimation With Expanded Bandwidth in Viscoelastic Phantoms and Tissues.
Ultrasound shear wave elastography (SWE) is a technique used to measure mechanical properties to evaluate healthy and pathological soft tissues. SWE typically employs an acoustic radiation force (ARF) to generate laterally propagating shear waves that are tracked in the spatiotemporal domains, and algorithms are used to estimate the wave velocity. The tissue viscoelasticity is often examined through analyzing the shear wave phase velocity dispersion curves, which is the variation of phase velocity with frequency or wavelength. A number of available methods to estimate dispersion exist, which can differ in resolution and variance. Moreover, most of these techniques reconstruct dispersion curves for a limited frequency band. In this work, we propose a novel method used for dispersion curve calculation. Our unique approach uses a generalized Stockwell transformation combined with a slant frequency-wavenumber analysis (GST-SFK). We tested the GST-SFK method on numerical phantom data generated using a finite-difference-based method in tissue-mimicking viscoelastic media. In addition, we evaluated the method on numerical shear wave motion data with different amounts of white Gaussian noise added. Additionally, we performed tests on data from custom-made tissue-mimicking viscoelastic phantom experiments, ex vivo porcine liver measurements, and in vivo liver tissue experiments. We compared results from our method with two other techniques used for estimating shear wave phase velocity: the two-dimensional Fourier transform (2D-FT) and the eigenvector (EV) method. Tests carried out revealed that the GST-SFK method provides dispersion curve estimates with lower errors over a wider frequency band in comparison to the 2D-FT and EV methods. In addition, the GST-SFK provides expanded bandwidth by a factor of two or more to be used for phase velocity estimation, which is meaningful for a tissue dispersion analysis in vivo.


Train Drivers' Work Related Stress and Job Satisfaction.
This study investigated which work-related stressors are rated highest by train drivers and which are strongest correlated with consideration to change profession. In a questionnaire, a total of 251 Swedish train drivers rated 17 work-related stressors, to which extent they had considered quitting their profession, and if they had experienced a PUT (person under train) accident. PUTs (when experienced) and irregular work hours are the main stressors, but the strongest predictors of consideration to change profession are those that are encountered often, and last over time (eg, irregular work hours, r = 0.61, and major organizational changes, r = 0.51). For effective reduction of stress and improved job satisfaction, focus should be on aspects that affect everyday life for drivers, such as better working shifts, less delays, and improved social climate.


Roles of nociceptin/orphanin FQ and nociceptin/orphanin FQ peptide receptor in respiratory rhythm generation in the medulla oblongata: an in vitro study.
Nociceptin/orphanin FQ (N/OFQ) is the endogenous agonist of the orphan opioid receptor-like receptor (NOP receptor, previously termed ORL1), a novel member of the opioid receptor family. The aim of the present study, using in vitro newborn rat preparations, was to elucidate the roles N/OFQ and the NOP receptor play in medullary generation of respiratory rhythm. The brainstem-spinal cord from 3-day-old Wistar rats was isolated and perfused with artificial cerebrospinal fluid (27.5 degrees C) equilibrated with oxygen 95% and carbon dioxide 5% at pH 7.4. Respiratory activity was recorded from the C4/C5 ventral roots. The effects of N/OFQ (10 nM, 30 nM, 100 nM) on respiratory frequency (fR) (bursts min(-1)) was measured. Drugs were administered through the recording chamber by means of a perfusion system. In addition, the effects of pretreatment with the classical non-selective opioid receptor antagonist naloxone 1 microM, and the selective NOP antagonist CompB 10 microM, were evaluated. Statistical significance was evaluated using ANOVA followed by Dunnett's test (P<0.05). N/OFQ reduced fR in a concentration-dependent manner. Pretreatment with CompB 10 microM prevented the N/OFQ 10 nM-induced fR reduction, whereas CompB itself was inactive. Pretreatment with naloxone did not prevent the N/OFQ-induced fR reduction. N/OFQ acts as a neuromodulator to reduce fR in the respiratory rhythm- generating centre of the medulla oblongata, and this action of N/OFQ is mediated by NOP receptors.


(Li0.91Mn0.09)Mn2O4.
Lithium manganese oxide crystals with composition (Li(0.91)Mn(0.09))Mn(2)O(4) were synthesized by a flux method. The crystals have a structure closely related to that of the cubic spinel LiMn(2)O(4), but 9% of the lithium ions in the tetrahedral 4a site are substituted by Mn(2+) ions. This substitution lowers the average Mn oxidation state below 3.5+, resulting in a Jahn-Teller distortion of the MnO(6) octahedron.


DNA methylation in urothelial carcinoma.
DNA methylation alterations are common in urothelial carcinoma, a prevalent cancer worldwide caused predominantly by chemical carcinogens. Recent studies have proposed sets of hypermethylated genes as promising diagnostic and prognostic biomarkers from urine or tissue samples, which require validation. Other studies have revealed intriguing links between specific carcinogens and DNA methylation alterations in cancer tissues or blood that might clarify carcinogenesis mechanisms and aid prevention. Like DNA methylation alterations, mutations in chromatin regulators are frequent, underlining the importance of epigenetic changes. However, the relations between the two changes and their functions in urothelial carcinogenesis remain unclear. Transcription factor genes with altered methylation deserve particular interest. Elucidating the functional impact of methylation changes is a prerequisite for their therapeutic targeting.


How do chiropractors manage clinical risk? A questionnaire study.
The literature on chiropractic safety tends to focus on adverse events and little is known about how chiropractors ensure safety and manage risk in the course of their daily practice. The purpose of this study was to investigate how chiropractors manage potentially risky clinical scenarios. We also sought to establish how chiropractors perceive the safety climate in their workplace and thus whether there is an observable culture of safety within the profession. An online questionnaire was designed to determine which of nine management options would be chosen by the respondent in response to four defined clinical case scenarios. Safety climate within the respondent's practice setting was measured by seeking the level of agreement with 23 statements relating to six different safety dimensions. 260 licensed chiropractors in Switzerland and 1258 UK members of The Royal College of Chiropractors were invited to complete the questionnaire. Questionnaire responses were analysed quantitatively in respect of the four clinical scenarios and the nine management options to determine the likelihood of each option being undertaken, with results recorded in terms of % likelihood. Gender differences in response to the management options for each scenario were evaluated using the Mann-Whitney U (MWU) test. Positive agreement with elements comprising each of the six safety dimensions contributed to a composite '% positive agreement' score calculated for each dimension. Questionnaire responses were received from 76% (200/260) of Swiss participants and 31% (393/1258) of UK members of The Royal College of Chiropractors. There was a general trend for Swiss and UK chiropractors to manage clinical scenarios where treatment appears not to be successful, not indicated, possibly harmful or where a patient is apparently getting worse, by re-evaluating their care. Stopping treatment and/or incident reporting to a safety incident reporting and learning system were generally found to be unlikely courses of action. Gender differences were observed with female chiropractors appearing to be more risk averse. Swiss and UK chiropractors tend to manage potentially risky clinical scenarios by re-evaluating the case. The unlikeliness of safety incident reporting is probably due to a range of recognised barriers, although Swiss and UK chiropractors are positive about local communication and openness which are important tenets for safety incident reporting. The observed positivity towards key aspects of clinic safety indicates a developing safety culture within the Swiss and UK chiropractic professions.


Higher Cumulative Blood Pressure in Midlife Predicts an Increased Risk of Atrial Fibrillation: Evidence From the Atherosclerosis Risk in Communities Study.
Elevated blood pressure (BP) is reportedly associated with an increased risk of atrial fibrillation (AF). However, the association between cumulative BP exposure in midlife and incident AF in mid-to-late life remains unclear. Participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study with 4 consecutive BP measurements and no prevalent AF at baseline were included. Cumulative BP was calculated as the area under the curve from visit 1 to visit 4. Incident AF was identified by study visit ECGs, hospital discharge codes, or death certificates. A total of 9892 participants were included (44.6% men and mean age 62.9±5.7 years at visit 4) with 1550 (15.7%) individuals who developed new-onset AF during an average follow-up of 15.4 years. The incidence rates of AF per 1000 person-years across the 4 quartiles of cumulative systolic BP were 7.9, 9.2, 12.5, and 16.9, respectively. After multivariable adjustment, the hazard ratios for incident AF among participants in the highest quartile of cumulative systolic BP, pulse pressure, and mean arterial pressure were 1.48 (95% CI, 1.27-1.72), 1.81 (95% CI, 1.53-2.13), and 1.22 (95% CI, 1.05-1.41), respectively, compared with those in the lowest quartile. The addition of cumulative systolic BP or pulse pressure slightly improved the ability to predict new-onset AF. Higher exposure to cumulative systolic BP, pulse pressure, and mean arterial pressure was significantly associated with increased risk of incident AF.


[Various aspects of diagnosis of food intolerance].
In the presence of food antigenes causing food intolerance in patients granulocytes isolated from these patients exhibited altered oxidative metabolism. This phenomenon may be used for diagnostics of food intolerance in vitro.


Environmental health and developmental disabilities: a life span approach.
Prenatal and childhood environmental exposures are an underrecognized primary cause of intellectual and other developmental disabilities. In addition, individuals with established disabilities are vulnerable to further harm from subsequent environmental exposures. In individuals with communicative impairment or limited ability to independently escape from hazards, these subsequent exposures, too, may occur undetected or untreated. This article introduces the subject of environmental health and developmental disabilities throughout the life span. In particular, we focus on ways that families, communities, and health professionals can prevent both primary and secondary disabilities through better awareness of common environmental health issues.


Disrupted placental serotonin synthetic pathway and increased placental serotonin: Potential implications in the pathogenesis of human fetal growth restriction.
Placental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR). The components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10-12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA. Gene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p < 0.05), while 5-HT receptor mRNA was significantly increased in FGR compared with control (p < 0.01). Placental TPH enzyme activity was significantly increased with a concomitant increase in the total placental 5-HT concentrations in FGR compared with control. This study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies.


Inherent features of wavelets and pulse coupled networks.
Biologically inspired image/signal processing like the pulse coupled neural network (PCNN) and the wavelet (packet) transforms are described. The two methods are applied to two-dimensional data in order to demonstrate the features of each method, pinpoint differences as well as similarities. The inherent properties (with respect to filtering, segmentation, etc.) of the two approaches with respect to detectors for physics experiments as well as remote sensing are discussed.


ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma.
Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.


Progression of relapsing-remitting demyelinating disease does not require increased TCR affinity or epitope spread.
In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-γ. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states.


Why don't nurses consistently take patient respiratory rates?
This is an investigation into nurses' practice of when they would not take and record a patient's respiratory rate. It reports results of qualitative, descriptive research involving interviews with ten ward nurses from three hospitals in New Zealand. Results affirm that, despite it being the most sensitive vital sign for managing patients, nurses acknowledged circumstances in which respiratory rate taking was missed. Reasons were complex and, contrary to expectations, not always associated with the introduction of technology to record other vital signs. Time pressures, work interruptions and rationalised judgements made by experienced nurses all contributed to incidences of missed respiratory rate taking. It is concluded that patient respiratory rate measures do not seem to be highly valued, calling into questions nurses' level of understanding of respiratory physiology, as well as the extent to which intuitive nursing practice is supported by critical analysis.


Emergency department care-related causal factors of in-patient deterioration.
Objective The aim of this study was to determine factors related to emergency department (ED) care causing in-patient deterioration. Methods This retrospective cohort study examined in-patient records using the human factors classification framework for patient safety in a regional health service in New South Wales, Australia, between March 2016 and February 2017. Deterioration was defined as either the initiation of a medical emergency team call, cardiac arrest or unplanned admission to the intensive care unit. Results Of the 1074 patients who deteriorated within 72 hours of admission via the ED, the care received in the ED was a contributing factor for 101 patients (9%). The most common human causal factors were poor communication between staff, medical management errors, delayed treatment, medical documentation errors, nursing management errors and unclear policies or guidelines. Communication issues occurred the most when patients had more comorbidities (P = 0.039) and were more likely to occur in the presence of a medical documentation error (odds ratio 4.4; 95% confidence interval 1.7-11.3). Unclear policies or guidelines as a factor was most frequent with a surgical diagnosis (34.5% vs 15.7% for surgical vs medical, respectively; P = 0.038) and in patients ≥80 years of age (30.0% vs 21.8% for age ≥80 vs <80 years, respectively; P = 0.027). Conclusion Quality monitoring and interventions that consider human factors are required to address preventable in-patient deterioration. What is known about the topic? The ED represents the hospital's point of contact for potentially life-threatening conditions. Adverse event rates for emergency admissions are more than double those of non-emergency admissions. Patients are at particular risk of deterioration on discharge from the ED to the ward in the first 72 hours. Predicting which patients will deteriorate following transfer to the ward remains challenging, with care in the ED hypothesised to play a role. What does this paper add? This paper reveals that in-patient deterioration relating to ED care could be reduced through the routine identification of causal factors within a human factors framework in any patient deterioration event and subsequent evidence-informed interventions to address these factors. It is also extrapolated that the implementation of any intervention should be informed by behaviour-change principles. What are the implications for practitioners? It is implied that there is a need for the clarification and revision of policies and guidelines pertaining to the management of elderly patients, education regarding the critical importance of the often clinically masked vital sign deviations in younger patients and improved communication between staff, especially regarding patients with more comorbidities. Reviews of adverse events, such as patient deterioration, should incorporate a human factors analysis. Regular collation of data following adverse events should occur, with interventions considering all aspects of the factors that led to the event.


Centipede venom: recent discoveries and current state of knowledge.
Centipedes are among the oldest extant venomous predators on the planet. Armed with a pair of modified, venom-bearing limbs, they are an important group of predatory arthropods and are infamous for their ability to deliver painful stings. Despite this, very little is known about centipede venom and its composition. Advances in analytical tools, however, have recently provided the first detailed insights into the composition and evolution of centipede venoms. This has revealed that centipede venom proteins are highly diverse, with 61 phylogenetically distinct venom protein and peptide families. A number of these have been convergently recruited into the venoms of other animals, providing valuable information on potential underlying causes of the occasionally serious complications arising from human centipede envenomations. However, the majority of venom protein and peptide families bear no resemblance to any characterised protein or peptide family, highlighting the novelty of centipede venoms. This review highlights recent discoveries and summarises the current state of knowledge on the fascinating venom system of centipedes.


Decreasing Radiograph Errors in Pediatric Sports Medicine Clinic.
Radiographs are frequently ordered for general musculoskeletal complaints in the outpatient setting. However, incorrect laterality, incorrect location, or unnecessary radiographs have been reported as errors in our clinics. This quality improvement (QI) project aimed to reduce incorrect duplicate radiographs in outpatient pediatric sports medicine clinic. The overall global goal was to stop unnecessary radiation exposure in our pediatric patients. Using QI methodology, we evaluated the current clinic flow, the process of ordering radiographs, and the completion of radiographs at the main sports medicine outpatient clinic. Staff communication, staff education, and patient participation were identified as the prominent gaps in our clinic process. We implemented interventions using progressive biweekly Plan-Do-Study-Act (PDSA) cycles to promote change and to reduce our radiographic errors. Retrospective baseline data demonstrated baseline errors of 9% (10/106) in the main outpatient clinic. After 6 months of PDSA cycles, we found no duplicate errors. Highly successful interventions included radiograph screening survey for families, staff education, and improved staff communication. The project was expanded to a second outpatient clinic with baseline errors of 6% (4/64). After 2 months of PDSA cycles, no duplicate errors were found. Our goal was to reduce incorrect duplicate radiographs in outpatient sports medicine clinic and limit unnecessary radiation exposure in our pediatric patients. A reduction in duplicate errors at 2 clinics occurred using the Institute for Healthcare Improvement model to facilitate change. Effective communication between physicians, clinical athletic trainers, radiology technologists, patients, and families drove the success of this quality improvement initiative.


Portal vein thrombosis: a clinician-oriented and practical review.
With advances in modern imaging techniques, portal vein thrombosis (PVT) is being increasingly diagnosed. It has a wide ranging clinical spectrum from being an asymptomatic state to a potentially life-threatening situation. It is not unusual to find it as an incidental finding in the abdominal imagings done for other reasons. It is commonly associated with cirrhosis and abdominal malignancies and also has a strong association with prothrombotic disorders. It is often difficult for the clinicians to decide whether PVT is acute or chronic. This poses great challenges to its management strategies that include anticoagulants, thrombolysis, and surgical options. Timely diagnosis and appropriate management have great bearings on its outcomes of morbidity and mortality. In this clinician-oriented review, we have provided a concise review of clinical aspects of PVT and discussed various management strategies while addressing the common questions that come to a physician's mind dealing with such a patient.