Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens.
High antibody reactivity toward microbial antigens in Crohn's disease (CD) patients is predictive of a more aggressive disease course. However, few ulcerative colitis (UC) patients exhibit serologic reactivity toward microbial antigens. Mucosal expression of IFN-γ plays a pivotal role in inflammatory bowel disease (IBD) pathogenesis. Recent genome-wide association studies (GWAS) surprisingly link UC, but not CD, risk loci to IFNG. We recently demonstrated that mucosal T cells from IBD patients exhibit distinct patterns of IFNG methylation compared to controls. This study evaluated the relationship between IFNG methylation and serologic and clinical profiles in peripheral T cells from IBD patients. DNA from peripheral T cells of 163 IBD patients (91 CD and 64 UC) and 42 controls was analyzed for methylation of eight IFNG sites. Serum markers ASCA, OmpC, I2, CBir, and pANCA were measured by enzyme-linked immunosorbent assay (ELISA). IFN-γ secretion was measured by ELISA. IBD patients requiring surgery exhibited reduced IFNG methylation compared to nonsurgical patients (P < 0.02). Enhancement of IFN-γ secretion (P < 0.003), along with high antibody responses toward multiple microbial antigens (P < 0.017) in UC, but not CD, patients was correlated with decreased IFNG methylation. pANCA levels were not correlated with IFNG methylation. Levels of IFNG methylation were correlated with immune response to microbial components and expression of IFN-γ in UC patients. Serological and epigenetic markers identify a subset of UC patients with an expression profile of a key TH1 pathogenic cytokine. These data may provide a useful tool to classify a more homogeneous subset of UC patients, allowing for improved diagnostics and targeted therapeutics.


An unusual case of congenital cytomegalovirus infection-related retinopathy.
Cytomegalovirus (CMV) is the most common congenital infection, and chorioretinitis is the most common ophthalmic manifestation of congenital CMV infection. We experienced a unique case of CMV retinopathy showing unusual retinal vessels. An infant boy weighing 1860 g was born at 36 weeks. He was diagnosed with severe symptomatic congenital CMV infection, which was confirmed by positive CMV-DNA in urine and whole blood, and he was referred to our ophthalmology department on his first day of life. Ophthalmoscopic examination and fluorescein angiography revealed no chorioretinitis but major retinal vascular occlusions and arterio-venous anastomosis associated with CMV detection in the aqueous humor. These findings regressed within a week after treatment with systemic gancyclovir administration. To our knowledge, there are no reports of these ocular issues associated with congenital CMV infection. These findings may be useful for the early and rapid diagnosis of congenital CMV infection.


Acute-phase proteins and levels of interleukin 1B, interleukin 6, tumor necrosis factor alpha, and interleukin 8 in children with pertussis.
To determine serum levels of acute-phase proteins and interleukin 1B, interleukin 6, tumor necrosis factor alpha, and interleukin 8 in children with pertussis. Cross-sectional study. Divisions of Infectious Diseases, Regional Hospital, and Pediatrics, University of Pavia, Varese, Italy. Eight children with pertussis, six with acute febrile infections, and eight healthy control children matched for sex, age, and time presentation over a 32-month study period. None. An immunoenzymatic assay was used to detect serum levels of all cytokines. Normal values of C-reactive protein, alpha 1-acid glycoprotein, and erythrocyte sedimentation rate were observed in the serum of patients with pertussis. The mean (+/- SD) detectable levels of tumor necrosis factor alpha (65.0 +/- 50.4 pg/mL) and interleukin 6 (32.3 +/- 17.8 pg/mL) were observed in the serum of patients with pertussis. In contrast, a nonsignificant increment of interleukin 1B levels (66.5 +/- 83.7 pg/mL) and interleukin 8 levels (12.7 +/- 17.8 pg/mL) was noted in the serum of the same patients. Increased and significant levels of all four cytokines were noted in most of the serum samples of patients with acute febrile infections. Acute-phase response is absent in patients with pertussis, whereas detectable and significant serum levels of tumor necrosis factor alpha and interleukin 6 were observed in some such patients.


An insertion of oleate desaturase homologous sequence silences via siRNA the functional gene leading to high oleic acid content in sunflower seed oil.
Classical sunflower varieties display a high linoleic acid content in their seeds [low oleic (LO) varieties] whereas genotypes carrying the Pervenets mutation display an increased oleic acid content of above 83% [high oleic (HO) varieties]. Despite the advantage in health terms of oleic acid, the nature of the mutation was still unknown. Previous work reported that HO genotypes carried a specific oleate desaturase (OD) allele. This enzyme catalyses the desaturation of oleic acid into linoleic acid. The present work demonstrates that this allele is organised in two parts: the first section present in both HO and LO genotypes carries a normal OD gene, the second section is specific to HO genotypes and carries OD duplications. The study of mRNA accumulation in LO and HO seeds revealed that the mutation is dominant and induces an OD mRNA down-regulation. Furthermore, OD small interfering RNA, characteristic of gene silencing, accumulated specifically in HO seeds. Considered together, these observations show that the mutation is associated with OD duplications leading to gene silencing of the OD gene and consequently, to oleic acid accumulation. This finding allowed the development of molecular markers characterising the mutation that can be used in breeding programmes to facilitate the selection of HO genotypes.


[The stress situation in ambulatory oral surgical interventions].
On the basis of results from various studies, the authors show that the psychic initial condition and the psychophysical stress during the operation are of paramount importance to the rise of complications.


Dilatation for assisted ventilation-induced laryngotracheal stenosis.
To assess the long-term results of dilatation and our experience with dilatation for assisted ventilation-induced laryngotracheal stenosis. A retrospective study of 32 patients primarily treated with dilatation for assisted ventilation-induced laryngotracheal stenosis between 1977 and 2002. A tertiary care center and university teaching hospital. There were 19 men and 13 women aged 15 to 76 years. The stenosis was cicatricial with some inflammatory process in 27 patients and completely mature in 5 patients. The stenosis involved the cricoid and the trachea in four patients. In 28 patients, the stenosis involved only the trachea. Dilatation was performed with serially sized rigid bronchoscopes. Endoscopic laser vaporization was never performed in this series. Six patients were treated with only one dilatation. The 26 remaining patients were treated with successively 2 to 10 dilatations (mean, 3.3 dilatations). The dilatation success rate was analyzed using the Kaplan-Meier method. Median duration of follow-up was 1.8 years. Mortality rate was 9.4%. The overall failure rate was 71.8%. Twenty patients presented with recurrent stenosis. The treatment of recurrent stenosis consisted of tracheal resection with end-to-end anastomosis (11 patients, 55%), cricotracheal anastomosis (5 patients, 25%), tracheal endoprosthesis (2 patients, 10%), and tracheotomy (1 patient, 5%). All patients who underwent tracheal or cricotracheal anastomosis were successfully treated. None of the variables under analysis (sex, age, medical history, cause for intubation, intubation type and duration, delay from initial injury, degree of stenosis, length of trachea involved, number of dilatations) were statistically related to the incidence of complications and the success rate of dilatations. We do not recommend dilatation technique as the sole treatment for assisted ventilation-induced laryngotracheal stenosis. This technique is helpful in case of emergency to restore an airway and useful for the assessment of stenosis.


Bose-Einstein Condensation for Two Dimensional Bosons in the Gross-Pitaevskii Regime.
We consider systems of N bosons trapped on the two-dimensional unit torus, in the Gross-Pitaevskii regime, where the scattering length of the repulsive interaction is exponentially small in the number of particles. We show that low-energy states exhibit complete Bose-Einstein condensation, with almost optimal bounds on the number of orthogonal excitations.


Secretory glycoconjugates in the epithelium of the goat prostate.
Secretory glycoconjugates in the epithelium of the goat prostate were investigated with various electron microscopical histochemical methods that involved periodic acid-thiocarbohydrazide-silver proteinate, colloidal gold-labelled lectin and related procedures. The three types of cells in the epithelium previously differentiated with the light microscope were substantiated: mucus-producing cells, protein-secreting cells and cells intermediate between both types. These three cell types contained varying amounts of neutral glycoconjugates; the histochemical nature of these carbohydrates was determined with particular emphasis upon the histophysiological functions of the accessory sex glands.


A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors.
Patients with advanced BRAFV600 mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.


Early-life interventions to prevent feather pecking and reduce fearfulness in laying hens.
Severe feather pecking, the pulling out of feathers of conspecifics, is a major welfare issue in laying hens. Possible underlying causes are fearfulness and lack of foraging opportunities. Because early life is a crucial stage in behavioral development, adapting the incubation and rearing environment to the birds' needs may reduce fearfulness and prevent the development of feather pecking. In a 2 × 2 factorial design study, we investigated whether a green light-dark cycle throughout incubation, which resembles natural incubation circumstances more than the standard dark incubation, and foraging enrichment with live larvae during rearing reduce fearfulness and feather pecking and increase foraging behavior of laying hen pullets from an early age onwards. In this 2-batch experiment, 1,100 ISA Brown eggs were incubated under either 0 h of light/24 h of darkness or 12 h of green LED light/12 h of darkness. After hatching, 400 female chicks (200 per batch) were housed in 44 pens (8-10 chicks per pen). During the entire rearing phase (0-17 wk of age), half of the pens received black soldier fly larvae in a food puzzle as foraging enrichment. We assessed fear of novel objects and humans, feather pecking, plumage condition, foraging behavior, and recovery time after a 3-fold vaccination (acute stressor). A slight increase in the number of foraging bouts was only seen with larvae provisioning (rate ratio 1.19, 95% CI 1.02-1.29, P = 0.008). Neither lighted incubation nor larvae provisioning affected fearfulness, feather pecking, plumage condition or recovery time after vaccination. In conclusion, the present study showed no effects of light during incubation and minor effects of foraging enrichment during rearing on the behavior of laying hen pullets. Further research is recommended on other welfare aspects.


Factors influencing the perception of profile beauty in Class III dental compensation: A comparative cross-sectional study according to three categories of assessors.
The main objective of this study was to evaluate the different factors influencing the perception of female profile facial beauty in Class III patients with protruded mandible that can be treated with orthodontic dental compensation: (1)severity of the protrusion, (2) the upper incisors inclination and (3) the presence of jawlines. The secondary objective was to determine if the rater's gender and profession played a role in the assessment of the preferred profile. A normal and smiling photographs of a female subject with normal facial and skeletal profile criteria were digitally manipulated to obtain 3 different mandibular sagittal positions: 0mm, +4mm and +8mm. Each position of the chin was evaluated with the presence or not of jawlines. In the smiling profiles, the same chin modifications were scored, and the maxillary incisor inclination was changed from 0 to +10 degrees with 5 degrees increments. A total of 320 raters (107 dentists, 103 orthodontists and 110 laypeople) scored the attractiveness of the different images using a Visual Analogue Scale. The limit of statistical significance was P<0.05. Generalized estimating equation (GEE) models were conducted to assess the predictors of variations in ratings within each set of photos, as well as the interactions of predictors where adjusted odds ratios (aOR) and their 95% confidence intervals were calculated and reported. In the profiles without a smile, image +4mm chin (Class III treated by compensation) and image +8-mm mandible (Class III not treated) were selected as the most and least attractive images, respectively, by almost all groups with no difference. The presence of jawlines has a positive role in facial attractiveness. In the smiling profiles, all the examiners showed a preference for image +4-mm chin and a slight protrusion of maxillary incisors (+5 degrees). No significant difference was found between genders in this study. Class III treated by compensation (+4mm) are more attractive than non-treated Class III (+8mm) by almost all groups with no difference. The presence of jawlines has a positive role in facial attractiveness. In the smiling profiles, all the examiners showed a preference for image +4-mm chin and a slight protrusion of maxillary incisors (+5 degrees). Orthodontists older than 50 years old are aware of the difficulty to treat a skeletal Class III and tend to accept it due to their long career experience. No significant difference was found between genders in this study.


Direct and indirect effects of petroleum production activities on the western fence lizard (Sceloporus occidentalis) as a surrogate for the dunes sagebrush lizard (Sceloporus arenicolus).
The dunes sagebrush lizard (Sceloporus arenicolus) is a habitat specialist of conservation concern limited to shin oak sand dune systems of New Mexico and Texas (USA). Because much of the dunes sagebrush lizard's habitat occurs in areas of high oil and gas production, there may be direct and indirect effects of these activities. The congeneric Western fence lizard (Sceloporus occidentalis) was used as a surrogate species to determine direct effects of 2 contaminants associated with oil and gas drilling activities in the Permian Basin (NM and TX, USA): herbicide formulations (Krovar and Quest) and hydrogen sulfide gas (H2S). Lizards were exposed to 2 concentrations of H2 S (30 ppm or 90 ppm) and herbicide formulations (1× or 2× label application rate) representing high-end exposure scenarios. Sublethal behavioral endpoints were evaluated, including sprint speed and time to prey detection and capture. Neither H2S nor herbicide formulations caused significant behavioral effects compared to controls. To understand potential indirect effects of oil and gas drilling on the prey base, terrestrial invertebrate biomass and order diversity were quantified at impacted sites to compare with nonimpacted sites. A significant decrease in biomass was found at impacted sites, but no significant effects on diversity. The results suggest little risk from direct toxic effects, but the potential for indirect effects should be further explored.


[Patient satisfaction in acute coronary syndrome. Improvement through the establishment of a chest pain unit].
Chest pain units (CPUs) were established primarily in the United States with the aim of reducing hospital admissions and costs, whilst improving quality of life and patient care. Clinical trials have shown that these units are safe and practical; however, there was a need to investigate to what extent patients are satisfied with the care in CPUs. The aim of this study is to evaluate the experiences of patients receiving CPU care and routine emergency department (ED) treatment for acute chest pain. Patients presenting with acute chest pain at the ED between May 2004 and June 2005 and at the CPU between July 2005 and May 2006 were evaluated in this retrospective analysis. Standardized data collection using all available clinical data as well as telephone follow-up was carried out. Evaluation was carried out on a school-mark basis and a quality assessment was performed. Of the total population, 479 patients (323 male, 156 female) were treated in the ED, whereas 1176 (743 male, 433 female) in the CPU. In the ED, 26 patients (5.4%) were diagnosed as ST segment elevation myocardial infarction (STEMI), 39 (8.1%) as non-ST segment elevation myocardial infarction (NSTEMI) and 16 (3.3%) as unstable angina pectoris (UAP). In 398 patients (83.1%) acute coronary syndrome (ACS) could be ruled out. In the CPU, the incidence of STEMI was 74 (6.3%), of NSTEMI 141 (12%) and of UAP 153 (13%). ACS was excluded in 808 patients (68.7%). Data on satisfaction with in-hospital treatment was available in 78.5% of cases. In the CPU, 92.2% of the patients judged their treatment as excellent/good, 5.9% as appropriate and 1.9% as poor. The distribution of satisfaction in the ED was significantly lower with 78.6% excellent/good, 18.5% appropriate and 2.9% poor. The establishment of a CPU at the University Medical Center of Mainz demonstrated a higher level of patient satisfaction compared to the treatment of patients with acute chest pain in the general ED.


Cellulose nanofibrils (CNFs) produced by different mechanical methods to improve mechanical properties of recycled paper.
In current study, CNFs produced by different mechanical methods, were used to improve the mechanical properties of recycled paper. The result showed the morphology of CNFs had great impact on reinforced effect and the length of fibrils determined their contribution in recycled paper strength. For different CNFs with similar diameter, the higher aspect ratio resulted in better reinforced effect. The CNFs produced by microfluidic homogenization and suitable PFI milling conditions (RM-CNF1) got best reinforced effect which improved tensile index and burst index by 35.5 % and 49.4 % at 5.0 wt% addition, respectively, due to their high aspect ratio. Although the CNFs produced by ball milling and ultrasonication (BU-CNF2) still had many bundles that were not fibrillated completely, their reinforced effect just below RM-CNF1 due to their special morphology and high retention rate. This work aims to study the influence of CNFs on recycled fibers reinforcement.


Exogenous attentional selection of transparent superimposed surfaces modulates early event-related potentials.
Using a transparent motion paradigm, [Valdes-Sosa, M., Bobes, M. A., Rodriguez, V., & Pinilla, T. (1998). Switching attention without shifting the spotlight object-based attentional modulation of brain potentials, Journal of Cognitive Neuroscience, 10, 137-151; Valdes-Sosa, M., Cobo, A., & Pinilla, T. (2000). Attention to object files defined by transparent motion, Journal of Experimental Psychological: Human Perception and Performance, 26, 488-505] found that when attention is endogenously directed to one surface, observers can more reliably report the direction of a brief translation of the cued than the uncued surface. Using a similar design [Reynolds, J. H., Alborzian, S., & Stoner, G. R. (2003). Exogenously cued attention triggers competitive selection of surfaces, Vision Research, 43, 59-66] found that even in the absence of an endogenous cue, the first translation acted as a potent exogenous cue that impaired the observer's ability to discriminate a subsequent translation of the other surface. We investigated the neural basis of this exogenous cueing effect by recording visual event-related potentials (ERPs) elicited by translations of the cued and uncued surfaces. Subjects were given the task of judging whether or not the first and second translations were identical in direction, and their performance was impaired when the second translation occurred on the uncued, as compared to the cued surface. The posterior C1 (75-110 ms) and N1 (160-210 ms) components of the ERP elicited by the second translation of the cued surface were larger than those elicited by translation of the uncued surface. These behavioral and ERP cueing effects were present even when the two surfaces were identical in color and thus could not be attributed to attention-related modulations of the gain of color channels. These findings provide evidence that exogenous cueing results in preferential selection of the cued surface at both early and intermediate stages of visual-cortical processing.


Direct antiviral agents for chronic hepatitis C virus infection improve health-related quality of life significantly in the long term.
Direct antiviral agents (DAAs) are new drugs for the treatment of chronic hepatitis C virus (HCV) infection. These drugs are very effective and well tolerated. HCV can cause liver disease as well as extrahepatic manifestations, including a profound negative impact on health-related quality of life (HRQL). To evaluate HRQL in the long term (> 6 months after finishing treatment) after successful treatment with DAAs. To the best of our knowledge, this is the first study that evaluates quality of life in the long term after DAA treatment. This is an observational study which included 100 patients treated with DAAs for chronic HCV infection between January 2015 and August 2018. Patients were assigned randomly. The average time after finishing treatment was 29.96 months. The Liver Disease Symptom Index (LDSI) 2.0 Questionnaire was used to evaluate quality of life before and after treatment. Seven of 9 parameters of the LDSI 2.0 Questionnaire showed significant improvement in the long term after successful treatment with DAAs. Two parameters (arthralgia and jaundice) did not improve significantly. Quality of life improved in both males and females similarly. Improvement did not correlate with the severity of liver fibrosis. Treatment with DAAs improves HRQL significantly in the long term.


Correlations between fibrinolytic function and acute myocardial infarction.
The diurnal variation of tissue plasminogen activator and plasminogen activator inhibitor--2 important factors in regulation of fibrinolysis--is well established, but its clinical implications are not yet fully understood. Fibrinolytic function was measured in a group of 133 patients less than 45 years of age, 3 months after they presented with myocardial infarction, and they were compared with an equal group of carefully matched control subjects. A sub-sample of 71 patients and 50 control subjects was examined 3 years later. Tissue plasminogen activator inhibitor plasma levels were higher in patients versus control subjects at 3 months and at 3 years after myocardial infarction, with a high degree of correlation between the 2 determinations (r = 0.87). Of all hemostatic parameters studied, only low tissue plasminogen activator activity and increased tissue plasminogen activator inhibitor levels were significantly different between patients with and without recurrent infarction during the 3-year period. In those patients with a second infarction greater than 3 years later, however, tissue plasminogen activator inhibitor concentration was not significantly related to reinfarction.


Resolution-limiting factors in 2-deoxyglucose autoradiography. I. Factors other than diffusion.
We measured the extent to which factors other than the diffusion of the radioactive label during tissue preparation limits the spatial resolving power of 2-deoxyglucose (2-DG) autoradiography. Radioactive swept frequency gratings were created using microcircuit lithography. The gratings consisted of alternating equal width radioactive and non-radioactive bars in groups of narrowing bar width (effective range 500-20 mum). The vertical thickness of the gratings ranged from 2.25 to 20 mum. The isotope in the radioactive bars was either 14C or 3H. A variety of X-ray films were exposed to these gratings and the resulting images scanned with microdensitometers or video digitizers to determine the fall off in image contrast (dark-bar values minus light-bar values) as a function of the number of dark bars (lines) per millimeter. The power of the isotope was the resolution limiting factor. Grating thickness and type of film made little difference. The limit of resolution with 14C was 10 lines/mm; with 3H, it was 25 lines/mm. The microdensitometer itself is apt to be a resolution limiting factor; the resolving power of those commonly used in autoradiography is unlikely to exceed 10 lines/mm. From measurements of the steepness of gray-matter to white-matter transitions in the image from a tissue section, we conclude that the resolution in the image is no worse than 1.6-3.2 lines/mm. Either the isotope or diffusion of the 2-DG during tissue preparation must be the factor that limits resolution.


Impacts of high-intensity exercise on the metabolomics profile of human skeletal muscle tissue.
The study aimed to identify and quantify the metabolites profile and metabolic pathways in human muscle tissue engaged during exhaustive high-intensity cycling exercise. Seven healthy physically active men performed a graded exercise test and an exhaustive supramaximal effort at 115% of maximal aerobic power with muscles biopsies performed in rest and immediately after exhaustion for quantifying of muscle metabolites changes by 1 H-NMR spectroscopy. The time until exhaustion (tlim) recorded was 224.7 ± 35.5 s whereas the muscle pH at exhaustion was 6.48 ± 0.05. A total of 54 metabolites were identified and quantified. The most enriched and impacted pathways included: beta oxidation of very long chain fatty acids, mitochondrial electron transport chain, alanine aspartate, and glutamate metabolism, citric acid cycle, arginine biosynthesis, propanoate metabolism, threonine and 2-oxobutanoate degradation and pyruvate metabolism. In addition, the muscle concentrations in Post exercise, compared to Pre increased significantly (p < 0.0398) for fumarate (42.0%), succinate (101.2%), glucose (249.7%), lactate (122.8%), O-acetylcarnitine (164.7%), glycerol (79.3%), AMP (288.2%), 2-oxobutyrate (121.0%), and methanol (58.5%), whereas decreased significantly (p < 0.010) for creatine phosphate (-70.2%), ADP (-56.5%), carnitine (-33.5%), and glutamate (-42.3%). Only the succinate was significantly correlated with tlim (r = -0.76; p = 0.0497). Besides the classical expected contribution of glycolytic and phosphagen energetic pathways, it was demonstrated that the high-intensity exercise is also associated with pathways indicatives of amino acid and fatty acid oxidation metabolisms, highlighting the inverse relation between changes in the intramuscular succinate levels and tlim.


Do higher preinfusion heart rates predict laboratory-induced panic attacks?
Baseline and preinfusion heart rates of 13 panic disorder patients who panicked during a placebo infusion were not significantly different from those of 57 panic disorder patients who did not panic during a placebo infusion. The change in preinfusion heart rates from baseline values also was not significantly different between the two groups.


Markedly increased serum aspartate aminotransferase activity in congestive heart failure.
Congestive heart failure usually features a mild to moderate increase in aspartate aminotransferase (AST) activity. A marked increase in AST may occur rarely and is usually preceded by prolonged shock or hypotensive episodes and is accompanied by hyperbilirubinemia. I report two patients with congestive heart failure in whom the AST activity was greater than 8000 U/L. No prior episodes of shock or hypotension occurred in these patients and the accompanying increase in bilirubin was slight. In both cases, the enzyme activity decreased sharply with improvement in the patients' circulatory status. Recognition of this entity is important to distinguish it from viral or drug-induced hepatitis.


Near infrared spectroscopy, cluster and multivariate analysis hyphenated to thin layer chromatography for the analysis of amino acids.
A method based on near-infrared spectroscopy (NIRS) was developed for the rapid and non-destructive determination and quantification of solid and dissolved amino acids. The statistical results obtained after optimisation of measurement conditions were evaluated on the basis of statistical parameters, Q-value (quality of calibrations), R(2), standard error of estimation (SEE), standard error of prediction (SEP), BIAS applying cluster and different multivariate analytical procedures. Experimental optimisation comprised the selection of the highest suitable optical thin-layer (0.5, 1.0, 1.5, 2.0, 2.5, 3.0 mm), sample temperature (10-30 degrees C), measurement option (light fibre, 0.5 mm optical thin-layer; boiling point tube; different types of cuvettes) and sample concentration in the range between 100 and 500 ppm. Applying the optimised conditions and a 115-QS Suprasil cuvette (V = 400 microl), the established qualitative model enabled to distinguish between different dissolved amino acids with a Q-value of 0.9555. Solid amino acids were investigated in the transflectance mode, allowing to differentiate them with a Q-value of 0.9155. For the qualitative and quantitative analysis of amino acids in complex matrices NIRS was established as a detection system directly onto the plate after prior separation on cellulose based thin-layer chromatography (TLC) sheets employing n-butanol, acetic acid and distilled water at a ratio of 8:4:2 (v/v/v) as an optimised mobile phase. Due to the prior separation step, the established calibration curve was found to be more stable than the one calculated from the dissolved amino acids. The found lower limit of detection was 0.01 mg/ml. Finally, this optimised TLC-NIRS method was successfully applied for the qualitative and quantitative analysis of L-lysine in apple juice. NIRS is shown not only to offer a fast, non-destructive detection tool but also to provide an easy-to-use alternative to more complicated detection methods such as mass spectrometry (MS) for qualitative and quantitative TLC analysis of amino acids in crude samples.


Nicotine primes the effect of cocaine on the induction of LTP in the amygdala.
In human populations, there is a well-defined sequence of involvement in drugs of abuse, in which the use of nicotine or alcohol precedes the use of marijuana, which in turn, precedes the use of cocaine. The term "Gateway Hypothesis" describes this developmental sequence of drug involvement. In prior work, we have developed a mouse model to study the underlying metaplastic behavioral, cellular and molecular mechanisms by which exposure to one drug, namely nicotine, affects the response to another drug, namely cocaine. We found that nicotine enhances significantly the changes in synaptic plasticity in the striatum induced by cocaine (Levine et al., 2011). Here we ask: does the metaplastic effect of nicotine on cocaine also apply in the amygdala, a brain region that is involved in the orchestration of emotions and in drug addiction? We find that pretreatment with nicotine enhances long-term synaptic potentiation (LTP) in response to cocaine in the amygdala. Both short-term (1 day) and long-term (7 days) pre-exposure to nicotine facilitate the induction of LTP by cocaine. The effect of nicotine on LTP is unidirectional; exposure to nicotine following treatment with cocaine is ineffective. This metaplastic effect of nicotine on cocaine is long lasting but reversible. The facilitation of LTP can be obtained for 24 but not 40 days after cessation of nicotine. As is the case in the striatum, pretreatment with Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, simulates the priming effect of nicotine. These results provide further evidence that the priming effect of nicotine may be achieved, at least partially, by the inhibition of histone acetylation and indicate that the amygdala appears to be an important brain structure for the processing of the metaplastic effect of nicotine on cocaine. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.


Identification and characterization of odorous gas emission from a full-scale food waste anaerobic digestion plant in China.
Odorous gas emission characteristic along with the successive processes of a typical full-scale food waste (FW) anaerobic digestion plant in China was investigated in September and January. Seasonal variations in pollutant concentration and principal component analysis (PCA) showed markedly different characteristics between the two months. However, the main reason for the seasonal difference at the sorting process differed from the reason for the seasonal difference at other treatment units. Most odorous volatile organic compound (VOC) concentrations tested near an anaerobic digestion tank were similar and low in both months. Odor indices, including odor contribution (OC) and odor activity value (OAV) of various odorants, were further calculated to evaluate the malodor degree and contribution to the nuisance smell of any odorant. Brought about by people's different dietary habits, H2S and sulfocompounds were found to be dominant contributors to the large total OVA in the January test. By contrast, oxygenated organic compounds played an important role on the sum of OVA in September.


Primary repair of complete transposition of the great arteries with complete atrioventricular septal defect.
We successfully corrected complete transposition of the great arteries associated with complete atrioventricular septal defect in a 50-day-old infant in concomitant arterial switch operation and two-patch repair. The combination of these 2 complex anomalies is very rare, and primary anatomical repair is feasible in such patients.


Risk factors and clinical outcomes of acute myeloid leukaemia with central nervous system involvement in adults.
Acute myeloid leukaemia (AML) with central nervous system (CNS) involvement in adults is uncommon, and studies of this subject are scant. We conducted a retrospective study to investigate the clinical aspects, cytogenetic abnormalities, molecular gene mutations and outcomes of adult AML patients with CNS involvement. Three hundred and ninety-five patients with newly diagnosed AML were reviewed. Twenty (5.1%) patients had CNS involvement, including 7 (1.8%) with initial CNS disease and 4 (1%) who suffered an isolated CNS relapse. The patients with CNS involvement were younger, had higher leukocyte, platelet, and peripheral blast cell counts, FAB M4 morphology, and chromosome translocations involving 11q23 (11q23 abnormalities) more frequently than did the patients without CNS involvement. No differences in sex, haemoglobin levels, serum LDH levels, immunophenotype of leukaemia cells, or molecular gene mutations were observed between the two groups. Multivariate analyses showed that age ≤ 45 years (OR, 5.933; 95% CI, 1.82 to 19.343), leukocyte counts ≥ 50,000/μl (OR, 3.136; 95% CI, 1.083 to 9.078), and the presence of 11q23 abnormalities (OR, 5.548; 95% CI, 1.208 to 25.489) were significant predictors of CNS involvement. Patients with initial CNS disease had 5-year overall survival and relapse-free survival rates that were similar to those without initial CNS disease. However, three of four patients who suffered an isolated CNS relapse died, and their prognosis was as poor as that of patients who suffered a bone marrow relapse. CNS involvement in adult patients with AML is rare. Three significant risk factors for CNS involvement including age ≤ 45 years, leukocyte counts ≥ 50,000/μl and the presence of 11q23 abnormalities were identified in this study. Future investigations to determine whether adult AML patients having these specific risk factors would benefit from CNS prophylactic therapy are necessary.


[Reaction time as an index of the dynamics of postoperative status in brain tumor patients].
This report is concerned with the dynamic indices of the time of the simple reaction and the time of the reaction of choice observed during the post-operative period in 53 patients with brain tumours of various sites. The possibility of using these indicators for evaluation of post-operative conditions in neurosurgical patients or in combined treatment is demonstrated.


Thermal ecology of allopatric lizards (Sphenomorphus) in southeast Australia : I. The environment and lizard critical temperatures.
The Sphenomorphus quoyi species complex (Lacertilia: Scincidae) of southeast Australia consists of three lizard species, distributed as continuous but largely allopatric populations, and a fourth species which has a disjunct distribution at high altitudes within the range of the other three. The four species have similar Voluntary temperatures (range of body temperatures within which normal activity occurs) despite the fact that they occupy different geographical areas.Altitudinal zonation is shown in the distribution pattern of the four species with S. quoyi and S. tympanum (warm temperate) restricted to the lower altitudes. The level of the mean daily minimum and maximum temperatures are different in each of the four species distribution areas. Similarly, the area occupied by each species is characterized by different daily sunlit and shade surface temperatures and different duration of ground surface subzero temperatures. Floristic composition of the four areas and the basking sites utilized by each species are also dissimilar.The lower temperature tolerances and the acclimation range of the Critical Minimum temperatures of S. quoyi and S. tympanum (warm temperate) exclude these species from the higher altitudes with the relatively lower environmental temperature levels. The Critical temperatures of the species which are found at high altitudes, do not explain why sympatry is not found with the lowland species.


General movements in early infancy: what do they tell us about the nervous system?
Developmental changes in muscle coordination patterns of normal and abnormal general movements (GMs) are described. GMs were studied simultaneously with video-recording and polymyography (polyEMG). GMs of normal full-term infants gradually lose their neonatally slow and 'writhing' character, to be turned into the elegant flow of small movements of 'fidgety' GMs at the age of 2-3 months. This transformation coincides with changes in the polyEMG. Tonic background activity decreases concurrent with a reduction in amplitude and duration of phasic bursts. The coordination between antagonistic muscles does not change, co-activation remains the prevailing pattern. Secondly, preliminary results on healthy preterms (n = 6) are presented. At the examination age of 33-34 weeks postmenstrual age the preterms showed so-called 'preterm' GMs, which are characterized by variation and graceful complexity. EMG burst duration was significantly longer during 'preterm' GMs than during 'writhing' GMs of full-term newborns. The percentage of co-activation during 'preterm' GMs varied considerably. The polyEMG of 'writhing' GMs of two preterms, who were followed longitudinally, differed from that of 'writhing' GMs of full-terms. At 'fidgety' age the EMG differences between preterms and full-terms had disappeared. Finally the first results on abnormal GMs are reported. A synchronized onset of muscle activity in all extremity muscles and 'packaging' of EMG-bursts into subunits of 5-8 Hz. seemed to be specific properties of these abnormal GMs. This could indicate a loss of supraspinal control.


Processes controlling the distribution and natural attenuation of dissolved phenolic compounds in a deep sandstone aquifer.
Processes controlling the distribution and natural attenuation (NA) of phenol, cresols and xylenols released from a former coal-tar distillation plant in a deep Triassic sandstone aquifer are evaluated from vertical profiles along the plume centerline at 130 and 350 m from the site. Up to four groups of contaminants (phenols, mineral acids, NaOH, NaCl) form discrete and overlapping plumes in the aquifer. Their distribution reflects changing source history with releases of contaminants from different locations. Organic contaminant distribution in the aquifer is determined more by site source history than degradation. Contaminant degradation at total organic carbon (TOC) concentrations up to 6500 mg l(-1) (7500 mg l(-1) total phenolics) is occurring by aerobic respiration NO3-reduction, Mn(IV)-/Fe(III)-reduction, SO4-reduction, methanogenesis and fermentation, with the accumulation of inorganic carbon, organic metabolites (4-hydroxybenzaldehyde, 4-hydroxybenzoic acid), acetate, Mn(II), Fe(II), S(-II), CH4 and H2 in the plume. Aerobic and NO3-reducing processes are restricted to a 2-m-thick plume fringe but Mn(IV)-/Fe(II)-reduction, SO4-reduction, methanogenesis and fermentation occur concomitantly in the plume. Dissolved H2 concentrations in the plume vary from 0.7 to 110 nM and acetate concentrations reach 200 mg l(-1). The occurrence of a mixed redox system and concomitant terminal electron accepting processes (TEAPs) could be explained with a partial equilibrium model based on the potential in situ free energy (deltaGr) yield for oxidation of H2 by specific TEAPs. Respiratory processes rather than fermentation are rate limiting in determining the distribution of H2 and TEAPs and H2 dynamics in this system. Most (min. 90%) contaminant degradation has occurred by aerobic and NO3-reducing processes at the plume fringe. This potential is determined by the supply of aqueous O2 and NO3 from uncontaminated groundwater, as controlled by transverse mixing, which is limited in this aquifer by low dispersion. Consumption to date of mineral oxides and SO4 is, respectively, <0.15% and 0.4% of the available aquifer capacity, and degradation using these oxidants is <10%. Fermentation is a significant process in contaminant turnover, accounting for 21% of degradation products present in the plume, and indicating that microbial respiration rates are slow in comparison with fermentation. Under present conditions, the potential for degradation in the plume is very low due to inhibitory effects of the contaminant matrix. Degradation products correspond to <22% mass loss over the life of the plume, providing a first-order plume scale half-life >140 years. The phenolic compounds are biodegradable under the range of redox conditions in the aquifer and the aquifer is not oxidant limited, but the plume is likely to be long-lived and to expand. Degradation is likely to increase only after contaminant concentrations are reduced and aqueous oxidant inputs are increased by dispersion of the plume. The results imply that transport processes may exert a greater control on the natural attenuation of this plume than aquifer oxidant availability.


The ABA receptor PYL9 together with PYL8 plays an important role in regulating lateral root growth.
Abscisic acid is a phytohormone regulating plant growth, development and stress responses. PYR1/PYL/RCAR proteins are ABA receptors that function by inhibiting PP2Cs to activate SnRK2s, resulting in phosphorylation of ABFs and other effectors of ABA response pathways. Exogenous ABA induces growth quiescence of lateral roots, which is prolonged by knockout of the ABA receptor PYL8. Among the 14 members of PYR1/PYL/RCAR protein family, PYL9 is a close relative of PYL8. Here we show that knockout of both PYL9 and PYL8 resulted in a longer ABA-induced quiescence on lateral root growth and a reduced sensitivity to ABA on primary root growth and lateral root formation compared to knockout of PYL8 alone. Induced overexpression of PYL9 promoted the lateral root elongation in the presence of ABA. The prolonged quiescent phase of the pyl8-1pyl9 double mutant was reversed by exogenous IAA. PYL9 may regulate auxin-responsive genes in vivo through direct interaction with MYB77 and MYB44. Thus, PYL9 and PYL8 are both responsible for recovery of lateral root from ABA inhibition via MYB transcription factors.


Classification and prevalence of spin in abstracts of non-randomized studies evaluating an intervention.
Spin represents specific reporting strategies, either intentional or unintentional, to convince the reader that the beneficial effect of the experimental intervention in terms of efficacy and safety is greater than that shown by the results. The objectives of this study were to 1) develop a classification of spin specific to non-randomized studies assessing an intervention and 2) estimate the prevalence of spin in abstracts of reports of such studies. In a first step, we developed a specific classification of spin for non-randomized studies by a literature review and pilot study. In a second step, 2 researchers trained in the field of methodology evaluated the prevalence of spin in the abstract of all non-randomized studies assessing an intervention published in the BioMed Central Medical Series journals between January 1, 2011 and December 31, 2013. All disagreements were resolved by consensus. We also determined whether the level of spin in abstract conclusions was high (spin reported without uncertainty or recommendations for further trials), moderate (spin reported with some uncertainty or recommendations for further trials) or low (spin reported with uncertainty and recommendations for further trials). Among the 128 assessed articles assessed, 107 (84%) had at least one example of spin in their abstract. The most prevalent strategy of spin was the use of causal language, identified in 68 (53%) abstracts. Other frequent strategies were linguistic spin, inadequate implications for clinical practice, and lack of focus on harm, identified in 33 (26%), 25 (20%), and 34 (27%) abstracts respectively. Abstract conclusions of 61 (48%) articles featured a high level of spin. Abstract of reports of non-randomized studies assessing an intervention frequently includes spin. Efforts to reduce the prevalence of spin in abstract for such studies are needed.


Hemispheric venous dysgenesis in a woman presenting with seizures, weakness and parkinsonism.
This report describes an unusual case of a woman who developed progressive hemiparesis, seizures and hemiparkinsonism associated with MRI and angiographic evidence of chronic venous hypertension in the contralateral cerebrum and cerebellum. In the absence of inflammatory or veno-occlusive disorders, the patient's clinical and neuroradiological findings point to a developmental disorder, such as a hemispheric venous dysgenesis, as the underlying lesion.


High-resolution computed tomographic appearance of MALToma of the lung.
MALToma of the lung is rare and advances in molecular techniques have only recently allowed accurate diagnostic classification of the previously termed "pseudolymphomas" by demonstrating that many are monoclonal B-cell proliferations of MALT tissue and therefore true low-grade lymphomas. No significant previous contribution was found in the literature regarding the high-resolution CT appearance (HRCT) of these tumours. We describe the high-resolution CT appearances in five cases presenting to our institution from 1994 to 1997. The HRCT scans (1-mm sections at 10- to 15-mm intervals) were performed as the opacities seen radiographically were thought to be part of a diffuse lung process. In one patient a spiral sequence was performed through the main airway. Multifocal, ill-defined nodules containing air bronchograms were seen in four cases and focal lobar consolidation in one case. Interlobular septal thickening, centrilobular micronodules and bronchial wall thickening were seen in two cases. Mediastinal lymphadenopathy and pleural reaction do not appear to be characteristic features. The appearance of multifocal consolidation is similar to that seen in bronchoalveolar cell carcinoma and cryptogenic organising pneumonia.


ADAP1 limits neonatal cardiomyocyte hypertrophy by reducing integrin cell surface expression.
The ArfGAP with dual PH domains 1 (ADAP1) regulates the activation of the hypertrophic mitogen-activated protein kinase ERK1/2 pathway in non-cardiomyocytes. However, its role in cardiomyocytes is unknown. Our aim was to characterize the role of ADAP1 in the hypertrophic process of cardiomyocytes. We assessed the expression of ADAP1 in the hearts of adult and neonatal rats by RT-qPCR and Western blotting and showed that it is preferentially expressed in cardiomyocytes. Adenoviral-mediated ADAP1 overexpression in cultured rat neonatal ventricular cardiomyocytes limited their serum-induced hypertrophic response as measured by immunofluorescence microscopy. Furthermore, ADAP1 overexpression completely blocked phenylephrine- and Mek1 constitutively active (Mek1ca) mutant-induced hypertrophy in these cells. The anti-hypertrophic effect of ADAP1 was not caused by a reduction in protein synthesis, interference with the Erk1/2 pathway, or disruption of the fetal gene program activation, as assessed by nascent protein labeling, Western blotting, and RT-qPCR, respectively. An analysis of cultured cardiomyocytes by confocal microscopy revealed that ADAP1 partially re-organizes α-actinin into dense puncta, a phenomenon that is synergized by Mek1ca overexpression. Biotin labeling of cell surface proteins from cardiomyocytes overexpressing ADAP1 revealed that it reduces the surface expression of β1-integrin, an effect that is strongly potentiated by Mek1ca overexpression. Our findings provide insights into the anti-hypertrophic function of ADAP1 in cardiomyocytes.


[Acceptability and results of postpartum proctological consultation for women who have had an obstetric injury of the anal sphincter].
Early management of perineal disorders after obstetric anal sphincter injury (OASI) may improve the functional prognosis. The objective was to assess the acceptability of the consultation and to report on its results. This unicentric retrospective study included 64 women who had LOSA 3 or 4 and who were offered a 3-month routine postpartum proctological consultation. The proposed diagnoses and recoveries were identified. Of the 5,070 women who gave birth vaginally, 64 women had LOSA (1.2%). 54 came to the clinic (84.3%). At the interview, 21 women had no complaints. A diagnosis of evacuation disorders or hemorrhoidal disease in particular was made in 10 women. A specific management was proposed to 16 women and a control consultation was proposed to 3 women. Of the 33 women with at least one symptom, 31 women were diagnosed and 27 women were offered specific management. A monitoring consultation was offered to 18 women. The main diagnoses were gas incontinence, dyschesia with or without abdominopererial asynchronism and decreased sphincter tone. The main measures undertaken were the extension of laxatives, the proposal of perineal massage and abdominal-perineal rehabilitation by biofeedback. Systematic proctological consultation was acceptable and allows for a specific management in the majority of cases. The assessment of its long-term impact remains to be defined.


Control of pH during plasmid preparation by alkaline lysis of Escherichia coli.
Alkaline lysis of Escherichia coli is usually the method of choice for plasmid preparation, but ''ghost bands" of denatured supercoiled DNA can result if the pH is too high or the period of lysis is too long. By replacing the usual sodium hydroxide lysis solution with an arginine buffer prepared in the range of pH 11.4 to 12.0, we were able to stabilize the pH during lysis and obtain plasmid that is suitably pure for restriction digestion and DNA sequencing.


Predictive article recommendation using natural language processing and machine learning to support evidence updates in domain-specific knowledge graphs.
Describe an augmented intelligence approach to facilitate the update of evidence for associations in knowledge graphs. New publications are filtered through multiple machine learning study classifiers, and filtered publications are combined with articles already included as evidence in the knowledge graph. The corpus is then subjected to named entity recognition, semantic dictionary mapping, term vector space modeling, pairwise similarity, and focal entity match to identify highly related publications. Subject matter experts review recommended articles to assess inclusion in the knowledge graph; discrepancies are resolved by consensus. Study classifiers achieved F-scores from 0.88 to 0.94, and similarity thresholds for each study type were determined by experimentation. Our approach reduces human literature review load by 99%, and over the past 12 months, 41% of recommendations were accepted to update the knowledge graph. Integrated search and recommendation exploiting current evidence in a knowledge graph is useful for reducing human cognition load.


An ultrastructural analysis of afferent terminals to the anterior pretectal nucleus in the cat.
The synaptic organization of three kinds of afferent projections in the feline anterior pretectal nucleus (PTA) was analyzed by a combination of the degeneration and retrograde transport of horseradish peroxidase (HRP) techniques, along with that of the degeneration and anterograde transport of HRP techniques. Retrograde labeling of PTA neurons was performed by injections of HRP in the dorsal accessory olivary nucleus (DAO). Three kinds of afferent sources of the PTA--the cerebral motor cortex, the anterior interpositus nucleus of the cerebellum, and the gracile nucleus--were subjected to electrolysis, suction, or injection of kainic acid or HRP for identification of axon terminals of each system. Axon terminals of these different afferent sources identified by degeneration or anterograde HRP transport techniques showed similar morphological features: They were relatively large (1-6.5 microns in diameter), contained round or ovoid synaptic vesicles, and made asymmetrical synaptic contacts. When the degeneration study was combined with the retrograde HRP transport technique, some degenerating terminals from the motor cortex, anterior interpositus, or gracile nuclei were found to synapse directly with HRP-labeled dendrites or somata of the PTA neurons projecting to the DAO. Each combination of the degeneration and anterograde HRP transport techniques revealed the fact that neither degenerating nor HRP-labeled terminals were found to synapse with the same neuronal structure. These observations indicate that the PTA neurons relay afferent inputs from three different sources directly to the DAO, and that there is a possibility of parallel processing rather than convergence of three different afferent systems via the PTA to the DAO.


Water maze performance of aged Sprague-Dawley rats in relation to retinal morphologic measures.
The spatial learning ability of aged male and female Sprague-Dawley rats was assessed using the Morris water maze. To determine the influence of age-related visual deficits on performance levels, retinal morphologic measures were correlated with water maze performance for each rat. Rats were first trained on the water maze task at 21 months of age and were retrained 3 or 4 times at 6-week intervals. After the last training session the rats were killed and their eyes were removed for histopathologic and morphometric evaluation of the retinas. There was a large degree of retinal degeneration in all of the aged Sprague-Dawley rats with an average decrease in the thickness of the retinal outer nuclear layer (photoreceptor nuclei containing layer) of 85% in old males and 95% in old females. Some rats, however, had less degeneration of the retinas than others, and the degree of retinal degeneration was strongly related to performance levels on the water maze task. Among the aged rats in this study with the least retinal degeneration, there was little evidence for a subset of rats that were unable, with extensive training, to learn a platform position. Of the 41 rats with the least retinal degeneration (out of a total of 81), only one was a clear non-learner on the water maze task, whereas, of the 27 rats with the most retinal degeneration, 20 were non-learners. These results illustrate the potentially serious confounding effects of deteriorating visual ability on attempts to assess cognitive functioning of aged albino rats on tasks requiring utilization of visual cues.


Cytidine-5'-diphosphocholine (Citicoline): a pilot study in patients with non-arteritic ischaemic optic neuropathy.
Our work evaluates visual function before and after treatment with cytidine-5-diphosphocholine (Citicoline) in patients with non-arteritic ischaemic optic neuropathy (NION). Twenty-six patients in which at least 6 months elapsed from NION, were randomly divided into two age-similar groups: 14 patients had Citicoline (Cebrolux-Tubilux, Italy, 1600 mg/diem for 60 days, followed by a 120-day period of wash out, days 60-180) (T-NION); 12 patients had no treatment during the same period (NT-NION). At day 180, in T-NION a second period of treatment (days 181-240) followed by a wash-out (days 241-360) was performed. Fourteen age-matched healthy subjects provided normative data. In all patients, pattern-electroretinogram (PERG), visual evoked potentials (VEPs) and visual acuity (VA) measurements were performed at baseline and at days 60 and 180. In T-NION, further measurements were achieved at days 240 and 360. At baseline, NT-NION and T-NION patients showed abnormal PERGs and VEPs, and reduced VA, compared to controls. At the end of treatment (days 60 and 240), T-NION patients showed improvement (P < 0.01) of PERGs, VEPs parameters and VA, compared to pre-treatment values. After wash out, functional improvements persisted compared to baseline. No changes in NT-NION patients were observed. Our results suggest a beneficial effect of oral Citicoline in NION.


Disulfide bond isomerization and the assembly of MHC class I-peptide complexes.
The presence of a disulfide bond inside the peptide binding groove of MHC class I molecules and of the thiol oxidoreductase ERp57 in the class I loading complex suggests that disulfide bond isomerization may play a role in peptide loading. Here we show that ERp57 and tapasin are disulfide linked inside the loading complex. Mutagenesis of cysteine 95 in tapasin not only abolishes formation of the ERp57-tapasin bond but also prevents complete oxidation of the class I heavy chain in the loading complex. The resulting MHC class I-beta2m heterodimers are poorly loaded with high-affinity peptides in the ER but nevertheless escape to the cell surface where they are unstable. These findings suggest a role for disulfide bond isomerization in tapasin-mediated peptide loading.


Implementation of a coordinated and tailored return-to-work intervention for employees with mental health problems.
Interventions to promote return to work (RTW) after sickness absence are often complex, involving numerous stakeholders and thus prone to implementation problems. To understand the outcomes of such interventions, researchers need to look beyond effectiveness data and incorporate systematic process evaluations. This article presents findings from a process evaluation of a coordinated and tailored RTW-intervention for employees with mental health problems. The purpose was to elucidate the implementation process and identify barriers for the feasibility and sustainability of the intervention. The evaluation draws on comprehensive data from observations of and documents from the intervention, a two-waved survey among participants (n = 76), two group interviews with the intervention team, three group interviews with municipal social insurance officers (SIOs), and ten individual interviews with participants. We identified several barriers to the feasibility and sustainability of the intervention: (1) the inclusion criteria were perceived as too narrow by those responsible for recruitment (SIOs); (2) waiting lists occurred; (3) participants had more severe mental health problems than expected; (4) key stakeholders had divergent expectations of the timeframe for RTW; (5) the SIOs felt insufficiently informed about the intervention; (6) the global financial downturn resulted in many participants losing their job, which impeded workplace-based RTW-efforts. This study points out important pitfalls in implementing RTW-interventions, pertaining to specification of the target population, consideration of contextual constraints, and ensuring cooperation between key stakeholders. Thorough assessment of local context and stakeholder needs and concerns is likely to improve the feasibility and sustainability of future RTW-interventions.


Application of machine learning for ancestry inference using multi-InDel markers.
Ancestry inference through population stratification plays an important role in forensic applications. Specifically, ancestry information inferred from forensic DNA evidence can provide vital clues for criminal investigations. Current advances in ancestry inference mostly focus on ancestry informative markers. Hereinto, multi-InDel was proposed as one of the compound markers performing well in complex ancestral classification in the subpopulation of Asia. However, research on analytical methods necessary to make reliable predictions is lacking. The newly proposed compound markers could be assessed with alternative methods. In this study, promising discriminant methods were explored using multi-InDel markers for forensic ancestry inference. As a prerequisite, the adopted multi-InDel markers were assessed by classical methods for population genetics, such as FST analysis, MDS and STRUCTURE. In addition, dimensionality reduction methods and serial reduction strategies were applied for data visualization. Subsequently, machine learning methods, including logistic regression (LR), support vector machine (SVM), k-nearest neighbors (KNN) and extreme gradient boosting (XGBoost), were evaluated by diverse approaches. As the result of multifarious analyses through comparisons and estimations, XGBoost with one-hot encoding was shown to be more effective in population stratification and ancestry inference for challenging cases with admixed populations.


Analysis of tissue volume and calcification of the 6th to 8th costal cartilage in 70 woman patients.
To study the tissue size, calcification characteristics and the correlation between calcification, age, and on whether side of the 6th, 7th, and 8th costal cartilages in women, so as to provide reference for clinical application. A total of 70 cases of female costal cartilage applied with dual-source CT three-dimensional reconstruction were selected from the radiology storage center of Second Xiangya Hospital. The length, width, thickness, calcification rate, calcification degree, calcification type, calcification location, and the relation between calcification, age, and side of bilateral 6th, 7th, and 8th costal cartilages were observed and analyzed on volume reconstruction and maximum density projection images. (1) The respective length, width, and thickness of 6th, 7th, and 8th costal cartilages on both sides were measured. There were significant differences in length, width, and thickness between unilateral costal cartilages with different ordinal numbers. (2) Significant difference was confirmed in the total calcification types of the 6th, 7th, and 8th costal cartilages. (3) The higher the age, the higher the calcification rate was. The calcification degree of the 6th, 7th, and 8th costal cartilages was higher with the increase of age. Preoperative three-dimensional reconstruction and image post-processing of costal cartilage with dual-source CT can accurately measure the amount of cartilage tissue and define the characteristics of calcification, so as to guide the clinical selection of costal cartilage. In female patients of different ages, the calcification rate of costal cartilage increased with age, but no positive correlation was observed.


Semi disposable reactor biosensors for detecting carbamate pesticides in water.
Two flow-injection biosensor systems using semi disposable enzyme reactor have been developed to determine carbamate pesticides in water samples. Acetylcholinesterase was immobilized on silica gel by covalent binding. pH and conductivity electrodes were used to detect the ionic change of the sample solution due to hydrolysis of acetylcholine. Carbamate pesticides inhibited acetylcholinesterase and the decrease in the enzyme activity was used to determine these pesticides. Parameters influencing the performance of the systems were optimized to be used in the inhibition procedure. Carbofuran and carbaryl were used to test these systems. Detection limits for the potentiometric and conductimetric systems were both at 10% inhibition corresponding to 0.02 and 0.3 ppm of carbofuran and carbaryl, respectively. Both systems also provided the same linear ranges, 0.02-8.0 ppm for carbofuran, and 0.3-10 ppm for carbaryl. The analysis of pesticides was done a few times before the reactor was disposed. Percentages of inhibition obtained from different reactors were reproducible, therefore, no recalibration was necessary when changing the reactor. The biosensors were used to analyze carbaryl in water samples from six wells in a vegetable growing area. Both systems could detect the presence of carbaryl in the samples and provided good recoveries of the added carbaryl, i.e., 80-106% for the potentiometric system and 75-105% for the conductimetric system. The presence of carbaryl in water samples analyzed by the biosensors was confirmed by gas chromatography-mass spectrometric system. These biosensors do not require any sample preconcentration and are suitable for detecting pesticides in real water samples.


The effect of environmental pollution on the function of enzymes of active skeleton muscle. Part 1: An adequate method to study the effect of metal ions on the activity of phosphofructokinase.
The possibilities of exact measuring the effect of metal ions on the activity of phosphofructokinase (PFK) by means of both a heat inactivation and an auxiliary enzyme system were studied. It was found that both methods are suitable for measuring the inhibition of phosphofructokinase by metal ions. It was further found that metal ion concentrations causing 50% deactivation of PFK could not considerably influence the measuring capacity of the auxiliary enzyme system.


Dietary supplementation of inulin alleviates metabolism disorders in gestational diabetes mellitus mice via RENT/AKT/IRS/GLUT4 pathway.
Gestational diabetes mellitus (GDM) has significant short and long-term health consequences for both the mother and child. There is limited but suggestive evidence that inulin could improve glucose tolerance during pregnancy. This study assessed the effect of inulin on glucose homeostasis and elucidated the molecular mechanisms underlying the inulin-induced antidiabetic effects during pregnancy. Female C57BL/6 mice were randomized to receive either no treatment, high-dose inulin and low-dose inulin for 7 weeks with measurement of biochemical profiles. A real-time2 (RT2) profiler polymerase chain reaction (PCR) array involved in glycolipid metabolism was measured. Inulin treatment facilitated glucose homeostasis in a dose-dependent manner by decreasing fasting blood glucose, advanced glycation end products and total cholesterol, and improving glucose tolerance. Suppressing resistin (RETN) expression was observed in the inulin treatment group and the expression was significantly correlated with fasting blood glucose levels. The ratios of p-IRS to IRS and p-Akt to Akt in liver tissue and the ratio of p-Akt to Akt in adipose tissue as well as the expression level of GLUT4 increased significantly after inulin treatment. Our findings indicated improvement of glucose and lipid metabolism by inulin was to activate glucose transport through the translocation of GLUT4 which was mediated by insulin signaling pathway repairment due to decreased expression of RETN and enhanced phosphorylation of IRS and Akt in GDM mice.


A Case Series of 4 Patients With Peristomal Pyoderma Gangrenosum: Review of Risk Factors and Treatment Response.
The literature on peristomal pyoderma gangrenosum (PPD) is scarce, and studies to date have included few patients. It is therefore difficult to determine the incidence of PPD, investigate risk factors, or evaluate the effectiveness of the different treatments available. We report on a series of 4 patients diagnosed with PPD at our hospital in 2013 and 2014, and review the clinical characteristics and responses to treatment. Three of the patients had inflammatory bowel disease and 1 had rectal cancer. Three patients responded favorably to initial treatment with 0.1% tacrolimus ointment (administered as monotherapy in 2 cases and combined with immunosuppressants in the other). However, on withdrawal of tacrolimus, the disease recurred in all 3 patients, requiring treatment reintroduction or modification.


Serotype distribution and antimicrobial resistance of invasive Streptococcus pneumoniae isolates in Bulgaria before the introduction of pneumococcal conjugate vaccine.
The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced as a mandatory vaccine in Bulgaria in April 2010. We report on the serotype distribution and the antimicrobial resistance of 222 invasive Streptococcus pneumoniae isolates collected from all age groups before the introduction of PCV10. PCV7, PCV10, and PCV13 covered 43.7, 59.9, and 78.8% of all invasive pneumococcal strains, and 64.2, 79.1, and 89.6% of isolates involving children less than 5 years of age. Penicillin resistance was found in 30.1% of the isolates responsible for meningitis and in 5.0% of isolates responsible for other invasive infections. Overall, erythromycin resistance was found in 19.4% of all invasive strains. The erm(B) was the most prevalent pneumococcal macrolide resistance genotype (63.2%) and dual mechanisms of both genes the erm(B) and mef(E) were detected in 15.8% of 19 erythromycin resistant isolates during the period 2006-2010. The prevalence and spread of serotypes 19F, 6B, and 19A during the last period may have contributed to the high predominance of erm(B) genotype in comparison of mef genotype, which was predominant in our country among erythromycin-resistant isolates before 2005. Continuing surveillance is required after the recent introduction of PCV10 in order to observe future developments of any serotype changes in the Bulgarian population, as well as surveillance of antimicrobial susceptibility of invasive S. pneumoniae isolates.


Mammalian histidine kinases.
Protein phosphorylation is one of the most ubiquitous and important types of post-translational modification for the regulation of cell function. The importance of two-component histidine kinases in bacteria, fungi and plants has long been recognised. In mammals, the regulatory roles of serine/threonine and tyrosine kinases have attracted most attention. However, the existence of histidine kinases in mammalian cells has been known for many years, although little is still understood about their biological roles by comparison with the hydroxyamino acid kinases. In addition, with the exception of NDP kinase, other mammalian histidine kinases remain to be identified and characterised. NDP kinase is a multifunctional enzyme that appears to act as a protein histidine kinase and as such, to regulate the activation of some G-proteins. Histone H4 histidine kinase activity has been shown to correlate with cellular proliferation and there is evidence that it is an oncodevelopmental marker in liver. This review mainly concentrates on describing recent research on these two types of histidine kinase. Developments in methods for the detection and assay of histidine kinases, including mass spectrometric methods for the detection of phosphohistidines in proteins and in-gel kinase assays for histone H4 histidine kinases, are described. Little is known about inhibitors of mammalian histidine kinases, although there is much interest in two-component histidine kinase inhibitors as potential antibiotics. The inhibition of a histone H4 histidine kinase by genistein is described and that of two-component histidine kinase inhibitors of structurally-related mammalian protein kinases. In addition, recent findings concerning mammalian protein histidine phosphatases are briefly described.


Differential endothelial hydrogen peroxide signaling via Nox isoforms: Critical roles for Rac1 and modulation by statins.
Statins have manifold protective effects on the cardiovascular system. In addition to lowering LDL cholesterol levels, statins also have antioxidant effects on cardiovascular tissues involving intracellular redox pathways that are incompletely understood. Inhibition of HMG-CoA reductase by statins not only modulates cholesterol synthesis, but also blocks the synthesis of lipids necessary for the post-translational modification of signaling proteins, including the GTPase Rac1. Here we studied the mechanisms whereby Rac1 and statins modulate the intracellular oxidant hydrogen peroxide (H2O2) via NADPH oxidase (Nox) isoforms. In live-cell imaging experiments using the H2O2 biosensor HyPer7, we observed robust H2O2 generation in human umbilical vein endothelial cells (HUVEC) following activation of cell surface receptors for histamine or vascular endothelial growth factor (VEGF). Both VEGF- and histamine-stimulated H2O2 responses were abrogated by siRNA-mediated knockdown of Rac1. VEGF responses required the Nox isoforms Nox2 and Nox4, while histamine-stimulated H2O2 signals are independent of Nox4 but still required Nox2. Endothelial H2O2 responses to both histamine and VEGF were completely inhibited by simvastatin. In resting endothelial cells, Rac1 is targeted to the cell membrane and cytoplasm, but simvastatin treatment promotes translocation of Rac1 to the cell nucleus. The effects of simvastatin both on receptor-dependent H2O2 production and Rac1 translocation are rescued by treatment of cells with mevalonic acid, which is the enzymatic product of the HMG-CoA reductase that is inhibited by statins. Taken together, these studies establish that receptor-modulated H2O2 responses to histamine and VEGF involve distinct Nox isoforms, both of which are completely dependent on Rac1 prenylation.


Medical students' learning experience and participation in communities of practice at municipal emergency care units in the primary health care system: a qualitative study.
Medical education has been criticised for not adapting to changes in society, health care and technology. Internationally, it is necessary to strengthen primary health care services to accommodate the growing number of patients. In Norway, emergency care patients are increasingly treated in municipal emergency care units in the primary health care system. This study explores medical students' learning experience and how they participated in communities of practice at two municipal emergency care units in the primary health care system. In this qualitative study, we collected data from March to May 2019 using semi-structured individual interviews and systematic observations of six ninth-semester medical students undergoing two-week clerkships at municipal emergency care units. The interview transcripts were thematically analysed with a social constructivist approach. A total of 102 systematic observations were used to triangulate the findings from the thematic analysis. Three themes illuminated what the medical students learned and how they participated in communities of practice: (i) They took responsibility for emergency care patients while participating in the physicians' community of practice and thus received intensive training in the role of a physician. (ii) They learned the physician's role in interprofessional collaboration. Collaborating with nursing students and nurses led to training in clinical procedures and insight into the nurses' role, work tasks, and community of practice. (iii) They gained in-depth knowledge through shared reflections when time was allocated for that purpose. Ethical and medical topics were elucidated from an interprofessional perspective when nursing students, nurses, and physicians participated. Our findings suggest that this was a form of clerkship in which medical students learned the physician's role by taking responsibility for emergency care patients and participating in multiple work tasks and clinical procedures associated with physicians' and nurses' communities of practice. Participating in an interprofessional community of practice for professional reflections contributed to in-depth knowledge of ethical and medical topics from the medical and nursing perspectives.


Pharmacogenetic testing and counselling in the community pharmacy: mixed-methods study of a new pharmacist-led service.
Pharmacogenetic (PGx) testing and counselling (short: PGx service) in the community pharmacy is not routinely practiced. We propose a comprehensive pharmacist-led service where PGx information is integrated into medication reviews. To evaluate the pharmacist-led service comprising PGx testing and counselling (PGx service) from the perspective of patients. For this mixed-methods study, we conducted two follow-up interviews F1 and F2 with patients recruited for the PGx service in a community pharmacy after 1st of January 2020. The semi-structured interviews were held by phone call and covered understanding of PGx, the implementation of recommendations, handling of PGx documents (list of concerned substances and PGx recommendation), gain in medication knowledge, and willingness to pay for the PGx service. We interviewed 25 patients in F1 and 42 patients in F2. Patients were generally able to understand and use results of the PGx service. At least one PGx recommendation was implemented for 69% of the patients. Handling of PGx documents ranged from patients having forgotten about the PGx results to patients consulting the list for every medication-related decision; the latter often expecting negative effects. Finally, 62% of the patients were willing to pay for the PGx service. For future PGx testing and counselling, HCPs should consider the patients' health literacy in a standardized way and use adequate communication skills to enhance the patient's understanding in PGx and to attenuate potential negative expectations.


Ubiquitination, intracellular trafficking, and degradation of connexins.
Gap junction channels provide a conduit for communication between neighboring cells. The function of gap junction channels is regulated by posttranslational modifications of connexins, the proteins that comprise these channels. Ubiquitination of connexins has increasingly been viewed as one mechanism by which cells regulate the level of connexins present in cells, as well as the corresponding intercellular communication. Here we review the current knowledge of connexin ubiquitination and the effects this may have on gap junctional communication.


The relation between skin histamine concentration, histamine sensitivity, and the resistance of cattle to the tick, Boophilus microplus.
Cattle with different degrees of resistance to Boophilus microplus have responses to tick allergen which correlate with their resistance level. The total amount of histamine in the skin also correlates with both resistance and the immediate hypersensitivity reactions, but the sensitivity to injected histamine does not. Treatment with the antihistamine drug mepyramine maleate suppresses the cutaneous hypersensitivity reactions. The results suggest that the main pharmacologically active agent in these reactions is histamine, and that the total amount of it available locally in the skin may have a role in the resistance to this parasite.


Early detection of deep vein thrombosis in patients with coronavirus disease 2019: who to screen and who not to with Doppler ultrasound?
Aim of the study is to evaluate the incidence of DVT in COVID-19 patients and its correlation with the severity of the disease and with clinical and laboratory findings. 234 symptomatic patients with COVID-19, diagnosed according to the World Health Organization guidelines, were included in the study. The severity of the disease was classified as moderate, severe and critical. Doppler ultrasound (DUS) was performed in all patients. DUS findings, clinical, laboratory's and therapeutic variables were investigated by contingency tables, Pearson chi square test and by Student t test and Fisher's exact test. ROC curve analysis was applied to study significant continuous variables. Overall incidence of DVT was 10.7% (25/234): 1.6% (1/60) among moderate cases, 13.8% (24/174) in severely and critically ill patients. Prolonged bedrest and intensive care unit admission were significantly associated with the presence of DVT (19.7%). Fraction of inspired oxygen, P/F ratio, respiratory rate, heparin administration, D-dimer, IL-6, ferritin and CRP showed correlation with DVT. DUS may be considered a useful and valid tool for early identification of DVT. In less severely affected patients, DUS as screening of DVT might be unnecessary. High rate of DVT found in severe patients and its correlation with respiratory parameters and some significant laboratory findings suggests that these can be used as a screening tool for patients who should be getting DUS.


Granulomatous Prostatitis After Intravesical Bacillus Calmette-Guérin Instillation Therapy: A Potential Cause of Incidental F-18 FDG Uptake in the Prostate Gland on F-18 FDG PET/CT in Patients with Bladder Cancer.
This study aimed to evaluate the possibility that Bacillus Calmette-Guérin (BCG)-induced granulomatous prostatitis can be a potential cause of benign F-18 FDG uptake. A total of 395 bladder cancer patients who underwent F-18 FDG PET/CT (PET/CT) were retrospectively evaluated. Patients were divided into two groups according to BCG therapy status. Elapsed time after BCG therapy, serum PSA level, results of prostate biopsy, and the SUVmax and uptake pattern in the prostate gland were reviewed. For patients who underwent follow-up PET/CT, the changes in SUVmax were calculated. While 35 % of patients showed prostate uptake in the BCG therapy group, only 1 % showed prostate uptake in the non-BCG therapy group (p < 0.001). Among 49 patients with FDG-avid prostate lesions, none had suspected malignancy during the follow-up period (median: 16 months). Five patients revealed granulomatous prostatitis on biopsy. The incidence of FDG-avid prostate lesions was significantly higher if the elapsed time after BCG therapy was less than 1 year compared to more than 1 year (p < 0.001). Serum PSA was normal in 88 % of patients. All patients with incidental F-18 FDG uptake in the prostate gland showed focal or multifocal prostate uptake, and median SUVmax was 4.7. In 16 patients who underwent follow-up PET/CT, SUVmax was decreased in 14 patients (88 %) without treatment, and no patients demonstrated further increased prostate uptake (p < 0.001). BCG-induced granulomatous prostatitis can be a potential cause of benign F-18 FDG uptake, especially in those with a history of bladder cancer treated with BCG. In BCG-induced granulomatous prostatitis, focal or multifocal prostate uptake is frequently seen within 1 year after BCG therapy, and the intensity of prostate uptake is decreased on the follow-up PET/CT without any treatment.


Mitochondrial reactive oxygen species and heme, non-heme iron metabolism.
Mitochondria are one of the most important organelles for eukaryotes, including humans, to produce energy. In the energy-producing process, mitochondria constantly generate reactive oxygen species as a by-product of electrons leaking out from the electron transport chain react with oxygen. The active oxygen, in turn, plays pivotal roles in mediating several signalings, including those that are implicated in the development of some diseases such as neurodegenerative disease, cardiovascular disease, and carcinogenesis. This signaling, derived from mitochondrial reactive oxygen species, also affects intracellular iron homeostasis by regulating the expression of transporters. Heme iron is incorporated into cells through HCP1, and non-heme iron is transported by DMT1 in absorptive cells. Intracellular iron is exported by ferroportin and bound with transferrin. In most types of cell including erythrocyte, transferrin-bound iron is incorporated through transferrin-transferrin receptor system. We previously reported that the expression of HCP1 and DMT1 was upregulated in cancer cells and that overexpression of manganese superoxide dismutase, which is a mitochondrial-specific superoxide dismutase, downregulated the expression. These findings indicate that mitochondrial reactive oxygen species is associated with iron-related oxidative reactions. Recently, a mitochondria-specific iron transporter, mitoferrin, was identified, and the relationships among mitochondria, iron transportation, and diseases have been increasingly clarified.


Allometry in Physarum plasmodium during free locomotion: size versus shape, speed and rhythm.
Physarum plasmodium is a giant unicellular organism whose length can vary by more than three orders of magnitude. Using plasmodia ranging in size from 100 μm to 10 cm, we investigated the size dependency of their thickness distributions and locomotion speeds during free locomotion. (1) In the longitudinal direction, the organism is thickest close to the front, and decreases exponentially in thickness towards the rear. The slenderness ratio varies with body size according to a power law, such that large plasmodia are long and flat, whereas small plasmodia are short and thick. (2) The mean locomotion speed is proportional to the mean maximum thickness of the frontal part. By conducting a dimensional analysis, possible physical models are discussed. (3) The intrinsic period of the thickness oscillation, which is related to shuttle streaming (period 1-2 min), increases logarithmically with body size. (4) Various characteristics exhibit size-independent, long-period (20±10 min) oscillations, including speed, shape and intrinsic thickness oscillation period. These variations are closely coupled to formation of the entire cell shape, including undulation of thickness along the longitudinal axis and timing of branching of the frontal tip. Based on these experimental results and those reported previously, we propose a simple mathematical model for cell locomotion.


Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives.
Apolipoprotein B (apoB) is emerging as the crucial lipoprotein trait for the role of lipoprotein lipids in the aetiology of coronary heart disease. In this study, we evaluated the effects of genetically predicted apoB on outcomes in first-degree relatives. Data on lipoprotein lipids and disease outcomes in first-degree relatives were obtained from the UK Biobank study. We did a univariable mendelian randomisation analysis using a weighted genetic instrument for apoB. For outcomes with which apoB was associated at a false discovery rate (FDR) of less than 5%, multivariable mendelian randomisation analyses were done, including genetic instruments for LDL cholesterol and triglycerides. Associations between apoB and self-reported outcomes in first-degree relatives were characterised for 12 diseases (including heart disease, stroke, and hypertension) and parental vital status together with age at death. Estimates were inferred causal effects per 1 SD elevated lipoprotein trait (for apoB, 1 SD=0·24 g/L). Replication of estimates for lifespan and type 2 diabetes was done using conventional two-sample mendelian randomisation with summary estimates from genome-wide association study consortia. In univariable mendelian randomisation, genetically elevated apoB in participants was identified to lead to a shorter lifespan in parents (fathers: 0·89 years of life lost per 1 SD higher apoB in offspring, 95% CI 0·63-1·16, FDR-adjusted p=4·0 × 10-10; mothers: 0·48 years of life lost per 1 SD higher apoB in offspring, 0·25-0·71, FDR-adjusted p=1·7 × 10-4). The effects were strengthened to around 2 years of life lost in multivariable mendelian randomisation and were replicated in conventional two-sample mendelian randomisation (odds ratio [OR] of surviving to the 90th centile of lifespan: 0·38 per 1 SD higher apoB in offspring, 95% CI 0·22-0·65). Genetically elevated apoB caused higher risks of heart disease in all first-degree relatives and a higher risk of stroke in mothers. Findings in first-degree relatives were replicated in two-sample multivariable mendelian randomisation, which identified apoB to increase (OR 2·32 per 1 SD higher apoB, 95% CI 1·49-3·61) and LDL cholesterol to decrease (0·34 per 1 SD higher LDL cholesterol, 0·21-0·54) the risk of type 2 diabetes. Higher apoB shortens lifespan, increases risks of heart disease and stroke, and in multivariable analyses that account for LDL cholesterol, increases risk of diabetes. British Heart Foundation, UK Medical Research Council, and UK Research and Innovation.


Preparation and in vivo evaluation of a newly developed bioglass ceramic.
This paper presents details of the fabrication of a glass ceramic, and its application as an artificial bone prosthetic material. This new bioglass ceramic, with composition of Na2O 8.4%, CaO 40.6%, P2O5 12% and SiO2 39%, had 160-190 MPa and 800-980 MPa of three-point bending strength and compressive strength respectively. The ceramic has a (Na, Ca) (P, Si) O3 crystalline phase with a uniform crystal size of about 10 microns, which was attributed to the high nucleation frequency. The rabbit condyle test showed that the material formed a tight chemical bond with biological texture and had good biocompatibility.


Regional variation and possible sources of brominated contaminants in breast milk from Japan.
This study focuses on the regional trends and possible sources of brominated organic contaminants accumulated in breast milk from mothers in southeastern (Okinawa) and northwestern (Hokkaido) areas of Japan. For persistent brominated flame retardants, polybrominated diphenyl ethers (PBDEs; major components, BDE-47 and BDE-153) were distributed at higher levels in mothers from Okinawa (mean, 2.1 ng/g lipid), while hexabromobenzene (HeBB) and its metabolite 1,2,4,5-tetrabromobenzene were more abundantly detected in mothers from Hokkaido (0.86 and 2.6 ng/g lipid), suggesting that there are regional differences in their exposure in Japan. We also detected naturally produced brominated compounds, one of which was identified as 2'-methoxy-2,3',4,5'-tetrabromodiphenyl ether (2'-MeO-BDE68) at higher levels in mothers from Okinawa (0.39 ng/g lipid), while the other was identified as 3,3',4,4'-tetrabromo-5,5'-dichloro-2,2'-dimethyl-1,1'-bipyrrole in mothers from Hokkaido (0.45 ng/g lipid). The regional variation may be caused by source differences, i.e. southern seafood for MeO-PBDEs and northern biota for halogenated bipyrroles in the Japanese coastal water.


Phenylbutazone-induced myelodysplastic syndrome with Philadelphia translocation.
We present a case of a 69-year-old white male with a 3-year history of a myelodysplastic syndrome probably induced by phenylbutazone, and which developed into an overt leukemic phase. Chromosome analysis in the leukemic phase revealed the bone marrow cells to contain a Philadelphia translocation [46,XY,t(9;22)(q34;q11)]. We discuss the possible association between a prior history of exposure to hemotoxins and myelodysplastic syndromes, and the rarity of a Ph translocation in drug-induced hematologic malignancy.


Effects of the adducted or abducted position of the arm on the course of the musculocutaneous nerve during anterior approaches to the shoulder.
Nerve injury is a common complication during anterior shoulder surgery. The purpose of the study was to evaluate the musculocutaneous nerve (MN) anatomically and to clarify the relationship of the MN to the glenoid labrum and coracoid process in different arm positions. The study was carried out on 40 shoulders of 20 adult cadavers fixed in 10% formaldehyde. The minimum distance of the MN at the entrance point of the nerve into the coracobrachialis to the anteromedial aspect of the coracoid tip and the distance between the MN and the top, middle, and inferior points of the glenoid labrum were measured. All measurements were performed with a digital caliper while the arm was in a neutral position, 45 degrees and 90 degrees of abduction, 90 degrees of abduction-internal rotation and 90 degrees of abduction-external rotation to evaluate whether arm position effects the results statistically or not. The results demonstrated that the position of the arm significantly changes the distance between the coracoid process (CP) and the MN or its cord. The change in distance between the glenoid labrum and the MN or its cord was also statistically significant. The distance between the CP and MN was greatest when the arm was abducted to 45 degrees (mean 3.4 cm) and least when the arm was positioned to 90 degrees of abduction-internal rotation (mean 2.0 cm). While the distance between the MN and the coracoid process was least at 90 degrees of abduction and internal rotation, the distance between the MN and glenoid labrum was lest with 90 degrees of abduction and external rotation. The distance between the glenoid labrum and MN was greatest with 45 degrees of abduction. The results of this study might be of use in avoiding the MN especially during Bristlow operations and certain rotator cuff procedures. Transferring the coracoid process during Bristow operations or placing arthroscopic portals when the arm is abducted to 45 degrees appears to be the safest position in terms of MN injury. Based on our results, when the arm needs to be abducted to 90 degrees during operation, externally rotating it may decrease the tension on the brachial plexus thus increasing the distance between the MN and the portals or retractors.


Single-particle combinatorial multiplexed liposome fusion mediated by DNA.
Combinatorial high-throughput methodologies are central for both screening and discovery in synthetic biochemistry and biomedical sciences. They are, however, often reliant on large-scale analyses and thus limited by a long running time and excessive materials cost. We here present a single-particle combinatorial multiplexed liposome fusion mediated by DNA for parallelized multistep and non-deterministic fusion of individual subattolitre nanocontainers. We observed directly the efficient (>93%) and leakage free stochastic fusion sequences for arrays of surface-tethered target liposomes with six freely diffusing populations of cargo liposomes, each functionalized with individual lipidated single-stranded DNA and fluorescently barcoded by a distinct ratio of chromophores. The stochastic fusion resulted in a distinct permutation of fusion sequences for each autonomous nanocontainer. Real-time total internal reflection imaging allowed the direct observation of >16,000 fusions and 566 distinct fusion sequences accurately classified using machine learning. The high-density arrays of surface-tethered target nanocontainers (~42,000 containers per mm2) offers entire combinatorial multiplex screens using only picograms of material.


The relationship between plasma FSH, testosterone levels and testicular histology in males with azoospermia.
The plasma FSH and testosterone levels were determined by the radioimmunological method in 27 men with azoospermia. The plasma FSH levels were elevated in the Sertoli-cell only syndrome and in the case of inhibited spermatogenesis. The plasma FSH level was normal in patients with normal spermatogenesis. The plasma testosterone level did not differ from the normal values in any of the above-mentioned groups of patients.


Vocal cord dysfunction.
Vocal cord dysfunction (VCD), generally characterized by paradoxical closure of the vocal cords during inspiration, is a common mimicker of asthma and of other conditions that cause upper airway obstruction. As a result, it is frequently overlooked and often misdiagnosed, resulting in administration of excessive medications or other unnecessary interventions, with resultant morbidity. This article explores the clinical features, proposed causes, diagnostic considerations, and management of VCD, as well as some differences between VCD and asthma that can aid in differentiating these two diagnoses in the clinical setting.