Automatic monitoring of biochemical parameters in tissue culture. Studies on synchronously growing mouse myeloma cells.
An instrument is described that will maintain a population of mammalian cells at constant cell density while automatically monitoring the growth rate of the culture and the extent of precursor incorporation into a variety of cell products. The apparatus was used in an investigation of cyclic changes in the incorporation of labelled precursors into the DNA, RNA, total protein and myeloma protein synthesized in synchronous cultures of a mouse myeloma line. The incorporation of [(3)H]uridine into trichloroacetic acid-insoluble material reveals a slight periodicity, with maxima and minima corresponding to late S phase and the mitotic phases respectively. The incorporation of [(3)H]lysine into total intracellular protein also shows a slight oscillation, with maxima and minima occurring during the respective G2 and mitotic phases. Cyclical changes in the synthesis of serologically precipitable myeloma protein were found to vary somewhat according to the conditions used to synchronize the cells. In experiments conducted with 4.0mm-thymidine, maximal incorporation of label took place during S phase or early G2 phase. Experiments with 1.0mm-thymidine revealed a significantly less marked periodicity of myeloma protein synthesis.


Fast algorithm for successive computation of group betweenness centrality.
In this paper, we propose a method for rapid computation of group betweenness centrality whose running time (after preprocessing) does not depend on network size. The calculation of group betweenness centrality is computationally demanding and, therefore, it is not suitable for applications that compute the centrality of many groups in order to identify new properties. Our method is based on the concept of path betweenness centrality defined in this paper. We demonstrate how the method can be used to find the most prominent group. Then, we apply the method for epidemic control in communication networks. We also show how the method can be used to evaluate distributions of group betweenness centrality and its correlation with group degree. The method may assist in finding further properties of complex networks and may open a wide range of research opportunities.


Comparison of two frailty screening tools for acutely admitted elderly patients.
Frailty is a clinical syndrome that arises due to age-related decline, diseases, malnutrition and lifestyle. Two major perspectives on frailty exists: frailty as a phenotype and frailty as an accumulation of deficits. The two types are measured by Fried's Phenotype (FP) and the Clinical Frailty Scale (CFS), respectively. The aim of this study was to investigate which model best predicts 90-day mortality in elderly patients acutely admitted to an emergency department in Denmark. This study comprised a prospective cohort with the following inclusion criteria: age > 65 years, acute admission and admission >24 h. Bispebjerg Hospital, Odense University Hospital and Hospital of Southwest Jutland participated in the study. The FP and the CFS were measured in all patients. Descriptive statistics, relative risk (RR), odds ratio (OR), risk difference and receiver-operating characteristics (ROC) analysis were performed. The outcome was 90-day mortality. A total of 1,030 patients participated (mean age: 78.2 years, 54% female). Among these, 221 were frail by the FP (score > 3) and 555 participants were frail by the CFS (score > 5). Within 90 days, 128 died. The analyses revealed significant associations between frailty and 90-day mortality. For the FP, the RR was 2.67 (95% confidence interval (CI): 1.93-3.69), p less-than 0.001; and for the CFS, the RR was 4.12 (95% CI: 2.65-6.42), p less-than 0.001. The adjusted OR for the CFS was 4.38 (95% CI: 2.68-7.13); for the FP, 3.88 (95% CI: 2.51-6.01). A significant association existed between frailty and 90-day mortality in the Danish cohort. However, the CFS is a better predictor of 90-day mortality the FP. Even so, the CFS still has a lack of sensitivity and specificity. none TRIAL REGISTRATION. not relevant.


Contextual Barriers of Respectful Workplace in Nursing: A Focused Ethnography.
Respectful relationship among nurses is an important influencing factor of positive work environment and nursing outcomes. Disrespectful interpersonal behaviors set the scene for an unpleasant and unhealthy workplace in nursing. This can be harmful to persons and their organization and affect health care outcomes. This study was designed in order to search for contextual barriers to respectful behaviors in the context of nursing. This study was a focused ethnography that was carried out in medical-surgical wards of Shahid Chamran Hospital in Isfahan in 2018-2019. The data collection method consisted of 140 h of participant observation and semi-structured interviews with 34 informants. The nformants comprised 29 nurses, 2 assistant nurses, a physician, and 2 patients who were selected by purposive sampling. The first author of the study made direct observations as an outsider. The data were analyzed by Spradley's method. Three main categories and eight subcategories were obtained from data analysis that are as follows: 1) Personal self: challenges of perceived respect (negative self-concept, unpleasant feelings, and ineffective communication), 2) Organizational-based perceived disrespect (poor organizational climate, inadequate job condition, restrictive organizational structure), 3) Social self: challenges of showed respect (implicit social norms, cultural gap). Individual and social attitudes, interactive communication, and organizational factors are the contextual determinants of a respectful workplace in nursing. Consequently, improving self-concept and effective communication skills as well as adjust organizational conditions and value conceptualization in society may effect a respectful workplace in nursing.


Influence of Excitation Frequency on the Performance of Peripheral Blood Flow Imaging using Electrical Impedance Tomography.
This paper presents a method for selecting the efficient excitation frequency of Electrical Impedance Tomography (EIT) for imaging peripheral blood flow with high spatial-temporal performance. Using a simulation study, we selected the excitation frequency of 16 kHz to visualize the pulsation of arteries with a high sensitivity. We then conducted a subjective study using 16 electrodes and showed that the conductivity distribution is similar to the anatomical structure of the forearm. Moreover, the integrated conductivity spectrum showed a peak corresponding to a heart rate measurement obtained using a PPG sensor at the fingertip. Therefore, we conclude that this system can capture the spatial-temporal signals related to peripheral artery blood flow by using the selected excitation frequency.


The draft genome sequence of Xanthomonas species strain Nyagatare, isolated from diseased bean in Rwanda.
We announce the genome sequence for Xanthomonas species strain Nyagatare, isolated from beans showing unusual disease symptoms in Rwanda. This strain represents the first sequenced genome belonging to an as-yet undescribed Xanthomonas species known as species-level clade 1. It has at least 100 kb of genomic sequence that shows little or no sequence similarity to other xanthomonads, including a unique lipopolysaccharide synthesis gene cluster. At least one genomic region appears to have been acquired from relatives of Agrobacterium or Rhizobium species. The genome encodes homologues of only three known type-three secretion system effectors: AvrBs2, XopF1 and AvrXv4. Availability of the genome sequence will facilitate development of molecular tools for detection and diagnostics for this newly discovered pathogen of beans and facilitate epidemiological investigations of a potential causal link between this pathogen and the disease outbreak.


Cell division in blue-green bacteria: stimulation of localized regions of peptidoglycan metabolism by ethanol.
D-Cycloserine was used to localize regions of active peptidoglycan metabolism as bulged, weakened areas in the lateral wall. Strain SN29 is a non-septate filamentous mutant of Agmenellum quadruplicatum and produces one to two such bulges per filament during exponential growth in the presence of D-cycloserine. The addition of ethanol to D-cycloserine inhibited filaments results in the production of many additional bulges in the lateral wall and is interpreted as evidence for the localized activation of peptidoglycan metabolism by ethanol. In the parent organism, D-cycloserine selectively inhibits cell division resulting in the formation of enlarged spindle-shaped cells. Cell separation was also affected. Chain formation was greatly reduced in septate mutants of A. quadruplicatum by growth in the presence of D-cycloserine. This was apparently due to the increase fragility of cells within the filaments.


A method of estimating the numbers of human and mouse T cell receptors for antigen alpha and beta chain V-genes.
T cell receptors for antigen (TCR) V-genes are under a very restrictive evolutionary pressure in order to maintain their biological activities of interacting with MHC class I or II molecules and processed peptides at the protein level. This is in contrast to immunoglobulin V-genes which can mutate more freely. As we have discussed before, 17 or less nucleotide differences between any two mouse lambda light chain V-genes can be due to somatic mutations induced by antigens, allelic variations, and the combination of these two mechanisms. Thus, a cut-off of 17 nucleotide differences has been used to estimate the numbers of the other human and mouse immunoglobulin chain V-genes. Except for mouse heavy chains where experimental study is not yet available, our estimated numbers are in good agreement with experimental findings. For TCR V-genes, however, this cut-off value should be modified as illustrated in the present analysis. Our estimation of the number of human TCR beta chain V-genes is also in good agreement with the recent experimental study of sequencing 685 kb of that gene locus. Estimations for the numbers of human alpha, mouse alpha and beta chain V-genes will wait for future experimental verification.


The effect of L-thyroxine treatment on chronic idiopathic urticaria and autoimmune thyroiditis.
Autoimmune thyroiditis (AT) is more prevalent in patients with chronic idiopathic urticaria CIU) than in the general population. Previous small studies without any controlled comparison reported that CIU remits in patients with CIU and AT treated with L-thyroxine. To determine whether l-thyroxine treatment can improve the clinical course of CIU in patients with the co-occurrence of AT and CIU. A total of 749 patients with CIU were retrospectively studied. Clinical and laboratory evaluation and classification of chronic urticaria were performed according to the EAACI/GA(2)LEN/EDF/WAO guidelines. After L-thyroxine treatment for 53 ± 19 days, euthyroidism was restored in all subjects. Urticaria activity score (UAS) was evaluated at baseline and after three and six months. The control group consisted of matched 44 euthyroid subjects with CIU. A total of 44 (5.9%) patients were diagnosed to have hypothyroidism related to AT. Autologous serum skin test (ASST) was found to be positive in 17 (38.6%) of them. There was no statistically significant difference in baseline UAS, between the ASST+ (3.94 ± 1.52) and the ASST- (3.63 ± 1.42; P = 0.27) hypothyroid subjects and the euthyroid CIU controls (3.73 ± 1.74). During the L-thyroxine treatment, a significant reduction of UAS was observed in both hypothyroid ASST+ and ASST- subjects. However, the mean UAS after three and six months of L-thyroxine treatment remained not significantly different from that in control euthyroid subjects with CIU. L-Thyroxine treatment has no effect on the course of CIU in patients with CIU and AT.


X-ray spectroscopy as a probe for lithium polysulfide radicals.
The discharge mechanism in lithium sulfur batteries is still unknown and has been purported to involve significant concentrations of polysulfide radicals. Methods capable of quantifying these species in solution are therefore of paramount importance to revealing electrochemical pathways. Here we utilize DFT based X-ray Absorption Spectroscopy (XAS) simulations at the sulfur K-edge to obtain the spectra of polysulfide molecules in neutral, radical (-1) and dianionic (-2) charge states. Our calculations indicate that, contrary to recent propositions, the observed low energy, pre-edge feature in S K-edge XAS near 2470 eV is not exclusively due to radical species, but rather arises predominantly from core-excitations of terminal atoms, at the ends of linear polysulfides, to σ* orbitals, consistent with our previous results for the dianionic species. We do however find a spectral feature unique to radicals, lying 0.5-1 eV below the established pre-edge, that arises from 1s → π* transitions of the terminal atoms. Existing measurements on polysulfides show no evidence for such transitions. We predict that detection of linear radicals in polysulfide mixtures using XAS is limited to high mole fractions (>20%), due to the relatively weak XAS intensity of this π* feature.


Rare Infant Case of Pulmonary Aspergilloma Highlighting Common Challenges With Voriconazole Dosing.
We describe a 6-week-old male-term infant with a pulmonary aspergilloma diagnosed following lobectomy for suspected pleuropulmonary blastoma, with characteristic histopathologic findings and Aspergillus detected by polymerase chain reaction. Intensive testing did not reveal primary or secondary immunodeficiency. During 5 weeks treatment with voriconazole including regular therapeutic drug monitoring and dose adjustment, a level in the target range was never achieved. When the patient developed photosensitivity, treatment was stopped without relapse over 12 months follow-up. Voriconazole dosing is notoriously challenging in children. We review the cumulative published experience with voriconazole use in infants to highlight even greater difficulty in infants. Pulmonary aspergillosis is typically a disease affecting immunocompromised or critically ill patients. In children, it is well described in those with chronic granulomatous disease (CGD) as a complication of immunosuppressive antineoplastic chemotherapy and rarely in extremely- or very-low birthweight premature neonatal intensive care patients. The diagnosis is extremely rare in children without underlying risk factors. To our knowledge, this is the first report of a pulmonary aspergilloma in an immunocompetent infant.


[Tension gastrothorax as a cause of death by obstructive shock - case report].
Tension gastrothorax is caused by the herniation of the stomach into the thorax due to a congenital defect of the diaphragm; the Bochdaleck diaphragmatic hernia (HDB) is the most frequent type. Tension gastrothorax should be considered as a differential diagnosis in patients with obstructive shock and tension pneumothorax. A previously healthy 10 month-old male infant, who presented increased respiratory distress, increased volume of the left hemithorax, absence of breath sounds, ipsilateral hyper-resonance, 76% saturation, cold skin and capillary filling > 5 seconds, followed by a cardio-respiratory arrest. Due to clinical suspicion of pneumothorax, needle decompression was performed reversing cardiac arrest, but with persistent hemodynamic and respiratory instability; chest radiograph suggested diaphragmatic hernia. He underwent surgery confirming the presence of a diaphragmatic hernia of 5 cm. The evolution of this case shows the difficulty differentiating a tension gastrothorax from tension pneumothorax in patients admitted to the emergency room who are in serious condition; therefore, a high index of suspicion is needed for its identification.


Hypokinesia and presenile dementia in a Dutch family with a novel insertion in the prion protein gene.
The clinical features and disease course of six patients from a family with autosomal dominant inheritance of presenile dementia and a hypokinetic syndrome are described. In the past, these patients have carried diagnoses of Pick's disease, Huntington's disease, Parkinson-dementia, and one patient was described as suffering from a 'peculiar type of presenile dementia' in a case report. In the two cases examined, the most distinctive neuropathological features were extensive globular deposits of periodic acid-Schiff plus diastase (PAS)-positive material, having tinctural properties of amyloid only to a limited degree, in the cerebellum and cerebral cortex. These globules stained positively with antibodies against prion protein. Southern blot of MspI-digested genomic DNA showed an abnormal band of approximately 950 bp in all three patients from which material was available. Direct sequencing of the abnormal allele revealed an insert consisting of eight extra 24-nucleotide repeats in the patients, which was absent in a healthy first degree relative who was considered well beyond the age of onset of symptoms in this family. The nucleotide sequence of the abnormal insert of 192 bp was different from that of a previously described insert of equal length. Adding to previous descriptions of mutations in the prion protein gene, this report emphasizes the clinical, neuropathological and genetic heterogeneity of inherited prion disease.


Double-Decker Silsesquioxanes Self-Assembled in One-Dimensional Coordination Polymeric Nanofibers with Emission Properties.
The urgent needs for photoactive materials in industry drive fast evolution of synthetic procedures in many branches of chemistry, including the chemistry of silsesquioxanes. Here, we disclose an effective protocol for the synthesis of novel double-decker silsesquioxanes decorated with two (styrylethynylphenyl)terpyridine moieties (DDSQ_Ta-b). The synthesis strategy involves a series of silylative and Sonogashira coupling reactions and is reported for the first time. DDSQ_Ta-b were employed as nanocage ligands to promote self-assembly in the presence of transition metals (TM), i.e., Zn2+, Fe2+, and Eu3+ ions, to form one-dimensional (1D) coordination polymeric nanofibers. Additionally, ultraviolet-promoted and reversible E-Z isomerization of the C═C bond within the ligand structures may be exploited to tune their emission properties. These findings render such complexes promising candidates for applications in materials chemistry. This is the first example of 1D coordination polymers bearing DDSQ-based nodes with TM ions.


The prevalence of psychiatric disorders among cancer patients.
Two hundred fifteen randomly accessed cancer patients who were new admissions to three collaborating cancer centers were examined for the presence of formal psychiatric disorder. Each patient was assessed in a common protocol via a psychiatric interview and standardized psychological tests. The American Psychiatric Association's DSM-III diagnostic system was used in making the diagnoses. Results indicated that 47% of the patients received a DSM-III diagnosis, with 44% being diagnosed as manifesting a clinical syndrome and 3% with personality disorders. Approximately 68% of the psychiatric diagnoses consisted of adjustment disorders, with 13% representing major affective disorders (depression). The remaining diagnoses were split among organic mental disorders (8%), personality disorders (7%), and anxiety disorders (4%). Approximately 85% of those patients with a positive psychiatric condition were experiencing a disorder with depression or anxiety as the central symptom. The large majority of conditions were judged to represent highly treatable disorders.


Cell Wall Anchoring of a Bacterial Chitosanase in Lactobacillus plantarum Using a Food-Grade Expression System and Two Versions of an LP TG Anchor.
Lactic acid bacteria (LAB) have attracted increasing interest recently as cell factories for the production of proteins as well as a carrier of proteins that are of interest for food and therapeutic applications. In this present study, we exploit a lactobacillal food-grade expression system derived from the pSIP expression vectors using the alr (alanine racemase) gene as the selection marker for the expression and cell-surface display of a chitosanase in Lactobacillus plantarum using two truncated forms of a LP × TG anchor. CsnA, a chitosanase from Bacillus subtilis 168 (ATCC23857), was fused to two different truncated forms (short-S and long-L anchors) of an LP × TG anchor derived from Lp_1229, a key-protein for mannose-specific adhesion in L. plantarum WCFS1. The expression and cell-surface display efficiency driven by the food-grade alr-based system were compared with those obtained from the erm-based pSIP system in terms of enzyme activities and their localisation on L. plantarum cells. The localization of the protein on the bacterial cell surface was confirmed by flow cytometry and immunofluorescence microscopy. The highest enzymatic activity of CsnA-displaying cells was obtained from the strain carrying the alr-based expression plasmid with short cell wall anchor S. However, the attachment of chitosanase on L. plantarum cells via the long anchor L was shown to be more stable compared with the short anchor after several repeated reaction cycles. CsnA displayed on L. plantarum cells is catalytically active and can convert chitosan into chito-oligosaccharides, of which chitobiose and chitotriose are the main products.


Occupational lead exposure and blood pressure.
Recent community studies have suggested that low level lead exposure is significantly associated with blood pressure in the general population. This finding is inconsistent with the results of recent occupational studies of lead exposed workers, although the occupational studies contained serious methodological weaknesses. The present study examined the relation between occupational lead exposure and diastolic and systolic blood pressure in randomly selected samples of 270 exposed and 158 non-exposed workers. Four exposure indicators were examined: employment at a lead battery plant nu a control plant, current blood lead value, current zinc protoporphyrin value, and time weighted average blood lead value. After controlling for other known risk factors such as age, education, income, cigarette usage, alcohol consumption, and exercise, the associations between exposure and blood pressure were small and non-significant. In the absence of a biologically feasible hypothesis regarding the mechanism by which low level lead exposure would influence blood pressure the present findings challenge the validity of the general population association.


Inhibition of Pre-Supplementary Motor Area by Continuous Theta Burst Stimulation Leads to More Cautious Decision-making and More Efficient Sensory Evidence Integration.
Decisions are made based on the integration of available evidence. The noise in evidence accumulation leads to a particular speed-accuracy tradeoff in decision-making, which can be modulated and optimized by adaptive decision threshold setting. Given the effect of pre-SMA activity on striatal excitability, we hypothesized that the inhibition of pre-SMA would lead to higher decision thresholds and an increased accuracy bias. We used offline continuous theta burst stimulation to assess the effect of transient inhibition of the right pre-SMA on the decision processes in a free-response two-alternative forced-choice task within the drift diffusion model framework. Participants became more cautious and set higher decision thresholds following right pre-SMA inhibition compared with inhibition of the control site (vertex). Increased decision thresholds were accompanied by an accuracy bias with no effects on post-error choice behavior. Participants also exhibited higher drift rates as a result of pre-SMA inhibition compared with the vertex inhibition. These results, in line with the striatal theory of speed-accuracy tradeoff, provide evidence for the functional role of pre-SMA activity in decision threshold modulation. Our results also suggest that pre-SMA might be a part of the brain network associated with the sensory evidence integration.


Inhibition of sperm binding to porcine ova by antibodies to equine zonae pellucidae.
Sera and follicular fluid from mares previously determined as having antibodies to the zona pellucida were exposed to porcine ovarian oocytes before insemination with boar spermatozoa in vitro. There was a dramatic decline in the number of spermatozoa bound to zonae compared to treatments with sera and follicular fluid from mares negative for zona antibodies. These data suggest that antibodies reactive with the zona pellucida may be responsible for reduced or even complete infertility in some mares. In a group of 50 randomly selected mares tested for antizona antibodies, 2 pregnant mares were found to be positive, one at 60 and the other at 90 days of gestation. The duration of zona antibodies was determined in 3 mares previously identified as zona positive. All were sampled at weekly intervals for at least 6 months. There was considerable variance in the presence of zona antibodies throughout the sampling period, suggesting that the presence of zona antibodies in mares does not necessarily correlate with their oestrous cycles. The periodic absence of detectable zona-reactive antibodies in zona positive mares suggests that multiple sampling may be required to eliminate the possibility of false negatives.


Frequency and risk factors stratification of hypertension among the rural population of Bangladesh.
Hypertension is one of the major risk factors of premature morbidity and mortality in our daily clinical practice. Various studies carried out in the urban settings, but there is scarcity of epidemiological data regarding hypertension among the rural people in Bangladesh. Therefore, this current study has been designed to find out the frequency and risk factors stratification of hypertension among the rural people in Jashore, Bangladesh. A cross-sectional study recruited 1812 participants above 18 years attending on national hypertensive week of 2019 in Bagherpara and Keshabpur upazila (subdistrict) health complex in Jashore, Bangladesh. 2020 International Society of Hypertension Global Hypertension Practice Guidelines had been demonstrated to classify hypertension. Out of the total study population, the frequency of hypertension was 20.6% (Grade 1 and Grade 2 hypertensive patients 15.8% and 4.9%, respectively), and high normal blood pressure was 9.0%. The mean age of the study population, Grade 1 hypertensive and Grade 2 hypertensive cohorts were 42 ± 16, 49 ± 15 and 51 ± 14 years, respectively, with a male and female ratio was 1:2. Progressive rise of mean systolic and diastolic blood pressure were noticed with increasing age. Age (P: <0.001), sex (P: 0.004), occupation (P: <0.001), BMI (P: <0.001), family (P: <0.001) and past history (P: <0.001) of hypertension, sedentary life style (P: 0.004), additional salt intake (P: <0.001) and smoking (P: 0.011) were significantly associated with hypertension following bivariate analysis. Multivariate logistic regression analysis revealed that age after 50 years (AOR = 1.866, 95% CI: 1.210-2.876), positive past history of hypertension (AOR = 3.493, 95% CI: 2.676-4.558), additional salt intake (AOR = 0.591, 95% CI: 0.453-0.770) and obesity (AOR = 3.389, 95% CI: 1.830-6.274) were significantly associated with developing hypertension. High frequency of hypertension was found among the rural population in Bangladesh where presence with a lot of significantly associated risk factors. The data would be helpful for the health policymakers dealing noncommunicable diseases to reach the sustainable goal and mitigate morbidity and mortality of cardiovascular diseases in Bangladesh.


Improving functional annotation of non-synonomous SNPs with information theory.
Automated functional annotation of nsSNPs requires that amino-acid residue changes are represented by a set of descriptive features, such as evolutionary conservation, side-chain volume change, effect on ligand-binding, and residue structural rigidity. Identifying the most informative combinations of features is critical to the success of a computational prediction method. We rank 32 features according to their mutual information with functional effects of amino-acid substitutions, as measured by in vivo assays. In addition, we use a greedy algorithm to identify a subset of highly informative features. The method is simple to implement and provides a quantitative measure for selecting the best predictive features given a set of features that a human expert believes to be informative. We demonstrate the usefulness of the selected highly informative features by cross-validated tests of a computational classifier, a support vector machine (SVM). The SVM's classification accuracy is highly correlated with the ranking of the input features by their mutual information. Two features describing the solvent accessibility of "wild-type" and "mutant" amino-acid residues and one evolutionary feature based on superfamily-level multiple alignments produce comparable overall accuracy and 6% fewer false positives than a 32-feature set that considers physiochemical properties of amino acids, protein electrostatics, amino-acid residue flexibility, and binding interactions.


Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease.
Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.


Effect of sevoflurane pretreatment in relieving liver ischemia/reperfusion-induced pulmonary and hepatic injury.
To investigate the effect of sevoflurane preconditioning on ischemia/reperfusion (I/R)-induced pulmonary/hepatic injury. Fifty-one Wistar rats were randomly grouped into sham, I/R, and sevoflurane groups. After reperfusion, the structural change of the lung was measured by Smith score, the wet and dry weights (W/D) were determined, malondialdehyde (MDA) myeloperoxidase (MPO) content was determined colorimetrically and by fluorescence, respectively, and matrix metalloprotein-9 (MMP-9) mRNA was quantified by RT-PCR. Biopsy and morphological analyses were performed on liver tissue, activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were determined, and tumor necrosis factor-alpha (TNF-α) level was determined. The sham group showed no changes in tissue structure. Structural lesions in the sevoflurane and I/R groups were mild and severe, respectively. Smith score, W/D, MDA, MPO, and MMP mRNA showed the same trend, and were increased in the I/R group and recovered in the sevoflurane group, compared with the sham group (both P<0.05). AST and ALT were significantly increased compared to the sham group (AST: 655±52.06 vs . 29±9.30 U/L; ALT: 693±75.56 vs . 37±6.71 U/L; P<0.05). In the sevoflurane group, AST and ALT levels were significantly decreased (464±47.71 and 516±78.84 U/L; P<0.001). TNF-α presented similar results. The protection of lung and liver by sevoflurane may be mediated by inhibited leukocyte recruitment and MMP-9 secretion.


Aerodynamics and pollen ultrastructure in Ephedra.
• Pollen dispersal is affected by the terminal settling velocity (Ut) of the grains, which is determined by their size, bulk density, and by atmospheric conditions. The likelihood that wind-dispersed pollen is captured by ovulate organs is influenced by the aerodynamic environment created around and by ovulate organs. We investigated pollen ultrastructure and Ut of Ephedra foeminea (purported to be entomophilous), and simulated the capture efficiency of its ovules. Results were compared with those from previously studied anemophilous Ephedra species.• Ut was determined using stroboscopic photography of pollen in free fall. The acceleration field around an "average" ovule was calculated, and inflight behavior of pollen grains was predicted using computer simulations. Pollen morphology and ultrastructure were investigated using SEM and STEM.• Pollen wall ultrastructure was correlated with Ut in Ephedra. The relative proportion and amount of granules in the infratectum determine pollen bulk densities, and (together with overall size) determine Ut and thus dispersal capability. Computer simulations failed to reveal any functional traits favoring anemophilous pollen capture in E. foeminea.• The fast Ut and dense ultrastructure of E. foeminea pollen are consistent with functional traits that distinguish entomophilous species from anemophilous species. In anemophilous Ephedra species, ovulate organs create an aerodynamic microenvironment that directs airborne pollen to the pollination drops. In E. foeminea, no such microenvironment is created. Ephedroid palynomorphs from the Cretaceous share the ultrastructural characteristics of E. foeminea, and at least some may, therefore, have been produced by insect-pollinated plants.


Compression of optical pulses spectrally broadened by self-phase modulation with a fiber bragg grating in transmission.
We demonstrate experimentally the compression of optical pulses, spectrally broadened by self-phase modulation occurring in the rod of a mode-locked Q-switched YLF laser, with an unchirped, apodized fiber Bragg grating in transmission. The compression is due to the strong dispersion of the Bragg grating at frequencies close to the edge of the photonic bandgap, in the passband, where the transmission is high. With the systems investigated, an 80-ps pulse, which is spectrally broadened, owing to self-phase modulation, with a peak nonlinear phase shift of D? = 7, is compressed to approximately 15 ps, in good agreement with theory and numerical simulations. The results demonstrate that photonic bandgap structures are promising devices for efficient pulse compression.


Metastatic Spinal Cord Compression and Steroid Treatment: A Systematic Review.
Systematic review. We conducted a systematic review of the literature to answer the following questions regarding the use of steroid therapy in metastatic spinal cord compression (MSCC): 1. In cases of MSCC, what is the effect of steroid administration before definitive radiotherapy or surgery on ambulatory status, bowel and bladder function and survival? 2. What steroid dosing regimens are associated with the best outcomes concerning neurological symptoms and complication prevention in cases of MSCC? Currently, there is significant variation in the initial bolus dose, daily maintenance dose and duration of treatment when steroids are used as a bridge to definitive therapy for MSCC. A literature search following PRISMA guidelines was conducted in June 2016, using Medline via Ovid SP, Medline via PubMed, Embase, Biosis Previews and the Cochrane Library. Search terms used in each database varied slightly to optimize results. All generic steroid formulations were included along with spinal cord compression or myelopathy combined with metastatic or malignant tumors. Papers discussing acute traumatic causes of spinal cord compression were excluded, as were papers discussing cord compression from nonmetastatic tumors or epidural lipomatosis. Subjects were limited to adult humans undergoing definitive treatment with radiotherapy or surgery. Of the 309 papers retrieved, 66 full text studies were reviewed and 6 papers were found to address the stated questions. There is a paucity of high quality literature evaluating the use of steroids in MSCC. On the basis of the evidence available an initial 10 mg intravenous bolus of dexamethasone followed by 16 mg PO QD has been associated with fewer complications compared with 100 mg bolus and 96 mg QD. Weaning of steroids should occur rapidly after definitive treatment. Risk of gastric bleeding or perforation can be managed with the routine use of proton-pump inhibitors. Level IIIa.


The corticotrophin-releasing factor-like peptide urocortin reverses key deficits in two rodent models of Parkinson's disease.
The potential neuroprotective action of the corticotrophin-releasing factor-related peptide urocortin (UCN) was investigated in the rat 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS) paradigms of Parkinson's disease. UCN (20 fmol) was either given at the same time as (T = 0) or 7 days after (T = +7) intracerebral 6-OHDA or LPS injection. At 14 days after 6-OHDA or LPS injection, circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given UCN at either T = 0 or T = +7 compared with animals given 6-OHDA or LPS and vehicle. Sham-treated rats showed no circling. Consistent with these observations, striatal dopamine concentrations were markedly higher in 6-OHDA/LPS + UCN rats vs. 6-OHDA/LPS + vehicle groups. Additionally, L-dihydroxyphenylalanine production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, whereas this was not the case in rats coadministered UCN. Finally, the numbers of tyrosine hydroxylase-positive cells recorded in the substantia nigra of 6-OHDA/LPS + vehicle-treated animals were markedly lower than those of sham-operated or 6-OHDA/LPS + UCN rats. Critically, UCN was effective in reversing lesion-induced deficits when given either at the same time as or 7 days after the neurotoxic insult. To our knowledge, this is the first time that such an effect has been demonstrated in vivo. The apparent ability of UCN to arrest the progression of or even reverse nigral lesions once established suggests that pharmacological manipulation of this system could have substantial therapeutic utility.


[Carney's triad].
The triad described by J.A. Carney in 1977 is characterized by the successive or concomitant occurrence of three rare tumours of different origin: gastric leiomyoblastoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. It is found mainly in young female patients with prevalent blood group A and may be incomplete, with only two of the three tumours occurring. The case of a young woman who developed gastric leiomyoblastoma and, six years later, pelvic paraganglioma is reported; she died of metastases from the paraganglioma with malignant hypertension. The 16 cases already published are reviewed. The authors insist upon the severity of paragangliomas and the need for a systematic search for the other tumours in patients who present with one tumour of the triad. A histogenetic interpretation relating the tumours to pathology of the neural crest is suggested.


Prospective analysis of complications 30 days after outpatient colonoscopy.
Our objective was to (1) determine whether more complications are reported by patients 30 days after outpatient colonoscopy than are discussed at our monthly morbidity and mortality conferences, (2) identify complications resulting in visits to the emergency department or physician's office or leading to hospitalization, and (3) assess which factors put patients at highest risk. A secondary goal was to determine the rate of work lost after outpatient colonoscopy. Trained interviewers performed standardized telephone interviews of consecutive outpatients undergoing colonoscopy at Georgetown University Hospital over a 1-year period. One thousand one hundred ninety-six patients were contacted 30 days after outpatient colonoscopy and participated in our study. Twenty patients had complications that required a visit to an emergency department or physician. Ninety percent of these cases (18) were detected at 30 days, but 15% (3) were discussed at morbidity and mortality conferences. All seven complications that necessitated hospitalization were identified at 30 days, but only two were discussed at our morbidity and mortality conference. The most common complications reported by patients were abdominal discomfort (5.4%) and rectal bleeding (2.1%). More complications are detected by means of contacting patients 30 days after outpatient colonoscopy than are discussed at our morbidity and mortality conferences.


Memory Buttons in Combination with Mobile Application-Induced Objective and Subjective Effects in Patients with Atopic Dermatitis.
Atopic dermatitis (AD) is a chronic skin condition where nonadherence often results in lack of disease control. We wanted to determine whether the combination of an electronic memory button and a supportive application (app) would affect the Quality of Life and subjective and objective severity measures among AD patients over one month following the patient's normal schedules of treatment. A randomized, investigator-blinded, prospective observational feasibility study for one month where patients diagnosed with AD were randomized based on POEM severity score and divided into 3 groups. The 3 groups were (1) the control group with two consultations, (2) in addition to group 1, patients also received electronic memory buttons to click every time they used their topical products, and (3) in addition to group 2, patients also received an app to track their treatment schedules. At both consultations, patients were evaluated using SCORAD, EASI, POEM, and DLQI. 96 patients were enrolled and randomized, of which 83 patients completed the study. EASI and SCORAD scores were lower in all groups at 2nd consultation (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (p < 0.05); however, these were highly significant for group 3 (. A reduction in severity following objective assessments of the AD was observed for all groups and was highly significant for patients offered a memory button and the corresponding app. Furthermore, patients reported a significant subjective beneficial effect if they used the memory button and app. This indicates that digital solutions may have a benefit in clinical practice and may reduce nonadherence and increase the wellbeing of the patients.


Respondent-driven sampling to assess outcomes of sexual violence: a methodological assessment.
Sexual violence is pervasive in eastern Democratic Republic of Congo (DRC). Survivors of sexual violence encounter numerous challenges, and women with a sexual violence-related pregnancy (SVRP) face even more complex sequelae. Because of the stigma associated with SVRP, there is no conventional sampling frame and, therefore, a paucity of research on SVRP outcomes. Respondent-driven sampling (RDS), used to study this "hidden" population, uses a peer recruitment sampling system that maintains strict participant privacy and controls and tracks recruitment. If RDS assumptions are met and the sample attains equilibrium, sample weights to correct for biases associated with traditional chain referral sampling can be calculated. Questionnaires were administered to female participants who were raising a child from a SVRP and/or who terminated a SVRP. A total of 852 participants were recruited from October 9, 2012, to November 7, 2012. There was rapid recruitment, and there were long referral chains. The majority of the variables reached equilibrium; thus, trends established in the sample population reflected the target population's trends. To our knowledge, this is the first study to use RDS to study outcomes of sexual violence. RDS was successfully applied to this population and context and should be considered as a sampling methodology in future sexual violence research.


Anthropogenic noise affects risk assessment and attention: the distracted prey hypothesis.
Many studies have focused on the effects of anthropogenic noise on animal communication, but only a few have looked at its effect on other behavioural systems. We designed a playback experiment to test the effect of noise on predation risk assessment. We found that in response to boat motor playback, Caribbean hermit crabs (Coenobita clypeatus) allowed a simulated predator to approach closer before they hid. Two hypotheses may explain how boat noise affected risk assessment: it masked an approaching predator's sound; and/or it reallocated some of the crabs' finite attention, effectively distracting them, and thus preventing them from responding to an approaching threat. We found no support for the first hypothesis: a silent looming object still got closer during boat motor playbacks than during silence. However, we found support for the attentional hypothesis: when we added flashing lights to the boat motor noise to further distract the hermit crabs, we were able to approach the crabs more closely than with the noise alone. Anthropogenic sounds may thus distract prey and make them more vulnerable to predation.


Overview of paediatric urology practice in lagos state university teaching hospital, Ikeja, Lagos, Nigeria.
Paediatric urology is one of the subspecialities of urology, and in most climes, it is practised by the urologists and paediatric surgeons, and likewise in the Lagos State University Teaching Hospital (LASUTH). The urologists see and manage most of these cases in LASUTH. There has been no formal training in this subspeciality. However, both the urologists and paediatric surgeons in LASUTH have acquired some measure of skill and experience over time by virtue of the relatively high volume of the cases seen. This study is aimed at reviewing the practice of paediatric urology in the urology division of LASUTH and to advocate for formal training in an otherwise rare but direly needed subspeciality. The ports of entry of paediatric patients with urologic conditions were assessed retrospectively over a 5-year period (2014-2018). The paediatric age range based on the Lagos State Government policy for health care is from birth to 12 years old. The ports of entry included the urologic outpatient department, paediatric and the adult surgical emergency units and the paediatric wards. Patients referred to and managed by the paediatric surgery division were excluded from this study. The total paediatric urology cases seen and managed by the urologist in LASUTH within the period of review were 421. A total of 363 paediatric urology cases were seen during the period under review, making up 7.96% of the urology cases seen at the surgical outpatient department. The most common cases managed were hypospadias, posterior urethral valves and hydronephrosis. A variety of other cases include priapism, circumcision and post-circumcision injuries, urethral prolapse, testicular torsion, cystic renal dysplasia, disorder of sexual differentiation and several others. Three hundred and seven surgical procedures were done in the period of review on 272 (64.6%) patients. There is a need for subspecialisation in paediatric urology to harness more specialists with a specific focus, training and interest in children and their urological conditions.


Cutting Balloon Angioplasty in the Treatment of Short Infrapopliteal Bifurcation Disease.
To evaluate the safety, feasibility, and effectiveness of cutting balloon angioplasty in the management of infrapopliteal bifurcation disease. Between November 2010 and March 2013, 23 patients (mean age 69.6±9.01 years, range 56-89; 16 men) suffering from critical limb ischemia were treated using cutting balloon angioplasty (single cutting balloon, T-shaped double cutting balloon, or double kissing cutting balloon technique) for 47 infrapopliteal artery bifurcation lesions (16 popliteal bifurcation and 9 tibioperoneal bifurcation) in 25 limbs. Follow-up consisted of clinical examination and duplex ultrasonography at 1 month and every 3 months thereafter. All treatments were technically successful. No 30-day death or adverse events needing treatment were registered. No flow-limiting dissection was observed, so no stent implantation was necessary. The mean postprocedure minimum lumen diameter and acute gain were 0.28±0.04 and 0.20±0.06 cm, respectively, with a residual stenosis of 0.04±0.02 cm. Primary and secondary patency rates were estimated as 89.3% and 93.5% at 6 months and 77.7% and 88.8% at 12 months, respectively; 1-year primary and secondary patency rates of the treated bifurcation were 74.2% and 87.0%, respectively. The survival rate estimated by Kaplan-Meier analysis was 82.5% at 1 year. Cutting balloon angioplasty seems to be a safe and effective tool in the routine treatment of short/ostial infrapopliteal bifurcation lesions, avoiding procedure-related complications, overcoming the limitations of conventional angioplasty, and improving the outcome of catheter-based therapy.


"Tuning into Kids": reducing young children's behavior problems using an emotion coaching parenting program.
This study evaluated a 6-session group parenting program, Tuning into Kids (TIK), as treatment for young children (aged 4.0-5.11 years) with behavior problems. TIK targets parent emotion socialization (parent emotion awareness, regulation and emotion coaching skills). Fifty-four parents, recruited via a child behavior clinic, were randomized into intervention (TIK) or waitlist (clinical treatment as usual). Parents reported emotion awareness/regulation, emotion coaching, empathy and child behavior (pre-intervention, post-intervention, 6-month follow-up); teachers reported child behavior and observers rated parent-child emotion coaching and child emotion knowledge (pre-intervention, follow-up). Data were analyzed using growth curve modeling and ANCOVA. Parents in both conditions reported less emotional dismissiveness and reduced child behavior problems; in the intervention group, parents also reported greater empathy and had improved observed emotion coaching skills; their children had greater emotion knowledge and reduced teacher-reported behavior problems. TIK appears to be a promising addition to treatment for child behavior problems.


Safety considerations of the use of second generation antipsychotics in the treatment of major depression: extrapyramidal and metabolic side effects.
Second generation antipsychotics (SGAs) are increasingly employed in the treatment of depression. Adjunctive aripiprizole and olanzapine/ fluoxetine combination (OFC) have been approved in the US in the treatment of depression. Quetiapine also appears to be poised for an FDA approval as an adjunctive treatment for resistant depression. Historically, first generation antipsychotics were thought to carry an enhanced risk of certain side effects in the treatment of mood disorders, including an enhanced risk of extrapyramidal symptoms (EPS). The second generation antipsychotics are also known to be associated with a variety of metabolic side effects. The use of SGA in a depressed population may pose risks that differ from use in other conditions such as bipolar disorder and schizophrenia. In this paper, the risk of extrapyramidal and metabolic side effects is reviewed in depressed patients treated with second generation antipsychotics.


[Human T-lymphotropic virus type I (HTLV-I): risk of transmission with transfusion].
PATHOGENIC ROLE: The human T-lymphotropic virus type I (HTLV-I), the first human retrovirus discovered, is the etiologic agent of adult T-cell leukemia/lymphoma (ATL) and of HTLV-I associated myelopathy or tropical spastic paraparesis (HAM/TSP) and has a widespread but uneven worldwide distribution. HTLV-I has a high seroprevalence in Southern Japan, the Caribbean basin and Sub-Sahara Africa. Blood transfusion, intravenous drug use, breast feeding and sexual contacts are major routes of contamination. IMPLICATIONS FOR BLOOD TRANSFUSION: The screening of blood donors for antibody to HTLV-I became systematic in 1989 in French West Indies and in 1991 in Continental France. This review deals with the transfusional implications of the HTLV-I, which belongs to the group of the blood-borne viruses: the prevalence of transfusion-linked HTLV-I infection before the implementation of the specific preventive measures, the parameters influencing the risk of transfusional contamination (the type of blood products, the age of the blood product with regards to its collection date, the proviral load of the blood donor), the prognosis of HTLV-I infection in patients contaminated by transfusion, the prophylactic strategies of transfusion contamination and the residual risk of infection through HTLV-I-infected risk blood products.


Dominant sugar utilizers in sediment of Lake Constance depend on syntrophic cooperation with methanogenic partner organisms.
Six strains of novel bacteria were isolated from profundal sediment of Lake Constance, a deep freshwater lake in Germany, by direct dilution of the sediment in mineral agar medium containing a background lawn of the hydrogen-scavenging Methanospirillum hungatei as a syntrophic partner. The numbers of colony-forming units obtained after incubation for more than 2 months were in the same range as those of total bacterial counts determined by DAPI staining (up to 10(8) cells per millilitre) suggesting that these organisms were dominant members of the community. Identical dilution series in the absence of methanogenic partners yielded numbers that were lower by two to three orders of magnitude. The dominant bacteria were isolated in defined co-culture with M. hungatei, and were further characterized. Growth was slow, with doubling times of 22-28 h at 28 degrees C. Cells were small, 0.5 x 5 microm in size, Gram-positive, and formed terminal oval spores. At 20 degrees C, glucose was fermented by the co-culture strain BoGlc83 nearly stoichiometrically to 2 mol of acetate and 1 mol of methane plus CO(2). At higher temperatures, also lactate and traces of succinate were formed. Anaerobic growth depended strictly on the presence of a hydrogen-scavenging partner organism and was inhibited by bromoethane sulfonate, which together indicate the need for a syntrophic partnership for this process. Strain BoGlc83 grew also aerobically in the absence of a partner organism. All enzymes involved in ATP formation via glycolysis and acetyl CoA were found, most of them at activities equivalent to the physiological substrate turnover rate. This new type of sugar-fermenting bacterium appears be the predominant sugar utilizer in this environment. The results show that syntrophic relationships can play an important role also for the utilization of substrates which otherwise can be degraded in pure culture.


Functional and genetic characterization of gas exchange and intrinsic water use efficiency in a full-sib family of Pinus pinaster Ait. in response to drought.
Drought is an important environmental factor in Mediterranean ecosystems affecting seedling recruitment, productivity or susceptibility to fires and pathogens. Studying water use efficiency in these environments is crucial due to its adaptive value allowing trees to cope with low water availability. We studied the phenotypic variability and genetic control of intrinsic water use efficiency (WUE(i)) and related traits in a full-sib family of Pinus pinaster under drought imposition. We detected significant differences in WUE(i) between clones of the same family and moderate heritability estimates that indicate some degree of genetic control over this trait. Stomatal conductance to water vapor was the trait most affected by drought imposition and it showed the strongest influence in WUE(i). Stomatal conductance to water vapor and specific leaf area (SLA) were the traits with highest heritabilities and they showed a significant genetic correlation with WUE(i), suggesting that selection of needles with low SLA values will improve WUE(i) in this species by reducing water losses through stomatal control.


Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes.
To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p < .0001) and increased the triglyceride/apoB48 ratio (i.e. the size) of chylomicrons (p < .001). Direct clearance of chylomicrons, a quantitatively significant pathway pretreatment, decreased by 90% on liraglutide (p < .001). Liraglutide also reduced VLDL1 -triglyceride secretion (p = .017) in parallel with reduced liver fat. Chylomicron-apoB48 production and particle size were related to insulin sensitivity (p = .015 and p < .001, respectively), but these associations were perturbed by liraglutide. In a physiologically relevant setting that mirrored regular feeding in subjects with T2D, liraglutide promoted potentially beneficial changes on postprandial apoB48 metabolism. Using our data in an integrated metabolic model, we describe how the action of liraglutide in T2D on chylomicron and VLDL kinetics could lead to decreased generation of remnant lipoproteins.


[Application of thoracoscopy in the diagnosis of pleuro-pulmonary disease].
Thoracoscopic examination was performed in 20 cases of pleuro-pulmonary diseases of uncertain etiology, 16 patients (80%) obtained positive thoracoscopic biopsy results while 4 false negative. Needle pleural biopsy was carried out in 10 cases and four of them gave correct diagnosis. After thoracoscopy thoracotomy were performed in 7 cases and all lesions were resected. Thirteen cases with advanced tumor or benign pleural diseases were treated conservatively. It was concluded that thoracoscopy is as an important technique in diagnosis of pleuro-pulmonary diseases.


[Therapeutic drug monitoring of methotrexate after its administration in high-dose protocols].
After HD-MTX infusions, i.e. at a dose>1 g/m2, monitoring of serum MTX concentrations is a standard practice which helps reducing the incidence of toxicity in patients with decreased clearance by guiding dose adjustment of leucovorin. Therapeutic monitoring of methotrexate is based on iterative measurements of serum concentration until concentration is below a certain threshold. This practice is supported by numerous observations of exposure-related toxicity as well as some clinical studies comparing drug exposure between patients with and without toxicity. Despite no prospective clinical study has clearly demonstrated the usefulness of methotrexate TDM, historical comparison reveals a huge reduction of toxicity-related events over past decades. Systematic monitoring may also help identifying patients with abnormally high methotrexate concentrations, who require immediate treatment with carboxypeptidase.


The hippocampus is sensitive to the mismatch in novelty between items and their contexts.
In previous functional magnetic resonance imaging (fMRI) studies of continuous recognition memory it was reported that new items elicit greater hippocampal activity than old (repeated) items (hippocampal 'novelty' effects). Rather than reflecting recency differences between new and old items, hippocampal novelty effects may instead reflect the novelty of the association between test items and the experimental context, or a mismatch in the novelty of the test item and the context. The present continuous recognition study assessed these possibilities by manipulating item-context associations on a trial-by-trial basis. Each trial comprised the presentation of an object-word (context-item) pair. Repeated items were paired either with the same context as on their first presentation, a different but previously presented context, or a new context. The task was to judge whether each item was old or new, regardless of the study status of the associated context. We found no evidence that hippocampal novelty effects reflected either item and context recency, or the novelty of the item-context association. Rather, enhanced hippocampal activity was elicited when the novelty of the item and its context mismatched. These findings support the possibility that hippocampal novelty effects reflect, at least in part, the disjunction in novelty between test items and their contexts.


Assessing dyspnea in patients with non-small cell lung cancer in the acute care setting.
Dyspnea is a common and often overlooked symptom in patients with lung cancer. Oncology nurses are positioned to promptly assess, triage, and intervene to minimize dyspnea, but improved assessment is needed. As a result, this pilot study explores the validity and feasibility of two assessment scales on measuring the perception of dyspnea in patients with non-small cell lung cancer in the acute care setting.


PROMIS--Prostate MR imaging study: A paired validating cohort study evaluating the role of multi-parametric MRI in men with clinical suspicion of prostate cancer.
Transrectal ultrasound-guided prostate biopsies are prone to detection errors. Multi-parametric MRI (MP-MRI) may improve the diagnostic pathway. PROMIS is a prospective validating paired-cohort study that meets criteria for level 1 evidence in diagnostic test evaluation. PROMIS will investigate whether multi-parametric (MP)-MRI can discriminate between men with and without clinically-significant prostate cancer who are at risk prior to first biopsy. Up to 714 men will have MP-MRI (index), 10-12 core TRUS-biopsy (standard) and 5mm transperineal template mapping (TPM) biopsies (reference). The conduct and reporting of each test will be blinded to the others. PROMIS will measure and compare sensitivity, specificity, and positive and negative predictive values of both MP-MRI and TRUS-biopsy against TPM biopsies. The MP-MRI results will be used to determine the proportion of men who could safely avoid biopsy without compromising detection of clinically-significant cancers. For the primary outcome, significant cancer on TPM is defined as Gleason grade >/= 4+3 and/or maximum cancer core length of ≥ 6 mm. PROMIS will also assess inter-observer variability among radiologists among other secondary outcomes. Cost-effectiveness of MP-MRI prior to biopsy will also be evaluated. PROMIS will determine whether MP-MRI of the prostate prior to first biopsy improves the detection accuracy of clinically-significant cancer.


The Association Between Internet Searches and Moisturizer Prescription in Japan: Retrospective Observational Study.
Heparinoid is a medication prescribed in Japan for skin diseases, such as atopic dermatitis and dry skin. Heparinoid prescription has increased with instances of internet blogs recommending its use as a cosmetic. This study aimed to examine the prescription trends in moisturizer use and analyze their association with internet searches. We used a claims database to identify pharmacy claims of heparinoid-only prescriptions in Japan. Additionally, we used Google Trends to obtain internet search data for the period between October 1, 2007, and September 31, 2017. To analyze the association between heparinoid prescriptions and internet searches, we performed an autoregressive integrated moving average approach for each time series. We identified 155,733 patients who had been prescribed heparinoid. The number of prescriptions increased from 2011 onward, and related internet searches increased from 2012 onward. Internet searches were significantly correlated with total heparinoid prescription (correlation coefficient=.25, P=.005). In addition, internet searches were significantly correlated with heparinoid prescription in those aged 20-59 years at -1-month lag in Google Trends (correlation coefficient=.30, P=.001). Google searches related to heparinoid prescriptions showed a seasonal pattern and increased gradually over the preceding several years. Google searches were positively correlated with prescription trends. In addition, in a particular age group (20-59 years), prescriptions increased with the increase in internet searches. These results suggest that people obtained health-related information on the internet and that this affected their behavior and prescription requests.


Perceived control over the medical procedure and its association with adjustment to a low-control situation: the case of infertility.
Illness perceptions were shown to be related to emotional and physical outcomes, as proposed by Leventhal's self-regulation model. These perceptions include the illness identity, its timeline, consequences, causes, and controllability, which later research found to include self-control and treatment control. The current study aimed to examine the role of a third type of perceived control: Control over the treatment procedures. We hypothesized that this type of control would be important for women undergoing infertility treatments, which are characterized by high uncertainty and low personal control. The sample included 194 Israeli women who were undergoing infertility treatments, 70% recruited in hospitals and the remainder in a fertility counseling center and website. All participants were married religious Jewish women, which added to the stress inherent in infertility. Study measures included the Illness Perception Questionnaire-Revised (IPQ-R), adapted to infertility, with an additional subscale assessing control over the procedure, and infertility-specific distress and well-being scales. Exploratory and confirmatory factor analyses supported the factor structure, including the distinct new subscale. A structural equations model showed that perceived consequences were most strongly related to distress and well-being. The three types of control were positively intercorrelated but differed in their associations with distress and well-being: Self-control over the problem and treatment control were unrelated to either measure while self-control over the procedure was related to greater well-being. These findings suggest that when control over the condition or the treatment outcomes is impossible, individuals may still benefit from control over external factors such as their health care. Healthcare providers can support them by seeking ways to increase their control over their treatment procedures, which may contribute to better psychological adjustment. Future studies should examine the role of perceived control over the procedures in other low-control situations (e.g., newly diagnosed cancer; aging-related declines).


Staging of cancer of the pancreas. Cancer of the Pancreas Task Force.
A new protocol for staging carcinoma of the exocrine pancreas has been retrospectively evaluated in 924 cases abstracted from 14 clinics and hospitals; these patients were treated between January 1, 1950, and December 31, 1976. Significant differences (P less than .05) were observed in the survival rates of Stage I patients, Stage II--III patients, and Stage IV patients who could be evaluated for survival. The median survival of Stage I patients treated by pancreatic resection (6.0 months) was approached in Stage II--III unresected cases with or without bypass procedures; these patients received radiation and/or chemotherapy postoperatively. It is suggested that his protocol may be useful in prospective clinical therapeutic investigations for the evaluation of newer protocols of medical, surgical, and radiotherapeutic treatment.


Effect of atrial fibrillation duration on plasma von Willebrand factor level.
von Willebrand factor (VWF) is an independent risk factor for adverse events in patients with non-valvular atrial fibrillation (NVAF). However, it is unclear if VWF level remains elevated and predictive of stroke during entire course of NVAF. In order to determine if VWF is a time-dependent blood variable, VWF antigen measured by latex immunoassay in 425 NVAF patients and 100 controls with normal sinus rhythm (NSR) was analyzed according to NVAF duration (<1 month: n = 76, 1-12 months: n = 98, and >12 months: n = 251). The mean VWF antigen level in NVAF patients with <1-month duration (167 ± 59%) was not different compared to those with 1-12 months (157 ± 50%, P = .24) and >12 months duration (156 ± 54%, P = .11) but higher compared to NSR controls (143 ± 48%, P = .003). Higher VWF level correlated with higher CHADS2 scores and with progressing intensity of blood stasis in the left atrium and thrombus formation in all three time periods of atrial fibrillation duration. Patients not treated with warfarin had VWF 30% higher in the first month compared to following months. von Willebrand Factor is steadily elevated throughout the course of dysrhythmia in NVAF patients treated with warfarin and in those with higher intensity of left atrium blood stasis.


Effects of mechanical deformation on energy conversion efficiency of piezoelectric nanogenerators.
Piezoelectric nanogenerators (PNGs) are capable of converting energy from various mechanical sources into electric energy and have many attractive features such as continuous operation, replenishment and low cost. However, many researchers still have studied novel material synthesis and interfacial controls to improve the power production from PNGs. In this study, we report the energy conversion efficiency (ECE) of PNGs dependent on mechanical deformations such as bending and twisting. Since the output power of PNGs is caused by the mechanical strain of the piezoelectric material, the power production and their ECE is critically dependent on the types of external mechanical deformations. Thus, we examine the output power from PNGs according to bending and twisting. In order to clearly understand the ECE of PNGs in the presence of those external mechanical deformations, we determine the ECE of PNGs by the ratio of output electrical energy and input mechanical energy, where we suggest that the input energy is based only on the strain energy of the piezoelectric layer. We calculate the strain energy of the piezoelectric layer using numerical simulation of bending and twisting of the PNG. Finally, we demonstrate that the ECE of the PNG caused by twisting is much higher than that caused by bending due to the multiple effects of normal and lateral piezoelectric coefficients. Our results thus provide a design direction for PNG systems as high-performance power generators.


Lipopolysaccharide impairs endothelial nitric oxide synthesis in rat renal arteries.
Impaired endothelium-dependent vasodilation may contribute to hypoperfusion and failure of abdominal organs, including the kidneys during endotoxin or septic shock. In this study, the short-term (2 h) effects of bacterial lipopolysaccharide (LPS) on endothelium-dependent vasodilation in rat renal and superior mesenteric arteries were documented. Rat renal and mesenteric arteries were dissected and exposed in vitro to LPS for two hours. The effects of LPS on vascular reactivity were determined and compared with time-matched controls. Endothelial nitric oxide (NO) release was determined using an NO microsensor in adjacent vessel segments. LPS impaired maximal acetylcholine (ACh)-induced endothelium-dependent vasodilation in renal arteries (62.5 +/- 8.8% vs. 34.4 +/- 7.5% in controls and LPS-exposed arteries), but not in mesenteric arteries. LPS did not alter the sensitivity of renal arteries to exogenous NO. ACh-dependent vasodilation was abolished after blocking NO synthesis with 10-4 mol/L L-NA in control and LPS-incubated renal arteries. When compared with controls, NO release induced by ACh and the receptor-independent calcium ionophore A23187 was significantly decreased (P < 0.05) in LPS-exposed renal segments and was fully abolished in endothelium-denuded segments, indicating that LPS attenuated receptor-dependent as well as receptor-independent endothelial NO release. In contrast, ACh- and A23187-induced NO release was normal in LPS-exposed mesenteric arteries. These results indicate that LPS-induced selective impairment of ACh-induced endothelium-dependent relaxation in rat renal arteries is caused by decreased endothelial NO release. This may contribute to the propensity for acute renal failure during septic shock.


Effect of competitive cues on reproductive morphology and behavioral plasticity in male fruitflies.
Phenotypic plasticity will be favored whenever there are significant fitness benefits of responding to environmental variation. The extent and nature of the plasticity that evolves depends on the rate of environmental fluctuations and the capacity to track and respond to that variability. Reproductive environments represent one arena in which changes can be rapid. The finding that males of many species show morphological, physiological, and behavioral plasticity in response to premating and postmating reproductive competition (RC) suggests that plasticity is broadly beneficial. The developmental environment is expected to accurately predict the average population level of RC but to be a relatively poor indicator of immediate RC at any particular mating. Therefore, we predict that manipulation of average RC during development should cause a response in plasticity "set" during development (e.g., size of adult reproductive structures), but not in flexible plasticity determined by the immediate adult environment (e.g., behavioral plasticity in mating duration). We tested this prediction in Drosophila melanogaster males by manipulating 2 independent cues of average RC during development: 1) larval density and 2) the presence or absence of adult males within larval culture vials. Consistent with the prediction, both manipulations resulted in the development of males with significantly larger adult accessory glands (although testis size decreased when males were added to culture vials). There was no effect on adult plasticity (mating duration, extended mating in response to rivals). The results suggest that males have evolved independent responses to long- and short-term variation in RC.


The new NMi orthovolt x-rays absorbed dose to water primary standard based on water calorimetry.
A new water calorimeter for orthovolt x-rays has been developed at NMi. The purpose of this calorimeter is to provide calibrations in terms of absorbed dose to water. Four internationally accepted CCRI qualities (100-250 kV) have been characterized. Correction factors have been determined with measurements, Monte Carlo calculations and heat transport models. The results of the calculations have been validated against measurements. The absorbed dose to water calibration coefficient, N(Dw,WCM), with the new calorimeter has been compared to the N(Dw,NCS) based on an air-kerma calibration coefficient, using the current NCS-10 dosimetry protocol. A good agreement is found for all beam qualities where the total uncertainty (1 SD) has decreased from 2.5% for N(Dw,NCS) to better than 1.5% for N(Dw,WCM), using the new water calorimeter.


[Biochemical reception and ionizing irradiation of the body].
The authors present the idea of the importance of studying the mechanism of biochemical reception of biologically active compounds (BAC) particularly the reception of prostaglandins after the effect of ionizing radiation on eucaryotes as a factor playing a significant role in understanding the radiation sickness pathogenesis. The perspectives of studying BAC reception are prognosticated for searching new radiomodifying agents (radioprotectors and means for treating radiation sickness).


The PSAP motif within the ORF3 protein of an avian strain of the hepatitis E virus is not critical for viral infectivity in vivo but plays a role in virus release.
The ORF3 protein of hepatitis E virus (HEV) is a multifunctional protein important for virus replication. The ORF3 proteins from human, swine, and avian strains of HEV contain a conserved PXXP amino acid motif, resembling either Src homology 3 (SH3) cell signaling interaction motifs or "late domains" involved in host cell interactions aiding in particle release. Using an avian strain of HEV, we determined the roles of the conserved prolines within the PREPSAPP motif in HEV replication and infectivity in Leghorn male hepatoma (LMH) chicken liver cells and in chickens. Each proline was changed to alanine to produce 8 avian HEV mutants containing single mutations (P64, P67, P70, and P71 to A), double mutations (P64/67A, P64/70A, and P67/70A), and triple mutations (P64/67/70A). The results showed that avian HEV mutants are replication competent in vitro, and none of the prolines in the PXXPXXPP motif are essential for infectivity in vivo; however, the second and third prolines appear to aid in fecal virus shedding, suggesting that the PSAP motif, but not the PREP motif, is involved in virus release. We also showed that the PSAP motif interacts with the host protein tumor suppressor gene 101 (TSG101) and that altering any proline within the PSAP motif disrupts this interaction. However, we showed that the ORF2 protein expressed in LMH cells is efficiently released from the cells in the absence of ORF3 and that coexpression of ORF2 and ORF3 did not act synergistically in this release, suggesting that another factor(s) such as ORF1 or viral genomic RNA may be necessary for proper particle release.


Peripheral arterial circulation in individuals with impaired glucose tolerance.
Employees of a telephone company in Naples (N = 1376) were screened by oral glucose tolerance test (OGTT, 75 g). All those with impaired glucose tolerance (IGT) (N = 69) plus 138 normoglycemic controls, matched by sex, age, and body mass index (BMI, kg/m2), were selected to participate in this study. All participants were retested by OGTT under the same conditions as the first test. The prevalence of signs of impaired peripheral arterial circulation (IPAC) were investigated by different methods: Rose questionnaire on intermittent claudication, digital pulse plethysmography (inclination time), and ankle blood pressure measurement (ankle/arm systolic blood pressure). Very few persons had symptoms of IPAC: 2 (3.1%) and 3 (2.4%), respectively, in IGT subjects and controls. No difference in the prevalence of abnormal vascular parameters was detected between IGT and normoglycemic individuals according to either digital pulse plethysmography (6.1% versus 8.8%, P = 0.36) or ankle blood pressure measurement (10.8% versus 9.6%, chi 2 = 0.06, NS); similar results were obtained when the prevalence of abnormalities was evaluated according to both methods combined (16.9% versus 16.8%). The finding remained very much the same after controlling for the effect of smoking. Individuals with IGT at both OGTTs were compared with individuals with normoglycemia at both tests: once again no significant difference was detected between the two groups in the prevalence of abnormal vascular findings (22.6% versus 16.7%, chi 2 = 0.66, NS). This suggests that IGT is not associated with increased prevalence of atherosclerotic peripheral arterial disease.


Near-infrared acetylene sensor system using off-axis integrated-cavity output spectroscopy and two measurement schemes.
For highly sensitive and accurate acetylene (C2H2) detection, a near-infrared (NIR) off-axis integrated-cavity output spectroscopy (OA-ICOS) sensor system based on an ultra-compact cage-based absorption cell was proposed. The absorption cell with dimensions of 10 cm × 8 cm × 6 cm realized a dense-pattern and an easily-aligned stable optical system. The OA-ICOS sensor system employed a 6cm-long optical cavity that was formed by two mirrors with a reflectivity of 99.35% and provided an effective absorption path length of ∼9.28 m. The performance of the C2H2 sensor system based on two measurement schemes, i.e. laser direct absorption spectroscopy (LDAS) and wavelength modulation spectroscopy (WMS) is reported. A NIR distributed feedback (DFB) laser was employed for targeting a C2H2 absorption line at 6523.88 cm-1. An Allan deviation analysis yielded a detection sensitivity of 760 parts-per-billion in volume (ppbv) for an averaging time of 304 s using the LDAS-based OA-ICOS. A detection sensitivity of 85 ppbv for an averaging time of 250 s was obtained using the WMS-based OA-ICOS, which was further improved by a factor of ~9 compared to the result obtained with the LDAS method. The proposed sensor system has the advantages of reduced size and cost with acceptable detection sensitivity, which is suitable for applications in trace gas sensing in harsh environments and weight-limited balloon-embedded observations.


Intrauterine environment and cognitive development in young twins.
Intrauterine factors important for cognitive development, such as birth weight, chorionicity and umbilical cord characteristics were investigated. A total of 663 twin pairs completed the Wechsler Intelligence Scale for Children-Revised and scores were available for Performance, Verbal and Total Intelligence Quotient (IQ). The intrauterine factors examined were birth weight, placental weight and morphology, cord knots, cord length and cord insertion. IQ scores for the varying levels of the intrauterine markers adjusting for gender and gestational age were calculated. The heritability of IQ and the association between IQ and intrauterine environment were examined. Twins with lower birth weight and cord knots had lower IQ scores. The aetiology of IQ is largely distinct from that of birth weight and cord knots, and non-shared environment may influence the observed relationships.


Biological Responses of Ceramic Bone Spacers Produced by Green Processing of Additively Manufactured Thin Meshes.
Bone spacers are exclusively used for replacing the tissue after trauma and/or diseases. Ceramic materials bring positive opportunities to enhance greater osteointegration and performance of implants, yet processing of porous geometries can be challenging. Additive Manufacturing (AM) opens opportunities to grade porosity levels in a part; however, its productivity may be low due to its batch processing approach. The paper studies the biological responses yielded by hydroxyapatite with β-TCP (tricalcium phosphate) ceramic porous bone spacers manufactured by robocasting 2-layer meshes that are rolled in green and sintered. The implants are assessed in vitro and in vivo for their compatibility. Human bone marrow mesenchymal stem cells attached, proliferated and differentiated on the bone spacers produced. Cells on the spacers presented alkaline phosphatase staining, confirming osteogenic differentiation. They also expressed bone-specific COL1A1, BGAP, BSP, and SPP1 genes. The fold change of these genes ranged between 8 to 16 folds compared to controls. When implanted into the subcutaneous tissue of rabbits, they triggered collagen fibre formation and mild fibroblastic proliferation. In conclusion, rolled AM-meshes bone spacers stimulated bone formation in vitro and were biocompatible in vivo. This technology may give the advantage to custom produce spacers at high production rates if industrially upscaled.


Role of aryl hydrocarbon receptor in mesencephalic circulation failure and apoptosis in zebrafish embryos exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and potent developmental toxicant in various animals, with developing fish being the most sensitive organisms. Although the expression of aryl hydrocarbon receptor (AHR) as well as the partner molecule, AHR nuclear translocator (ARNT) in the brain has been reported, the effect of TCDD on the brain remains to be clarified in detail. Previously, we reported local circulation failure and apoptosis in dorsal midbrain caused by TCDD in developing zebrafish. In the present experiments, we investigated the effects of morpholino antisense oligos against aryl hydrocarbon receptor 2 (zfAHR2) (AHR2-MO) on toxicological endpoints caused by TCDD in developing zebrafish. AHR2-MO but not its negative homologue (4mis-AHR2-MO) improved TCDD-evoked circulation failure in mesencephalic vein and reduced the occurrence of apoptosis in dorsal midbrain, with concomitant inhibition of CYP1A induction in vascular endothelium. Injection of bovine serum albumin (BSA) into the general circulation, followed by immunohistochemistry with anti-BSA, showed that TCDD raised vascular permeability to albumin in dorsal midbrain, which was blocked by AHR2-MO and N-acetlycystein. In the absence of TCDD, development of embryos injected with AHR2-MO appeared normal at least until 60 h after fertilization. It is concluded that AHR2 activation in the vascular endothelium of the zebrafish embryo midbrain is involved in the mesencephalic circulation failure and apoptosis elicited by TCDD. This is the further evidence that vascular endothelium is the target of TCDD in relation to local circulation failure and apoptosis in dorsal midbrain.


Primary and secondary orbit surgery: the transconjunctival approach.
The transconjunctival approach to the orbit is underutilized because of concern regarding inadequate exposure and higher postoperative rates of lower eyelid shortening and ectropion. All patients who had a transconjunctival incision performed for orbital surgery over the last 6 years (1990 to 1996) were studied. Patients who had a transconjunctival blepharoplasty were excluded. A total of 35 patients, average age 32 years, had 45 transconjunctival incisions performed. Lateral canthotomy or cantholysis was not done. Operations fell into three categories: fracture plating alone, 10 (22 percent); split-calvarial bone graft placement with or without plating, 26 (58 percent); and orbital decompression, 9 (20 percent). The overall incidence of ectropion was 6.7 percent (3 of 45). One patient (2 percent) had transient ectropion, and two patients (4 percent) had persistent ectropion, which required surgical correction. Ectropion occurred only in those lower eyelids that had a previous transcutaneous incision (3 of 18 = 17 percent). None occurred in those eyelids that had no prior incision or only a previous transconjunctival incision. The transconjunctival approach without a lateral canthotomy provides safe access to the orbit in eyelids that have not had a previous transconjunctival incision.


Hysteresis in the gas sorption isotherms of metal-organic cages accompanied by subtle changes in molecular packing.
Structural deformation in response to gas sorption is rarely observed for porous molecular solids, when compared to porous framework materials. Here, we describe the effect of chemical modification on the exterior of lantern-type metal-organic cages on the emergence and then disappearance of cooperative gas uptake. The results suggest that supramolecular design of ligands can be used to reveal this behaviour.


Bronchopulmonary torulopsosis.
A patient had clinical and radiographic findings suggestive of allergic bronchopulmonary aspergillosis. Further studies excluded this diagnosis but indicated that the patient's respiratory disease was due to the yeast Torulopsis glabrata, usually nonpathogenic in normal human hosts. The patient had no evidence of invasive disease. Total serum IgE was elevated but IgE antibody against T. glabrata could not be demonstrated by skin test or radioimmunoassay. Demonstration of elevated IgG antibody against T. glabrata antigen by radioimmunoassay was of value in suggesting the diagnosis. The patient responded to prednisone therapy with clinical and radiographic improvement and with a sharp decline in total serum IgE, and a lesser degree of decline in total serum IgG and IgA. Bronchopulmonary torulopsosis may be rare but should be considered in cases where the diagnosis of allergic bronchopulmonary aspergillosis cannot be established. Because IgE antibody could not be incriminated in this disease the term allergic bronchopulmonary torulopsosis was not used in this case.


Assessment of animal diseases caused by bacteria resistant to antimicrobials: sheep and goats.
In this opinion, the antimicrobial-resistant bacteria responsible for transmissible diseases that constitute a threat to the health of sheep and goats have been assessed. The assessment has been performed following a methodology based on information collected by an extensive literature review and expert judgement. Details of the methodology used for this assessment are explained in a separate opinion. A global state of play on antimicrobial resistance in clinical isolates of Staphylococcus aureus, Escherichia coli (non-VTEC), Pseudomonas aeruginosa, Dichelobacter nodosus, Moraxella ovis, Mannheimia haemolytica, Pasteurella multocida, Mycoplasma ovipneumoniae, Mycoplasma agalactiae, Trueperella pyogenes, Streptococcus uberis, Bibersteinia trehalosi, Campylobacter fetus, Mycoplasma mycoides subsp. capri, Mycoplasma capricolum subsp. capricolum, Fusobacterium necrophorum is provided. Among those bacteria, EFSA identified E. coli with ≥ 66% certainty as being the most relevant antimicrobial-resistant bacteria in sheep and goat in the EU based on the available evidence. The animal health impact of these most relevant bacteria, as well as their eligibility for being listed and categorised within the animal health law framework will be assessed in separate scientific opinions.


SIRT5 rs12216101 T>G variant is associated with liver damage and mitochondrial dysfunction in patients with non-alcoholic fatty liver disease.
Sirtuin 5, encoded by the SIRT5 gene, is a NAD+-dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101 T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD). The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics in vitro were investigated by high-performance liquid chromatography. In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101 T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101 T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels. The SIRT5 rs12216101 T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD. In this study we discovered that the SIRT5 rs12216101 T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD.


Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice.
Preautonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus play a large role in the regulation of hepatic functions via the autonomic nervous system. Activation of hepatic sympathetic nerves increases glucose and lipid metabolism and contributes to the elevated hepatic glucose production observed in the type 2 diabetic condition. This augmented sympathetic output could originate from altered activity of liver-related PVN neurons. Remarkably, despite the importance of the brain-liver pathway, the cellular properties of liver-related neurons are not known. In this study, we provide the first evidence of overall activity of liver-related PVN neurons. Liver-related PVN neurons were identified with a retrograde, trans-synaptic, viral tracer in male lean and db/db mice and whole-cell patch-clamp recordings were conducted. In db/db mice, the majority of liver-related PVN neurons fired spontaneously; whereas, in lean mice the majority of liver-related PVN neurons were silent, indicating that liver-related PVN neurons are more active in db/db mice. Persistent, tonic inhibition was identified in liver-related PVN neurons; although, the magnitude of tonic inhibitory control was not different between lean and db/db mice. In addition, our study revealed that the transient receptor potential vanilloid type 1-dependent increase of excitatory neurotransmission was reduced in liver-related PVN neurons of db/db mice. These findings demonstrate plasticity of liver-related PVN neurons and a shift toward excitation in a diabetic mouse model. Our study suggests altered autonomic circuits at the level of the PVN, which can contribute to autonomic dysfunction and dysregulation of neural control of hepatic functions including glucose metabolism.SIGNIFICANCE STATEMENT A growing body of evidence suggests the importance of the autonomic control in the regulation of hepatic metabolism, which plays a major role in the development and progression of type 2 diabetes mellitus. Despite the importance of the brain-liver pathway, the overall activity of liver-related neurons in control and diabetic conditions is not known. This is a significant gap in knowledge, which prevents developing strategies to improve glucose homeostasis via altering the brain-liver pathway. One of the key findings of our study is the overall shift toward excitation in liver-related hypothalamic neurons in the diabetic condition. This overactivity may be one of the underlying mechanisms of elevated sympathetic activity known in metabolically compromised patients and animal models.


Efficacy and tolerability of once-daily venlafaxine extended release (XR) in outpatients with major depression. The Venlafaxine XR 209 Study Group.
This was a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of once-daily venlafaxine extended release (XR) in out-patients with DSM-IV major depression. Patients were randomly assigned to venlafaxine XR (75-225 mg) once daily or placebo for up to 8 weeks. The primary efficacy variables were the 21-item Hamilton Rating Scale for Depression (HAM-D) total score and HAM-D depressed mood item, the Montgomery-Asberg Depression Rating Scale (MADRS) total scores, and the Clinical Global Impressions (CGI) Severity scale. Data were analyzed on a modified intent-to-treat basis using the last-observation-carried-forward method. Venlafaxine XR (N = 91) was significantly more effective than placebo (N = 100) beginning at Week 2 on the CGI Severity scale, at Week 3 on the HAM-D depressed mood item, and at Week 4 on the HAM-D and MADRS; this superiority was maintained through Week 8. The most common treatment-emergent adverse events associated with venlafaxine XR were nausea, insomnia, and somnolence. The incidence of nausea was highest during the first week, decreased by 50% during the second week, and was comparable to that of placebo from Week 3 onward. These results demonstrate that venlafaxine XR is an effective and well-tolerated treatment of major depression.


Fracture of the carpal scaphoid in children. A clinical and roentgenological study of 108 cases.
A series of 108 carpal scaphoid fractures in children was analysed with respect to the site, type and treatment of the fracture. The patients were followed until radiological fusion occurred. All fractures united and healed completely with conservative treatment. Ninety-four fractures, 41 of which were avulsions, were located in the distal third of the scaphoid. There were 13 waist fractures, and one avulsion fracture was located in the proximal pole of the scaphoid. The great number of avulsion fractures and the location of the fractures in the distal third of the scaphoid is very typical in children. In three neglected cases marked bone resorption was seen on the fracture surface 3 weeks after the injury. Because non-union is possible especially in neglected cases of waist fractures, control radiographs should be taken 1 or 2 weeks after the injury if the fracture is not visible on the primary radiographs but is suspected clinically. Immobilization with an adequate plaster cast is mandatory in all transverse fractures of the carpal scaphoid in children.