The compensatory dynamic of inter-hemispheric interactions in visuospatial attention revealed using rTMS and fMRI.
A balance of mutual tonic inhibition between bi-hemispheric posterior parietal cortices is believed to play an important role in bilateral visual attention. However, experimental support for this notion has been mainly drawn from clinical models of unilateral damage. We have previously shown that low-frequency repetitive TMS (rTMS) over the intraparietal sulcus (IPS) generates a contralateral attentional deficit in bilateral visual tracking. Here, we used functional magnetic resonance imaging (fMRI) to study whether rTMS temporarily disrupts the inter-hemispheric balance between bilateral IPS in visual attention. Following application of 1 Hz rTMS over the left IPS, subjects performed a bilateral visual tracking task while their brain activity was recorded using fMRI. Behaviorally, tracking accuracy was reduced immediately following rTMS. Areas ventro-lateral to left IPS, including inferior parietal lobule (IPL), lateral IPS (LIPS), and middle occipital gyrus (MoG), showed decreased activity following rTMS, while dorsomedial areas, such as Superior Parietal Lobule (SPL), Superior occipital gyrus (SoG), and lingual gyrus, as well as middle temporal areas (MT+), showed higher activity. The brain activity of the homologues of these regions in the un-stimulated, right hemisphere was reversed. Interestingly, the evolution of network-wide activation related to attentional behavior following rTMS showed that activation of most occipital synergists adaptively compensated for contralateral and ipsilateral decrement after rTMS, while activation of parietal synergists, and SoG remained competing. This pattern of ipsilateral and contralateral activations empirically supports the hypothesized loss of inter-hemispheric balance that underlies clinical manifestation of visual attentional extinction.


Impact of Ramadan fasting on intraocular pressure, visual acuity and refractive errors.
Fasting evidently influences a variety of physiological parameters that can impact the ocular system. Among these modifications are alterations in insulin secretion, sympathetic activity, free fatty acids, lipid profile, melatonin, cortisol, electrolytes and catecholamines. In this study, we investigated the possible alterations in intraocular pressure (IOP), visual acuity and refractive errors during Ramadan fasting. IOP, visual acuity and refractive errors of both eyes of volunteers were measured on the first and last days of Ramadan (once in the morning and evening). Body weight was measured so as to estimate the amount of dehydration. Data from the two examinations was analysed using one-way analysis of variance. A p-value of less than 0.05 was considered statistically significant. 58 healthy, fasting male volunteers with a mean age of 40.7 +/- 7.1 years participated in the study. Statistical analysis demonstrated no difference in IOP, visual acuity or refractive errors on the first and last days of Ramadan, or within a single day (from morning to evening). Our results reveal that Islamic Ramadan fasting does not profoundly affect physiological IOP, refractive error or visual acuity values in healthy volunteers. However, more detailed investigations using animal models should be designed to evaluate whether fasting has a pivotal influence on pathological conditions.


Evaluation of a surgical technique for repair of equine accessory carpal bone fractures.
In 9 horses, osteotomies were performed to simulate accessory carpal bone fractures. Screw fixation, aided by a large C-clamp, was performed on 6 of the 9 horses. Three were treated conservatively, as controls, with fractures not repaired; they remained clinically lame throughout the 6-month study. Fibrocartilaginous nonunion developed in each of the 3 controls. At 150 days, the principals were free of lameness, with evidence of bony union. The results of clinical, radiographic, and pathologic evaluations showed surgical repair to be superior to prolonged rest in treating equine accessory carpal bone fractures.


Nasopharyngeal Microbiome Diversity Changes over Time in Children with Asthma.
The nasopharynx is a reservoir for pathogens associated with respiratory illnesses such as asthma. Next-generation sequencing (NGS) has been used to characterize the nasopharyngeal microbiome of infants and adults during health and disease; less is known, however, about the composition and temporal dynamics (i.e., longitudinal variation) of microbiotas from children and adolescents. Here we use NGS technology to characterize the nasopharyngeal microbiomes of asthmatic children and adolescents (6 to 18 years) and determine their stability over time. Two nasopharyngeal washes collected 5.5 to 6.5 months apart were taken from 40 children and adolescents with asthma living in the Washington D.C. area. Sequence data from the 16S-V4 rRNA gene region (~250 bp) were collected from the samples using the MiSeq platform. Raw data were processed in mothur (SILVA123 reference database) and Operational Taxonomic Units (OTU)-based alpha- and beta-diversity metrics were estimated. Relatedness among samples was assessed using PCoA ordination and Procrustes analyses. Differences in microbial diversity and taxon mean relative proportions were assessed using linear mixed effects models. Core microbiome analyses were also performed to identify stable and consistent microbes of the nasopharynx. A total of 2,096,584 clean 16S sequences corresponding to an average of 167 OTUs per sample were generated. Representatives of Moraxella*, Staphylococcus*, Dolosigranulum, Corynebacterium, Prevotella, Streptococcus*, Haemophilus*, Fusobacterium* and a Neisseriaceae genus accounted for 86% of the total reads. These nine genera have been previously found in the nasopharynxes of both infants and adults, but in different proportions. OTUs from the five genera highlighted (*) above defined the nasopharyngeal core microbiome at the 95% level. No significant differences in alpha- and beta-diversity were observed between seasons, but bacterial mean relative proportions of Haemophilus, Moraxella, Staphylococcus and Corynebacterium varied significantly between summer-fall and age groups (inter-patient variation). Additionally, OTUs varied significantly within patients between time points in 35 of the 40 patients analyzed. Future cross-sectional studies should be mindful of the temporal dynamics of the nasopharyngeal microbiota.


[Carcinoma of salivary glands--a clinical analysis of 342 cases].
342 cases with carcinoma of salivary glands were analysed. 152 tumors were located in parotid, 42 in submaxillary, 17 in sublingual and 131 in minor salivary glands. Pathological diagnosis were 106 mucoepidermoid carcinoma, 80 adenoid cystic carcinoma, 54 malignant mixed tumor, 40 adenocarcinoma, 38 papillary cystadenocarcinoma, 17 acinic cell carcinoma, 5 squamous cell carcinoma, and 2 undifferentiated carcinoma. The 3, 5, 10 and 15 year survival rates of these 342 cases were 76.6%, 65.9%, 48% and 29%, respectively. The difference between survival rate and relapse-free survival rate was about 8%. The prognosis of acinic cell carcinoma and mucoepidermoid carcinoma was much better than that of squamous cell carcinoma, adenocarcinoma and undifferentiated carcinoma. The survival rates, according to location, were: minor salivary gland tumors the highest, and those of submaxillary gland tumors the lowest. Postoperative radiotherapy improved the survival rate of adenoid cystic carcinoma. The overall recurrence rate was 37.4%, the neck lymph node metastasis rate 14.3% and the distant metastasis rate 9.1%.


Association of Asthma With Treatments and Outcomes in Children With Critical Influenza.
Hospitalization for severe influenza infection in childhood may result in postdischarge sequelae. To evaluate inpatient management and postdischarge sequelae in children with critical respiratory illness owing to influenza with or without preexisting asthma. This was a prospective, observational multicenter study of children (aged 8 months to 17 years) admitted to a pediatric intensive care or high-acuity unit (in November 2019 to April 2020) for influenza. Results were stratified by preexisting asthma. Prehospital status, hospital treatments, and outcomes were collected. Surveys at approximately 90 days after discharge evaluated postdischarge health resource use, functional status, and respiratory symptoms. A total of 165 children had influenza: 56 with preexisting asthma (33.9%) and 109 without it (66.1%; 41.1% and 39.4%, respectively, were fully vaccinated against influenza). Fifteen patients with preexisting asthma (26.7%) and 34 without it (31.1%) were intubated. More patients with versus without preexisting asthma received pharmacologic asthma treatments during hospitalization (76.7% vs 28.4%). Of 136 patients with 90-day survey data (82.4%; 46 with preexisting asthma [33.8%] and 90 without it [66.1%]), a similar proportion had an emergency department/urgent care visit (4.3% vs 6.6%) or hospital readmission (8.6% vs 3.3%) for a respiratory condition. Patients with preexisting asthma more frequently experienced asthma symptoms (78.2% vs 3.3%) and had respiratory specialist visits (52% vs 20%) after discharge. Of 109 patients without preexisting asthma, 10 reported receiving a new diagnosis of asthma (11.1%). Respiratory health resource use and symptoms are important postdischarge outcomes after influenza critical illness in children with and without preexisting asthma. Less than half of children were vaccinated for influenza, a tool that could mitigate critical illness and its sequelae.


Systolic Blood Pressure and Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.
Lower systolic blood pressure (SBP) levels are associated with poor outcomes in patients with heart failure. Less is known about this association in heart failure with preserved ejection fraction (HFpEF). To determine the associations of SBP levels with mortality and other outcomes in HFpEF. A propensity score-matched observational study of the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry included 25 354 patients who were discharged alive; 8873 (35.0%) had an ejection fraction of at least 50%, and of these, 3915 (44.1%) had stable SBP levels (≤20 mm Hg admission to discharge variation). Data were collected from 259 hospitals in 48 states between March 1, 2003, and December 31, 2004. Data were analyzed from March 1, 2003, to December 31, 2008. Discharge SBP levels less than 120 mm Hg. A total of 1076 of 3915 (27.5%) had SBP levels less than 120 mm Hg, of whom 901 (83.7%) were matched by propensity scores with 901 patients with SBP levels of 120 mm Hg or greater who were balanced on 58 baseline characteristics. Thirty-day, 1-year, and overall all-cause mortality and heart failure readmission through December 31, 2008. The 1802 matched patients had a mean (SD) age of 79 (10) years; 1147 (63.7%) were women, and 134 (7.4%) were African American. Thirty-day all-cause mortality occurred in 91 (10%) and 45 (5%) of matched patients with discharge SBP of less than 120 mm Hg vs 120 mm Hg or greater, respectively (hazard ratio [HR], 2.07; 95% CI, 1.45-2.95; P < .001). Systolic blood pressure level less than 120 mm Hg was also associated with a higher risk of mortality at 1 year (39% vs 31%; HR, 1.36; 95% CI, 1.16-1.59; P < .001) and during a median follow-up of 2.1 (overall 6) years (HR, 1.17; 95% CI, 1.05-1.30; P = .005). Systolic blood pressure level less than 120 mm Hg was associated with a higher risk of heart failure readmission at 30 days (HR, 1.47; 95% CI, 1.08-2.01; P = .02) but not at 1 or 6 years. Hazard ratios for the combined end point of heart failure readmission or all-cause mortality associated with SBP level less than 120 mm at 30 days, 1 year, and overall were 1.71 (95% CI, 1.34-2.18; P < .001), 1.21 (95% CI, 1.07-1.38; P = .004), and 1.12 (95% CI, 1.01-1.24; P = .03), respectively. Among hospitalized patients with HFpEF, an SBP level less than 120 mm Hg is significantly associated with poor outcomes. Future studies need to prospectively evaluate optimal SBP treatment goals in patients with HFpEF.


Molecular basis of bluetongue virus neutralization.
Molecular and serological analyses of bluetongue virus serotypes 10 and 11 and their intertype reassortants indicate that the viral RNA segment L2 codes for the serotype-specific antigen. Individual RNA segments of parental and reassortant viruses were characterized by oligonucleotide fingerprint analyses. Analyses of their virion polypeptides by Cleveland peptide mapping (Cleveland et al., J. Biol. Chem. 252:1102-1106, 1977) demonstrated that the L2 gene segregated colinearly with the viral P2 protein, implicating it as the antigen that is responsible for the viral serotype specificity.


Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia.
Sickle cell anemia (SCA) presents a complex pathophysiology which can be affected by a number of modifying factors, including genetic and biochemical ones. In Brazil, there have been no studies verifying βS-haplotypes effect on oxidative stress parameters. This study evaluated βS-haplotypes and Hb F levels effects on oxidative stress markers and their relationship with hydroxyurea (HU) treatment in SCA patients. The studied group was composed by 28 SCA patients. Thirteen of these patients were treated with HU and 15 of them were not. We used molecular methodology (PCR-RFLP) for hemoglobin S genotype confirmation and haplotypes identification. Biochemical parameters were measured using spectrophotometric methods (Thiobarbituric-acid-reactive substances and Trolox equivalent antioxidant capacity levels, catalase and GST activities) and plasma glutathione levels by High-performance liquid chromatography coupled to electrochemical detection. We found the highest frequency of Bantu haplotype (48.2%) which was followed by Benin (32.1%). We observed also the presence of Cameroon haplotype, rare in Brazilian population and 19.7% of atypical haplotypes. The protective Hb F effect was confirmed in SCA patients because these patients showed an increase in Hb F levels that resulted in a 41.3% decrease on the lipid peroxidation levels (r =-0.74, p=0.01). Other biochemical parameters have not shown differential expression according to patient's haplotypes. Bantu haplotype presence was related to the highest lipid peroxidation levels in patients (p < 0,01), but it also conferred a differential response to HU treatment, raising Hb F levels in 52.6% (p = 0.03) when compared with the group with the same molecular profile without HU usage. SCA patients with Bantu haplotype showed the worst oxidative status. However these patients also demonstrated a better response to the treatment with HU. Such treatment seems to have presented a "haplotype-dependent" pharmacological effect.


Tea polyphenols protect against Flavobacterium columnare-induced gill injury via suppression of oxidative stress, inflammation, and apoptosis in grass carp.
Flavobacterium columnare (F. columnare) is one of the deadliest fish pathogens causing bacterial gill rot disease in various freshwater fish species globally. Tea polyphenols (TPs) are an inexpensive product extracted from tea that have received much attention as a feed additive in aquaculture. The current study was designed to investigate the underlying mechanisms and protective effects of dietary TPs against F. columnare-induced gill injury via suppression of oxidative stress, apoptosis, and inflammation in grass carp. TPs were not supplemented to the diet (control) and were supplemented at 40, 80, 120, 160 or 200 mg/kg diet. The feeding experiment was carried out for 60 days, followed by a 3-Day F. columnare challenge test. The results showed that 120 mg/kg TPs in the diet exerted the following five protective effects in fish gill: (1) control gill-rot disease and improved histopathology, (2) inhibit excessive apoptosis, (3) enhance the activity of antioxidant enzymes and upregulate related gene expression via the Nrf2/Keap1 pathway, (4) increase the activity of immune enzymes, And (5) mediate inflammatory cytokine gene expression via the JAK/STAT3 pathway. Taken together, dietary supplementation with TPs is a compelling approach to protect the gill function of fish against F. columnare.


Email-based promotion of self-help for subthreshold depression: Mood Memos randomised controlled trial.
Subthreshold depression is common, impairs functioning and increases the risk of major depression. Improving self-help coping strategies could help subthreshold depression and prevent major depression. To test the effectiveness of an automated email-based campaign promoting self-help behaviours. A randomised controlled trial was conducted through the website: www.moodmemos.com. Participants received automated emails twice weekly for 6 weeks containing advice about self-help strategies. Emails containing general information about depression served as a control. The principal outcome was depression symptom level on the nine-item Patient Health Questionnaire (PHQ-9) (trial registration: ACTRN12609000925246). The study recruited 1326 adults with subthreshold depression. There was a small significant difference in depression symptoms at post-intervention, favouring the active group (d = 0.17, 95% CI 0.01-0.34). There was a lower, although non-significant, risk of major depression in the active group (number needed to treat (NNT) 25, 95% CI 11 to ∞ to NNT(harm) 57). Emails promoting self-help strategies were beneficial. Internet delivery of self-help messages affords a low-cost, easily disseminated and highly automated approach for indicated prevention of depression.


Low autonomic arousal as vulnerability to externalising behaviour in infants with hostile mothers.
Maternal psychopathology and the child's autonomic nervous system functioning are risk factors for aggressive behaviour later in life. While research has shown that maternal psychopathology already affects young children, less is known about the association between autonomic functioning and aggressive behaviour in young children. In addition, maternal psychopathology and autonomic nervous system functioning may interact to determine the risk of aggressive behaviour. In a sample of 375 infants and their mothers, maternal psychiatric symptoms were assessed with the Brief Symptom Inventory and toddler aggressive behaviour with the Child Behaviour Checklist. Infant heart rate was recorded at 14 months. Maternal psychiatric problems, including hostility and depression, were associated with toddler aggressive behaviour. Maternal psychiatric problems interacted with mean heart rate (P=0.01) and HF variability (P=0.03) in their effect on toddler aggressive behaviour. Mothers with high psychiatric problems, in particular, high hostility, were more likely to have toddlers with high aggressive behaviour. Moreover, in the presence of maternal risk factors, low autonomic arousal renders children particularly susceptible to aggressive behaviour.


Disease stage-related survival in idiopathic pulmonary fibrosis patients treated with nintedanib and pirfenidone: An exploratory study.
GAP (gender-age-physiology) and TORVAN are multi-parametric prognostication scores for idiopathic pulmonary fibrosis (IPF). We compared their prognostic value in patients treated with nintedanib or pirfenidone and explored their effect on patient survival in relation to disease staging. Retrospective evaluation of 235 naïve IPF patients (M = 179; mean age 69.8 yrs±7.1; 102 treated with nintedanib and 133 with pirfenidone), referred to two Italian academic centers between February 2012 and December 2019. During a median follow-up of 4.2 years, the incidence rate of death was 14.5 per 100 person-years (95% CI: 12 to 17.4), with no differences between nintedanib and pirfenidone (log-rank p = 0.771). According to time-ROC analysis, GAP and TORVAN showed a similar discrimination performance at 1, 2, and 5 years. Survival of GAP-2/GAP-3 IPF patients treated with nintedanib was worse than that of patients in GAP-1 (HR 4.8, 95% CI: 2.2 to 10.5 and HR 9.4, 95% CI: 3.8 to 23.2). TORVAN I patients treated with nintedanib exhibited better survival than those in stages III (HR 3.1, 95% CI: 1.4 to 6.6) and IV (HR 10.5, 95% CI: 3.5 to 31.6). A significant treatment x stage interaction was observed for both disease staging indexes (p = 0.042 for treatment by GAP interaction and p = 0.046 for treatment by TORVAN interaction). A better survival was associated with nintedanib in patients with mild disease (GAP-1 or TORVAN I stage) and with pirfenidone in GAP-3 or TORVAN IV cases, although these findings did not always reach statistical significance. GAP and TORVAN similarly perform in IPF patients on anti-fibrotic therapy. However, the survival of patients treated with nintedanib and pirfenidone appears to be differently affected by disease staging.


Impact of the US Maternal Tetanus, Diphtheria, and Acellular Pertussis Vaccination Program on Preventing Pertussis in Infants <2 Months of Age: A Case-Control Evaluation.
Infants aged <1 year are at highest risk for pertussis-related morbidity and mortality. In 2012, Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccine was recommended for women during each pregnancy to protect infants in the first months of life; data on effectiveness of this strategy are currently limited. We conducted a case-control evaluation among pertussis cases <2 months old with cough onset between 1 January 2011 and 31 December 2014 from 6 US Emerging Infection Program Network states. Controls were hospital-matched and selected by birth certificate. Mothers were interviewed to collect information on demographics, household characteristics, and healthcare providers. Provider-verified immunization history was obtained on mothers and infants. Mothers were considered vaccinated during pregnancy if Tdap was received ≥14 days before delivery; trimester was calculated using Tdap date, infant's date of birth, and gestational age. Odds ratios were calculated using multivariable conditional logistic regression; vaccine effectiveness (VE) was estimated as (1 - odds ratio) × 100%. A total of 240 cases and 535 controls were included; 17 (7.1%) case mothers and 90 (16.8%) control mothers received Tdap during the third trimester of pregnancy. The multivariable VE estimate for Tdap administered during the third trimester of pregnancy was 77.7% (95% confidence interval [CI], 48.3%-90.4%); VE increased to 90.5% (95% CI, 65.2%-97.4%) against hospitalized cases. Vaccination during pregnancy is an effective way to protect infants during the early months of life. With a continuing resurgence in pertussis, efforts should focus on maximizing Tdap uptake among pregnant women.


Comparing outcomes in patients with persistent asthma: a registry of two therapeutic alternatives.
Clinical trials have demonstrated improved efficacy of fluticasone propionate/salmeterol (100/50 mcg) in a single device (FSC) compared with montelukast (10 mg) (MON). This study was designed to assess asthma control, asthma-related quality of life, asthma-related emergency department (ED) visit/hospitalization, treatment-related satisfaction, and productivity losses in patients newly started on FSC or MON. Patients who were newly prescribed FSC or MON during a regularly scheduled office visit were enrolled in a prospective observational study by nearly 500 physicians from eight managed care plans. Patient survey data were collected at baseline and at months 1, 3, 6, and 12, to measure study outcomes. ED visits/inpatient stays were reported from commercial claims data. Multivariate analyses assessed 12-month outcomes, controlling for several baseline patient characteristics. A total of 1414 patients >or= 15 years old were enrolled in the registry (FSC, n = 1061; MON, n = 353), 90% of which completed a 12-month survey. FSC patients had significantly greater improvement in both asthma control and quality of life, and reported significantly higher satisfaction with their medication (p = 0.003) and fewer days at work/school with asthma symptoms (p = 0.04) than MON. Other parameters of productivity losses such as missed work/school days due to asthma were not significantly different between the two groups. FSC use was also significantly associated with a lower risk of an asthma-related ED visit/hospitalization compared with MON (odds ratio = 0.35, 95% confidence interval: 0.15-0.92). In a 12-month office-based observational study, patients age 15 and older with persistent asthma, newly started on FSC, improved in symptom, quality of life, treatment, and utilization-related outcomes compared with patients newly started on MON. These results should be interpreted in light of the inherent limitations of non-randomized, uncontrolled studies.


[Reaction of Chinese hamster cell culture to the cytotoxic action of imuran in the early and late stationary growth phases].
It has been shown that when cells are incubated for a long time without medium change, imuran exerts a much greater effect on the viability of cells in the late stationary phase of growth than in the early stationary phase. When nutrient medium supplemented with 10% serum was changed for the medium with 0.5% serum, or when a partial change of medium (one third of the volume) was carried out daily from day 4, these differences were only slightly pronounced. Thus, the degree of cell response to imuran in the early and late stationary phases of growth depends upon the way of cell maintaining in the resting state.


Statin therapy and the risk for diabetes among adult women: do the benefits outweigh the risk?
The purpose of this review was to examine statin therapy and the risk for diabetes among adult women using a selective review. The literature contains reports of new-onset diabetes associated with statin use. While many studies do not report sex-specific results, there is evidence indicating the risk to benefit ratio may vary by gender. However, the absolute effects are not clear because women have historically been under-represented in clinical trials. A review of the literature indicates that the cardiovascular benefits of statins appear to outweigh the risk for statin-related diabetes. However, the effect may depend upon baseline diabetes risk, dose, and statin potency. Rigorous, long-term studies focused on the risks and benefits of statins in women are unavailable to sort for gender-specific differences. Until this changes, individualized attention to risk assessment, and strong prevention with lifestyle changes must prevail.


Do sun- versus shade-grown kiwifruits perform differently upon storage? An overview of fruit maturity and nutraceutical properties of whole and fresh-cut produce.
Fresh-cut produce represents a good method to save about 25% of the kiwifruit not useful to meet the fresh fruit-marketing standard due to improper size and shape. For that reason, fresh-cut kiwifruit has been extensively studied. However, the comprehension of the influence of some aspects of cultivation might further increase the shelf life as well as the nutritional values of that fruit. This study explored the hypothesis that kiwifruits grown fully exposed to sunlight or partially shaded differently perform upon storage as whole fruit and as minimally processed produce. Flesh firmness (FF), total solids soluble (SSC), ascorbate (AAT), flavonoids (TFO), and phenols (TF) contents were evaluated in sliced and whole fruit upon 3 days of storage at 4 °C after 75 days of cold chamber storage at 0 °C. The activities of two enzymes related to the softening process, polygalacturonase (PG) and pectinmethylesterase (PME), were evaluated as well. FF and SSC were constitutively higher in sun-exposed fruit, and those characteristics remained higher during the storage as whole fruit. Greater constitutive content of AAT, TFO, and TP was found in sun-exposed whole fruit, although after cutting the reduction in their content was significantly lower in shaded fruits. PME and PG activities were higher only in whole shaded fruits, whereas no relevant differences occurred after cutting. In summary, sun-exposed fruits were more suitable for the fresh-fruit market, whereas the shaded counterpart displayed a good predisposition for use as fresh-cut produce, maintaining similar fruit maturity properties but higher nutraceutical values when sliced than fruit grown under full sun.


Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk.
Particulate air pollution is associated with cardiovascular disease. Acute phase response is causally linked to cardiovascular disease. Here, we propose that particle-induced pulmonary acute phase response provides an underlying mechanism for particle-induced cardiovascular risk. We analysed the mRNA expression of Serum Amyloid A (Saa3) in lung tissue from female C57BL/6J mice exposed to different particles including nanomaterials (carbon black and titanium dioxide nanoparticles, multi- and single walled carbon nanotubes), diesel exhaust particles and airborne dust collected at a biofuel plant. Mice were exposed to single or multiple doses of particles by inhalation or intratracheal instillation and pulmonary mRNA expression of Saa3 was determined at different time points of up to 4 weeks after exposure. Also hepatic mRNA expression of Saa3, SAA3 protein levels in broncheoalveolar lavage fluid and in plasma and high density lipoprotein levels in plasma were determined in mice exposed to multiwalled carbon nanotubes. Pulmonary exposure to particles strongly increased Saa3 mRNA levels in lung tissue and elevated SAA3 protein levels in broncheoalveolar lavage fluid and plasma, whereas hepatic Saa3 levels were much less affected. Pulmonary Saa3 expression correlated with the number of neutrophils in BAL across different dosing regimens, doses and time points. Pulmonary acute phase response may constitute a direct link between particle inhalation and risk of cardiovascular disease. We propose that the particle-induced pulmonary acute phase response may predict risk for cardiovascular disease.


A workflow for segmenting soil and plant X-ray computed tomography images with deep learning in Google's Colaboratory.
X-ray micro-computed tomography (X-ray μCT) has enabled the characterization of the properties and processes that take place in plants and soils at the micron scale. Despite the widespread use of this advanced technique, major limitations in both hardware and software limit the speed and accuracy of image processing and data analysis. Recent advances in machine learning, specifically the application of convolutional neural networks to image analysis, have enabled rapid and accurate segmentation of image data. Yet, challenges remain in applying convolutional neural networks to the analysis of environmentally and agriculturally relevant images. Specifically, there is a disconnect between the computer scientists and engineers, who build these AI/ML tools, and the potential end users in agricultural research, who may be unsure of how to apply these tools in their work. Additionally, the computing resources required for training and applying deep learning models are unique, more common to computer gaming systems or graphics design work, than to traditional computational systems. To navigate these challenges, we developed a modular workflow for applying convolutional neural networks to X-ray μCT images, using low-cost resources in Google's Colaboratory web application. Here we present the results of the workflow, illustrating how parameters can be optimized to achieve best results using example scans from walnut leaves, almond flower buds, and a soil aggregate. We expect that this framework will accelerate the adoption and use of emerging deep learning techniques within the plant and soil sciences.


Rural cooperative coding project.
Data quality is the cornerstone on which other quality activities are built. The importance of accurately coded data cannot be overlooked. The Rural Cooperative Coding Project sought to collaborate with rural hospitals in Utah to improve the quality of that data through an individualized educational program allowing open and active discussions. We hope that this project has assisted rural facilities in building and enhancing their own ongoing coding and data quality improvement activities.


X-ray powder diffraction and microscopic analysis of crystalluria in dogs with ethylene glycol poisoning.
Most of the urinary crystals in 2 dogs intoxicated with ethylene glycol had prismatic (rod-like, hippurate-like), and to a less extent, hemp seed or spindle shapes. Using X-ray powder diffraction and optical analysis, these crystals were identified as calcium oxalate monohydrate. A few crystals of calcium oxalate dihydrate (envelope shape) were also observed in the urine sediment. Their presence was confirmed by the appearance of weak X-ray peaks having interplanar spacings ranging from 0.617 to 0.620 nm, which are thought to correspond to the 200 X-ray reflection of calcium oxalate dihydrate. Thus, the 6-sided hippurate-like crystals in the urine of ethylene glycol-poisoned dogs are actually calcium oxalate monohydrate.


Discrete epidemic models.
The mathematical theory of single outbreak epidemic models really began with the work of Kermack and Mackendrick about decades ago. This gave a simple answer to the long-standing question of why epidemics woould appear suddenly and then disappear just as suddenly without having infected an entire population. Therefore it seemed natural to expect that theoreticians would immediately proceed to expand this mathematical framework both because the need to handle recurrent single infectious disease outbreaks has always been a priority for public health officials and because theoreticians often try to push the limits of exiting theories. However, the expansion of the theory via the inclusion of refined epidemiological classifications or through the incorporation of categories that are essential for the evaluation of intervention strategies, in the context of ongoing epidemic outbreaks, did not materialize. It was the global threat posed by SARS in that caused theoreticians to expand the Kermack-McKendrick single-outbreak framework. Most recently, efforts to connect theoretical work to data have exploded as attempts to deal with the threat of emergent and re-emergent diseases including the most recent H1N1 influenza pandemic, have marched to the forefront of our global priorities. Since data are collected and/or reported over discrete units of time, developing single outbreak models that fit collected data naturally is relevant. In this note, we introduce a discrete-epidemic framework and highlight, through our analyses, the similarities between single-outbreak comparable classical continuous-time epidemic models and the discrete-time models introduced in this note. The emphasis is on comparisons driven by expressions for the final epidemic size.


GAPDH enhances group II intron splicing in vitro.
Group II introns are autocatalytic RNAs which self-splice in vitro. However, in vivo additional protein factors might be involved in the splicing process. We used an affinity chromatography method called 'StreptoTag' to identify group II intron binding proteins from Saccharomyces cerevisiae. This method uses a hybrid RNA consisting of a streptomycin-binding affinity tag and the RNA of interest, which is bound to a streptomycin column and incubated with yeast protein extract. After several washing steps the bound RNPs are eluted by addition of streptomycin. The eluted RNPs are separated and the proteins identified by mass-spectrometric analysis. Using crude extract from yeast in combination with a substructure of the bl1 group II intron (domains IV-VI) we were able to identify four glycolytic enzymes; glucose-6-phosphate isomerase (GPI), 3-phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and triosephosphate isomerase (TPI). From these proteins GAPDH increases in vitro splicing of the bl1 group II intron by up to three times. However, in vivo GAPDH is not a group II intron-splicing factor, since it is not localised in yeast mitochondria. Therefore, the observed activity reflects an unexpected property of GAPDH. Band shift experiments and UV cross linking demonstrated the interaction of GAPDH with the group II intron RNA. This novel activity expands the reaction repertoire of GAPDH to a new RNA species.


The combined effect of subcutaneous granulocyte- colony stimulating factor and myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride on post-infarction left ventricular function, the RIGENERA 2.0 trial: study protocol for a randomized controlled trial.
Several clinical trials and recent meta-analyses have demonstrated that administration of recombinant human granulocyte-colony stimulating factor (G-CSF) is safe and, only in patients with large acute myocardial infarction (AMI), is associated with an improvement in left ventricular ejection fraction. Moreover, the mobilization and engraftment of the bone marrow-derived cells may differ significantly among patients, interfering with the restoration of left ventricular function after treatment. Therefore, the clinical potential application of the G-CSF has not yet been fully elucidated. The RIGENERA 2.0 trial is a multicenter, phase II, placebo-controlled, randomized, open-label, with blinded evaluation of endpoints (PROBE) trial in which 120 patients with an acute ST-elevation myocardial infarction (STEMI) undergoing successful revascularization but with residual myocardial dysfunction will be enrolled. In cases where there is a left ventricular ejection fraction (LVEF) ≤ 45% the patient will be electronically randomized (1:1 ratio) to receive either subcutaneous recombinant human G-CSF (group 1) or placebo (group 2) both added on top of optimal standard of care. Both groups will undergo myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride (MCE) whilst undergoing the echocardiogram. The primary efficacy endpoint is the evaluation of the LVEF at 6 months after AMI assessed by cardiac magnetic resonance. Secondary efficacy endpoints are the evaluation of LVEF at 6 months after AMI assessed by echocardiography, left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) assessed by cardiac magnetic resonance and echocardiography at 6 months, together with the incidence of major adverse clinical events (MACE) defined as death, myocardial infarction, sustained cardiac arrhythmias, cardiogenic shock, stroke and re-hospitalization due to heart failure at 1 year. The RIGENERA 2.0 trial will test whether G-CSF administration and MCE, through the enhancement of the bone marrow-derived cells homing in the myocardium, determines an improvement in regional and global contractile function, myocardial perfusion and infarct extension in patients with large AMI. The results of the present study are expected to envision routine clinical use of this safe, affordable and reproducible approach in patients with successful revascularization after AMI. ClinicalTrials.gov: NCT02502747 (29 June 2015); EudraCT: 2015-002189-21 (10 July 2015).


[The nutritional importance and physiopathology of molybdenum in man].
Molybdenum is an essential trace element taking part in the active site of three human enzymes: xanthine oxidase, aldehyde oxidase and sulfite oxidase, playing a role in the detoxification of the organism and/or the production of important intermediary products. The perturbation of the first two enzymes has no established clinical consequence, but a decrease in activity of the third one is harmful for the organism, particularly the nervous system during pre- or post-natal development. The anomalies in the function of these enzymes are generally inherited and linked to the impaired production of the molybdenum cofactor, an organic molecule complexed to the element in the active site. However, several pathological cases in animals and one case in man have been clearly attributed to molybdenum deficiency. It is the reason why molybdenum supplementation has been recommended in long term total parenteral nutrition in infants and adults.


Using Crowdsourcing to Develop a Peer-Led Intervention for Safer Dating App Use: Pilot Study.
Smartphone-based dating apps are rapidly transforming how people seek potential sexual and romantic partners. However, they can also increase the risk of unsafe sexual behaviors, harassment, and infringement of personal privacy. Current research on interventions for safer dating app use remains insufficient. The goal of this study was to describe the development of an intervention for safer dating app usage using crowdsourcing and peer-led approaches. This paper describes the development of an intervention program designed to promote safer dating app use among college students. Crowdsourcing and peer-led approaches were adopted during key stages of the development process. Focus group discussions were held to assess the experience and needs of dating app users. A crowdsourcing contest then solicited ideas for performance objectives for the intervention. These objectives were grouped to further identify practical strategies. A one-day intensive workshop was subsequently held with peer mentors to brainstorm ideas for the production of creative interventional materials. The intervention programs were produced and tested in a pilot study. The app's effectiveness will be evaluated in a cluster randomized controlled trial. The intervention program consists of a risk assessment tool, a first-person scenario game, and four short videos. The risk assessment tool, comprised of 14 questions, will give the participant a score to determine their level of risk of adverse events when using dating apps. The scenario game is a first-person simulation game where the players are presented with choices when faced with different scenarios. The short videos each last 2-4 minutes, with points of discussion aimed at addressing the risks of using dating apps. The programs were piloted and were found to be relatable and helpful when further modifications were made. Potential challenges identified during the development process included data management and analysis, sustaining peer mentors' interests and participation, and balancing between providing more information and perpetuating social stigma around dating app use. By integrating new approaches, such as crowdsourcing and the peer-led approach, in developing an intervention for safer dating app use, our development process provides a viable model for developing future interventions to address the risks associated with dating app use.


Laparoscopy-assisted distal gastrectomy for early gastric cancer: is it beneficial for patients of heavier weight?
In this retrospective review, we evaluated the advantages and disadvantages of LADG for patients of heavier weight with early gastric cancer. LADG has been used to treat early gastric cancer. We and others have reported less operative blood loss, less pain, early recovery of bowel activity, early restart of oral intake, and a shorter hospital stay with LADG compared with a conventional open method. There is, however, little information on the advantages of LADG for obese patients with early gastric cancer. Between January 1996 and March 2002, 76 patients with preoperatively diagnosed early gastric carcinoma underwent LADG in our department. We classified these patients into 2 groups on the basis of body mass index (BMI). Nineteen patients had a high-BMI (>/= 24.2 kg/m2), and 57 patients had a normal-BMI (<24.2 kg/m2). We collected data by retrospectively reviewing the medical charts. Extension of the minilaparotomic incision or conversion to laparotomy was needed in 6 (32%) of the 19 patients in the high-BMI group, whereas only 3 (5%) of 57 patients in the normal-BMI group required either. In the high-BMI group, Roux-en-Y anastomosis rather than Billroth I anastomosis was adopted more often than in the normal-BMI group, due to the difficulty of the reconstruction (58% versus 4%, P = 0.001). Significantly longer operative time (370 +/- 61 minutes versus 317 +/- 58 minutes, P = 0.015) and prolonged recovery of bowel activity (3.5 +/- 1.0 days versus 2.6 +/- 1.0 days, P = 0.007) were observed in the patients in the high-BMI group. In the current study, LADG in patients of heavier weight was accompanied by more technical difficulties, and the disadvantages of longer operative time and delayed recovery of bowel activity was observed in patients of heavier weight. Heavier weight appears to be an ominous factor in the successful completion of LADG and should be considered in the decision to use LADG. There are still benefits of a decreased incidence of serious wound and hernia complications in successful cases.


Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases.
We report nine novel DNA alterations in the RET proto-oncogene in 12 unrelated cases identified by DNA sequencing of exons 10 and 11 of the gene. The novel variants K666E, IVS9-11G-->A, D631V in cis with H665Q, D631E (with C634Y), E623K (in trans with C618S), 616delGAG (in trans with C609Y), Y606C, C630R, and R635-T636insELCR;T636P were detected in patients with various clinical presentations ranging from thyroid goiter, medullary thyroid carcinoma, and pheochromocytoma to classic multiple endocrine neoplasia type 2A. When novel DNA alterations are found, extended family studies can be helpful in determining the clinical significance of such findings. Segregation within families suggests that K666E and T636insELCR;T636P are likely to be disease-causing mutations. However, the mechanism by which they affect the normal activity of the RET receptor is unclear. Absence of segregation with disease was observed for E623K and 616delGAG. For the remainder of the DNA alterations, family studies were not possible, and the clinical significance of these novel variants needs further assessment. Additional case reports, animal models, and/or functional studies are needed to determine the clinical significance of these newly identified variants.


Monitoring quality of care through linkage of administrative data: national trends in bloodstream infection in U.K. PICUs 2003-2012.
Interventions to reduce hospital-acquired bloodstream infection have succeeded in reducing rates in U.S. PICUs, but there is a lack of evidence for the impact of similar interventions in the United Kingdom. We assessed variation in bloodstream infection rates within and between PICUs over a 10-year period, during which time infection control strategies (care bundles) were implemented. Observational study linking laboratory data to national audit data of pediatric intensive care admissions (Paediatric Intensive Care Audit Network). Twenty PICUs in England and Wales, 2003-2012. One hundred and two thousand nine hundred ninety-nine children less than 16 years. Implementation of infection control strategies in PICU captured through a survey of clinicians. Rates of bloodstream infection per 1,000 bed-days were estimated from samples taken between 2 days after admission and up to 2 days following discharge from PICU. Two percent of children experienced at least one bloodstream infection, corresponding to 5.11 (95% CI, 4.90-5.31) per 1,000 bed-days. There was a significant difference in trends preimplementation of infection control strategies (annual decrease of 8.0%; 95% CI, 6.3-9.7%) versus postimplementation (annual decrease of 13.4%; 95% CI, 10.3-16.4%). By 24 months postimplementation, the rate of bloodstream infection had fallen 25.5% and was 15.1% lower than would have been expected if preimplementation trends had continued. Our population-based study of PICUs in England and Wales demonstrates a steady decline in bloodstream infection rates over time. In addition, there was a significant and incremental further decrease in rates associated with timing of implementation of infection control strategies. Assessment of bloodstream infection trends before as well as after implementation of infection control strategies can be facilitated using data linkage and is important to avoid overestimating the impact of unit-level interventions to improve infection control. Advances in collection and linkage of real-time data could further support quality improvement efforts.


5-fluorouracil enhances exosome-dependent accumulation of polyadenylated rRNAs.
The antimetabolite 5-fluorouracil (5FU) is a widely used chemotherapeutic for the treatment of solid tumors. Although 5FU slows DNA synthesis by inhibiting the ability of thymidylate synthetase to produce dTMP, the drug also has significant effects on RNA metabolism. Recent genome-wide assays for 5FU-induced haploinsufficiency in Saccharomyces cerevisiae identified genes encoding components of the RNA processing exosome as potential targets of the drug. In this report, we used DNA microarrays to analyze the effect of 5FU on the yeast transcriptome and found that the drug causes the accumulation of polyadenylated fragments of the 27S rRNA precursor and that defects in the nuclear exoribonuclease Rrp6p enhance this effect. The size distribution of these RNAs and their sensitivity to Rrp6p suggest that they are normally degraded by the nuclear exosome and a 5'-3' exoribonuclease. Consistent with this hypothesis, 5FU inhibits the growth of RRP6 mutants with defects in the degradation function of the enzyme and it interferes with the degradation of an rRNA precursor. The detection of poly(A)(+) pre-RNAs in strains defective in various steps in ribosome biogenesis suggests that the production of poly(A)(+) pre-rRNAs may be a general result of defects in rRNA processing. These findings suggest that 5FU inhibits an exosome-dependent surveillance pathway that degrades polyadenylated precursor rRNAs.


Industry 4.0 towards Forestry 4.0: Fire Detection Use Case.
Forestry 4.0 is inspired by the Industry 4.0 concept, which plays a vital role in the next industrial generation revolution. It is ushering in a new era for efficient and sustainable forest management. Environmental sustainability and climate change are related challenges to promote sustainable forest management of natural resources. Internet of Forest Things (IoFT) is an emerging technology that helps manage forest sustainability and protect forest from hazards via distributing smart devices for gathering data stream during monitoring and detecting fire. Stream processing is a well-known research area, and recently, it has gained a further significance due to the emergence of IoFT devices. Distributed stream processing platforms have emerged, e.g., Apache Flink, Storm, and Spark, etc. Querying windowing is the heart of any stream-processing platform which splits infinite data stream into chunks of finite data to execute a query. Dynamic query window-based processing can reduce the reporting time in case of missing and delayed events caused by data drift.In this paper, we present a novel dynamic mechanism to recommend the optimal window size and type based on the dynamic context of IoFT application. In particular, we designed a dynamic window selector for stream queries considering input stream data characteristics, application workload and resource constraints to recommend the optimal stream query window configuration. A research gap on the likelihood of adopting smart IoFT devices in environmental sustainability indicates a lack of empirical studies to pursue forest sustainability, i.e., sustainable forestry applications. So, we focus on forest fire management and detection as a use case of Forestry 4.0, one of the dynamic environmental management challenges, i.e., climate change, to deliver sustainable forestry goals. According to the dynamic window selector's experimental results, end-to-end latency time for the reported fire alerts has been reduced by dynamical adaptation of window size with IoFT stream rate changes.


Stigma experience of people with epilepsy in Mexico and views of health care providers.
Epilepsy is a neurological disorder with neurobiological, cognitive, psychological, and social consequences. Epilepsy stigma is a social determinant of ill health that affects the quality of life of people who suffer from epilepsy and that renders a poor social prognosis even worse than the clinical one. From a phenomenological approach, between January and July 2011, we explored the experience of epilepsy stigma through 25 in-depth qualitative interviews with 10 persons with temporal lobe epilepsy (PWE) (we avoided terms such as "epileptics" or "epileptic patients" because they can be labeling and stigmatizing), 10 carers (CEs) of PWE who attended the epilepsy clinic of the Institute of Neurology and Neurosurgery of Mexico, and 5 physicians specialized in epilepsy. The objective of the study was to identify the following: perceptions that could indicate any form of discrimination due to having epilepsy, reactions of people in front of a person having seizures, and social functioning of PWE since epilepsy onset, particularly their interpersonal relationships and participation in educational or working activities. Through the health providers' narratives, we explored the mainstream care practices, their perspectives on epilepsy, and their views about how the disease should be addressed. Thematic guidelines were elaborated for each type of participant. All information was processed with the use of the computer-assisted data analysis, Atlas.ti5. We made a codification of broad themes that corresponded to the main topics of the interview guidelines and then proceeded to finer categorization to elaborate the analytical categories. Epilepsy was attached to a powerful stereotype that includes notions of contamination, danger, sin, divine punishment, supernatural forces, and madness. Internalized, interpersonal, and institutional stigma prevents PWE from participating in school and employment and reduces their opportunities to establish peer and couple relationships. Mexican's overt impunity of structural discrimination towards PWE shows a lack of available legal resources that protect their human rights. The narrow biomedical concept that physicians have of epilepsy is consistent with the limited medical practices that are offered to treat epilepsy at the health services in Mexico. Comprehensive treatment and integrated services for epilepsy must incorporate psychosocial programs that include epilepsy stigma as a major component of the disease.


Anchorage of synthetic peptides onto liposomes via hydrazone and alpha-oxo hydrazone bonds. preliminary functional investigations.
Synthetic peptidoliposomes have been designed and prepared according to a chemoselective ligation. Two aldehyde-functionalized lipidic anchors were synthesized and incorporated into the lipidic bilayers of unilamellar liposomes during their preparation. Complementary hydrazino acetyl peptides were synthesized on the solid phase using N,N',N'-tri(tert-butyloxycarbonyl)-hydrazino acetic acid and further coupled to the aldehyde groups displayed at the surface of the vesicles. Coupling yields were measured by amino acid hydrolysis following total acid hydrolysis. The ligation methodology proved superior to the simple insertion of lipopeptides, which was performed for comparison in terms of yields, implementation, and reproducibility. To check whether the grafted-peptides were accessible and functional, cytoplasmic sequences of LAMP protein (lysosomal associated membrane protein), which is involved in intracellular membrane trafficking, have been selected. Using this model, we demonstrated in vitro the specific interaction of the synthetic LAMP-peptidoliposomes with the cytoplasmic adaptor protein AP-3, a result that contributes to the understanding of protein sorting in cells. Thus, these results clearly indicate the usefulness of such peptidoliposomes, easily prepared by hydrazone chemoselective ligation, as a tool for biological investigation.


Neurophobia: why, how much, consequences and solutions.
This article was migrated. The article was marked as recommended. The term neurophobia was defined by Jozefowicz as "a fear of the neural sciences and clinical neurology that is due to the students' inability to apply their knowledge of basic sciences to clinical situations, leading to a paralysis of thought or action". In this paper we review what we see as the key aspects of neurophobia. What gives rise to it? Notable among multiple causes are how basic and clinical neurosciences are taught, the peculiarities of neurological patient history, examination and differential diagnosis in the field, and how neurology and neurologists are seen from outside the field. We will also review the extent of the issue, for in view of its prevalence, many students will reject a specialty in increasing demand (as the incidence of neurological disorders will not cease to grow), along with its consequences: more patient referrals to neurology (owing to neurophobia or defensive medicine), or over-prescription of ancillary tests for diagnosis. Finally we will look at the solutions proposed, especially those aiming to bring about changes in the form and content of teaching, how the teaching of neurological examination and of new technologies is to be approached, and the use of those technologies as teaching aids.


Genistein activates apolipoprotein A-I gene expression in the human hepatoma cell line Hep G2.
Soy phytoestrogens have been shown to increase plasma levels of HDL cholesterol and apolipoprotein (apo) A-I, its major protein component, in animal studies and in some human studies. The human hepatoma cell line Hep G2 was used to study the effect of the phytoestrogens genistein and daidzein on apo A-I secretion and gene expression in liver cells. Both genistein and daidzein increased apo A-I secretion in a dose-dependent fashion. Apo A-I concentration in the media of treated cells was increased approximately fivefold by 10 micromol/L genistein (P: < 0.001) and approximately onefold by 10 micromol/L daidzein (P: < 0.001) compared with control cells. The effect of genistein on apo A-I secretion was similar to that observed with 17-beta-estradiol. Treatment of cells with genistein for 24 h increased the transcriptional activity of the apo A-I gene as measured by nuclear run-on assay. Transfection experiments with plasmids containing regulatory regions of the apo A-I gene cloned in front of the luciferase reporter gene indicated that the 5' region of the apo A-I gene contained between nucleotides -256 and -41 is responsible for the increased expression of this gene by genistein.


Risk estimates of dengue in travelers to dengue endemic areas using mathematical models.
Dengue has emerged as a frequent problem in international travelers. The risk depends on destination, duration, and season of travel. However, data to quantify the true risk for travelers to acquire dengue are lacking. We used mathematical models to estimate the risk of nonimmune persons to acquire dengue when traveling to Singapore. From the force of infection, we calculated the risk of dengue dependent on duration of stay and season of arrival. Our data highlight that the risk for nonimmune travelers to acquire dengue in Singapore is substantial but varies greatly with seasons and epidemic cycles. For instance, for a traveler who stays in Singapore for 1 week during the high dengue season in 2005, the risk of acquiring dengue was 0.17%, but it was only 0.00423% during the low season in a nonepidemic year such as 2002. Risk estimates based on mathematical modeling will help the travel medicine provider give better evidence-based advice for travelers to dengue endemic countries.


Median Nerve and Carpal Tunnel Morphology Before and After Endoscopic Carpal Tunnel Release: A 6-Year Follow-up Study.
Our purpose was to describe structural and morphological features of the median nerve and carpal tunnel on magnetic resonance imaging (MRI) studies obtained before, immediately after, 6 weeks after, and 6 years after endoscopic carpal tunnel release (ECTR). In this prospective cohort study, 9 patients with a diagnosis of carpal tunnel syndrome (CTS) underwent ECTR. Standardized MRI studies were obtained before ECTR, immediately after ECTR, and 6 weeks and 6 years after surgery. Structural and morphological features of the median nerve and carpal tunnel were measured and assessed for each study with comparisons made between each time point. All 9 patients had complete symptom resolution postoperatively. On the immediate postoperative MRI, there was a discrete gap in the transverse carpal ligament in all patients. There was retinacular regrowth noted at 6 weeks in all cases. The median nerve cross-sectional area and the anterior-posterior dimension of the carpal tunnel at the level of the hamate increased immediately after surgery and these changes were maintained at 6 years. We defined structural and morphological changes on MRI for the median nerve and carpal tunnel in patients with continued symptom resolution 6 years after ECTR. Changes in median nerve and carpal tunnel morphology that occur immediately after surgery remain unchanged at mid-term follow-up in asymptomatic patients. Established imaging criteria for CTS may not apply to postoperative patients. Magnetic resonance imaging appears to be of limited clinical utility in the workup of persistent or recurrent CTS.


Can prior exposure to stress enhance resilience to ocean warming in two oyster species?
Securing economically and ecologically significant molluscs, as our oceans warm due to climate change, is a global priority. South eastern Australia receives warm water in a strengthening East Australia Current and so resident species are vulnerable to elevated temperature and marine heat waves. This study tested whether prior exposure to elevated temperature can enhance resilience of oysters to ocean warming. Two Australian species, the flat oyster, Ostrea angasi, and the Sydney rock oyster, Saccostrea glomerata, were obtained as adults and "heat shocked" by exposure to a dose of warm water in the laboratory. Oysters were then transferred to elevated seawater temperature conditions where the thermal outfall from power generation was used as a proxy to investigate the impacts of ocean warming. Shell growth, condition index, lipid content and survival of flat oysters and condition of Sydney rock oysters were all significantly reduced by elevated seawater temperature in the field. Flat oysters grew faster than Sydney rock oysters at ambient temperature, but their growth and survival was more sensitive to elevated temperature. "Stress inoculation" by heat shock did little to ameliorate the negative effects of increased temperature, although the survival of heat-shocked flat oysters was greater than non-heat shocked oysters. Further investigations are required to determine if early exposure to heat stress can enhance resilience of oysters to ocean warming.


Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa.
Junctional epidermolysis bullosa (JEB), a group of hereditary skin fragility disorders, is associated with a wide variety of phenotypes, although all forms are characterised by trauma induced skin blistering and tissue separation at the dermal-epidermal junction zone. A subgroup, coined JEB-other, is associated with mutations in the COL17A1 gene encoding collagen XVII or, more rarely, with mutations in the laminin 332 genes LAMA3, LAMB3, or LAMC2. The objective of this study is comprehensive genotype-phenotype analysis in JEB-other patients with COL17A1 mutations and elucidation of disease mechanisms underlying different skin phenotypes. COL17A1 mutations and their clinical and cellular consequences were systematically analysed in 43 patients with JEB-other. Cell culture, RT-PCR, and protein biochemistry were applied to assess the effects of splice site mutations-that is, the nature and amounts of transcripts and polypeptides synthesised and their association with the phenotypic outcome. 34 distinct COL17A1 mutations were disclosed, 12 of them novel. mRNA and protein analyses demonstrated that patients with only about 12-14% of the physiological collagen XVII levels had mild cutaneous involvement and a long life span. In contrast to complete null phenotypes, presence of minor amounts of collagen XVII protein in JEB skin is associated with mild phenotypic manifestations. The data have significant implications for design of molecular therapies for JEB, since they suggest that already a low extent of collagen XVII restoration will improve skin stability and alleviate symptoms.


Regulation of Human Macrophage M1-M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1.
Macrophages (Mf) are a heterogeneous population of tissue-resident professional phagocytes and a major component of the leukocyte infiltrate at sites of inflammation, infection, and tumor growth. They can undergo diverse forms of activation in response to environmental factors, polarizing into specialized functional subsets. A common hallmark of the pathologic environment is represented by hypoxia. The impact of hypoxia on human Mf polarization has not been fully established. The objective of this study was to elucidate the effects of a hypoxic environment reflecting that occurring in vivo in diseased tissues on the ability of human Mf to polarize into classically activated (proinflammatory M1) and alternatively activated (anti-inflammatory M2) subsets. We present data showing that hypoxia hinders Mf polarization toward the M1 phenotype by decreasing the expression of T cell costimulatory molecules and chemokine homing receptors and the production of proinflammatory, Th1-priming cytokines typical of classical activation, while promoting their acquisition of phenotypic and secretory features of alternative activation. Furthermore, we identify the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig-like immunoregulatory receptor family, as a hypoxia-inducible gene in Mf and demonstrate that its engagement by an agonist Ab reverses the M2-polarizing effect of hypoxia imparting a M1-skewed phenotype to Mf. Finally, we provide evidence that Mf infiltrating the inflamed hypoxic joints of children affected by oligoarticular juvenile idiopatic arthritis express high surface levels of TREM-1 associated with predominant M1 polarization and suggest the potential of this molecule in driving M1 proinflammatory reprogramming in the hypoxic synovial environment.


Visualization and analysis of microarray and gene ontology data with treemaps.
The increasing complexity of genomic data presents several challenges for biologists. Limited computer monitor views of data complexity and the dynamic nature of data in the midst of discovery increase the challenge of integrating experimental results with information resources. The use of Gene Ontology enables researchers to summarize results of quantitative analyses in this framework, but the limitations of typical browser presentation restrict data access. Here we describe extensions to the treemap design to visualize and query genome data. Treemaps are a space-filling visualization technique for hierarchical structures that show attributes of leaf nodes by size and color-coding. Treemaps enable users to rapidly compare sizes of nodes and sub-trees, and we use Gene Ontology categories, levels of RNA, and other quantitative attributes of DNA microarray experiments as examples. Our implementation of treemaps, Treemap 4.0, allows user-defined filtering to focus on the data of greatest interest, and these queried files can be exported for secondary analyses. Links to model system web pages from Treemap 4.0 enable users access to details about specific genes without leaving the query platform. Treemaps allow users to view and query the data from an experiment on a single computer monitor screen. Treemap 4.0 can be used to visualize various genome data, and is particularly useful for revealing patterns and details within complex data sets.


The Differential Impact of a Response's Effectiveness and its Monetary Value on Response-Selection.
While known reinforcers of behavior are outcomes that are valuable to the organism, recent research has demonstrated that the mere occurrence of an own-response effect can also reinforce responding. In this paper we begin investigating whether these two types of reinforcement occur via the same mechanism. To this end, we modified two different tasks, previously established to capture the influence of a response's effectiveness on the speed of motor-responses (indexed here by participants' reaction times). Specifically, in six experiments we manipulated both a response's 'pure' effectiveness and its outcome value (e.g., substantial versus negligible monetary reward) and measured the influence of both on the speed of responding. The findings strongly suggest that post action selection, responding is influenced only by pure effectiveness, as assessed by the motor system; thus, at these stages responding is not sensitive to abstract representations of the value of a response (e.g., monetary value). We discuss the benefit of distinguishing between these two necessary aspects of adaptive behavior namely, fine-tuning of motor-control and striving for desired outcomes. Finally, we embed the findings in the recently proposed Control-based response selection (CBRS) framework and elaborate on its potential for understanding motor-learning processes in developing infants.


Psychological symptoms and marital satisfaction in spouses of Operation Iraqi Freedom veterans: relationships with spouses' perceptions of veterans' experiences and symptoms.
Much research has shown that spouses of combat veterans with posttraumatic stress disorder (PTSD) have higher rates of psychological and marital distress than do spouses of veterans without PTSD; however, very few studies have examined potential mechanisms of this increased vulnerability. The current study examined spouses of National Guard soldiers recently returned from deployments in Iraq. In addition to documenting elevated levels of psychological symptoms in these spouses, the authors found that spouses experienced greater symptom severity when they perceived high levels of symptoms in soldiers but the soldiers endorsed low levels of symptoms. Furthermore, spouses' marital satisfaction was negatively linked to soldiers' self-reported symptom severity only when spouses perceived that soldiers had experienced low levels of combat activity while deployed. When spouses perceived high levels of such activity, soldiers' self-reported symptoms had no relationship with spouses' marital satisfaction. These findings highlight the importance of interpersonal perceptions in intimate relationships and are consistent with the notion that uncontrollable attributions for a relative's mental health problems may provide a buffer against relationship distress. (PsycINFO Database Record (c) 2008 APA, all rights reserved).


Perioperative Outcomes for Laparotomy Compared to Robotic Surgical Staging of Endometrial Cancer in the Elderly: A Retrospective Cohort.
This study aimed to compare outcomes of endometrial cancer (EMCA) staging in elderly patients performed either robotically or via laparotomy. A retrospective, multi-institutional chart review was conducted of all robotic and laparotomy staging surgeries for EMCA between 2003 and 2009. Charts were reviewed for intraoperative and postoperative complications and morbidities. Seven hundred forty-six women were identified who had undergone EMCA staging either robotically or via laparotomy; 89 and 93 patients 70 years or older underwent staging for EMCA via robotic and laparotomy, respectively. Both groups had similar age and body mass index. Among elderly patients being staged robotically, a higher incidence of pelvic lymphadenectomy, and decreased blood loss, incidence of blood transfusion, and overall complications were seen compared to laparotomy. Postoperatively, elderly patients staged robotically had a shorter median hospital stay (1 vs 4 days, P < 0.001), with no increase in readmission or return to the operating theater. No vessel, bowel, or genitourinary injuries occurred. Vaginal cuff dehiscence after robotic surgery was not significantly different, but wound and fascial complications were significantly increased in patients undergoing laparotomy. Thromboembolism rates were similar between both groups. Elderly patients can safely undergo robotic EMCA staging with improved outcomes compared to laparotomy. The benefits of robotic staging include higher incidence of completion of lymphadenectomy, decreased hospital stay (without an increase in readmissions or reoperations), decreased transfusions, and decreased wound and fascial complications.


Studies of plant colonisation by closely related Bacillus amyloliquefaciens biocontrol agents using strain specific quantitative PCR assays.
Certain strains of Bacillus amyloliquefaciens can colonize plants and improve growth and stress management. In order to study these effects, bacterial growth dynamics on plants and in the rhizosphere are of interest calling for specific analytical tools. For that purpose, quantitative real-time PCR (qPCR) assays were developed in order to differentiate among three closely related B. amyloliquefaciens subsp. plantarum strains (UCMB5033, UCMB5036, UCMB5113) and to determine their levels with high accuracy. Oligonucleotide primers were designed for strain unique gene sequences and used for SYBR green based qPCR analysis. Standard curves covered a wide linear range (10(6)) of DNA amounts with the lowest detection level at 50 fg. Post-reaction melting curve analysis showed only a single product. Accurate threshold cycles were obtained, even in the presence of high excess of related Bacillus strains and total bacterial DNA from soil. Analysis of Bacillus colonisation after seed treatment of two oilseed rape cultivars (Oase and Ritz) grown on agar support showed a time dependent effect but that the bacteria mostly were found on root tissues and little on green tissues. The colonisation on plants grown in soil varied among the Bacillus strains where Oase seemed to house more bacteria than Ritz. Applied as a mixture, all three Bacillus strains co-existed on the roots of plants grown in soil. The qPCR assay in combination with other techniques will be a powerful tool to study plant interactions of these B. amyloliquefaciens biocontrol agents to further understand the requirements for successful interactions and improvement of plant properties.


Dengue virus NS4A cytoplasmic domain binding to liposomes is sensitive to membrane curvature.
Dengue virus (DENV) infection is a growing public health threat with more than one-third of the world's population at risk. Non-structural protein 4A (NS4A), one of the least characterized viral proteins, is a highly hydrophobic transmembrane protein thought to induce the membrane alterations that harbor the viral replication complex. The NS4A N-terminal (amino acids 1-48), has been proposed to contain an amphipathic α-helix (AH). Mutations (L6E; M10E) designed to reduce the amphipathic character of the predicted AH, abolished viral replication and reduced NS4A oligomerization. Nuclear magnetic resonance (NMR) spectroscopy was used to characterize the N-terminal cytoplasmic region (amino acids 1-48) of both wild type and mutant NS4A in the presence of SDS micelles. Binding of the two N-terminal NS4A peptides to liposomes was studied as a function of membrane curvature and lipid composition. The NS4A N-terminal was found to contain two AHs separated by a non-helical linker. The above mentioned mutations did not significantly affect the helical secondary structure of this domain. However, they reduced the affinity of the N-terminal NS4A domain for lipid membranes. Binding of wild type NS4A(1-48) to liposomes is highly dependent on membrane curvature.


Differences in the prognosis among severe trauma and medical patients requiring mechanical ventilation.
Objetive. To find the differences between the prognosis of the patients with severe traumatism injury and those who were admitted with medical pathology who also required mechanical ventilation in our ICU. Patients and Method. Retrospective descriptive study in a polyvalent ICU of a third level hospital for a period of 8 years. Epidemiological variables such as age, sex, average stay, mortality, APACHE II at admission and days of mechanical ventilation, were analyzed in patients with severe traumatism injury and patients with medical pathology that were admitted in ICU and received mechanical ventilation during this period. Results. During the study period were admitted 208 patients with severe traumatism injury and 732 medical patients, all of them required mechanical ventilation. Patients with severe traumatism injury are more younger (41.8 vs 55.3 years, p = 0.001) and entered ICU in a state of minor severity, according to the prognostic index APACHE II (14.8 vs 17.4, p < 0.001), despite which they required more days of mechanical ventilation (9.8 vs 7.8 days, p = 0.017) and had a higher average stay (11.4 vs 9.4 days, p = 0.027), although the mortality was significantly lower (38.2% vs 28.2%, p = 0.005). Multivariate analysis showed as independent variables associated with mortality, the APACHE II (p < 0.0001), the average stay in ICU (p < 0.0001), days of mechanical ventilation (p < 0.0001) and type patient (p = 0.016). Conclusions. Patients with severe traumatic injury that require mechanical ventilation despite to be admitted in ICU in a state of greater severity, having an increased ICU stay and more days of mechanical ventilation, have a better prognosis than medical patients that required also mechanical ventilation at ICU stay, likely to be younger.


mHealth Intervention for Motor Skills: A Randomized Controlled Trial.
Children's motor skills are a critical foundation for physical activity. The objective was to determine the effectiveness and feasibility of a mobile app-based intervention delivered to parents to improve preschoolers' motor skills. This randomized controlled trial randomly assigned children to : (1) Motor Skills, including instructional lessons, peer modeling videos, behavioral scaffolding, and structured activities or 2) Free Play. Both groups received a 12-week app-based intervention informed by social cognitive theory to deliver 12 hours (12-minutes per day, 5× per week) of instruction. The children were aged 3 to 5 y; parents and children had no mobility impairments. The primary outcome variables were children's motor skills percentile score assessed with the Test of Gross Motor Development, third edition (TGMD-3) at baseline, end-of-intervention (week 12), and follow-up (week 24); and feasibility and acceptability. Seventy-two children (4.0 ± 0.8 y) participated. Between baseline and week 12, children in the Motor Skills condition significantly improved total TGMD-3 percentile (+13.7 Motor Skills vs -5.3 Free Play, P < .01), locomotor skills percentile (+15.5 Motor Skills vs -4.8 Free Play, P < .01), and ball skills percentile (+8.3 Motor Skills vs -7.3 Free Play, P < .01) compared with children in the comparator group. Significant differences were sustained at follow-up (week 24). Adherence did not significantly differ between conditions (71% for Motor Skills; 87% for Free Play). Parents in both arms reported high scores on satisfaction, helpfulness, and ease of use. Clinicians and educators may encourage parents to enhance their child's motor skills through structured at-home programs.


Solid acid proton conductors: from laboratory curiosities to fuel cell electrolytes.
The compound CsH2PO4 has emerged as a viable electrolyte for intermediate temperature (200-300 degrees C) fuel cells. In order to settle the question of the high temperature behavior of this material, conductivity measurements were performed by two-point AC impedance spectroscopy under humidified conditions (p[H2O] = 0.4 atm). A transition to a stable, high conductivity phase was observed at 230 degrees C, with the conductivity rising to a value of 2.2 x 10(-2) S cm(-1) at 240 degrees C and the activation energy of proton transport dropping to 0.42 eV. In the absence of active humidification, dehydration of CsH2PO4 does indeed occur, but, in contradiction to some suggestions in the literature, the dehydration process is not responsible for the high conductivity at this temperature. Electrochemical characterization by galvanostatic current interrupt (GCI) methods and three-point AC impedance spectroscopy (under uniform, humidified gases) of CsH2PO4 based fuel cells, in which a composite mixture of the electrolyte, Pt supported on carbon, Pt black and carbon black served as the electrodes, showed that the overpotential for hydrogen electrooxidation was virtually immeasurable. The overpotential for oxygen electroreduction, however, was found to be on the order of 100 mV at 100 mA cm(-2). Thus, for fuel cells in which the supported electrolyte membrane was only 25 microm in thickness and in which a peak power density of 415 mW cm(-2) was achieved, the majority of the overpotential was found to be due to the slow rate of oxygen electrocatalysis. While the much faster kinetics at the anode over those at the cathode are not surprising, the result indicates that enhancing power output beyond the present levels will require improving cathode properties rather than further lowering the electrolyte thickness. In addition to the characterization of the transport and electrochemical properties of CsH2PO4, a discussion of the entropy of the superprotonic transition and the implications for proton transport is presented.


[Diarrhea and fever after vacation in the south. Specific to tropics only in every 5th patient].
Post-travel medicine is mainly European medicine: Some 80% of the diseases are ubiquitous in nature, and only 20% tropics-specific. The leading symptoms are diarrhoea (68%), fever (20%) and skin conditions (9%), sometimes in combination. The travel history is of decisive importance for the diagnosis. Quite simple questions aimed at identifying the start of the illness, symptoms, destination, travel class and vaccinations can be useful for differentiation purposes. For the acute diagnosis, such aids as urine stick test, centrifuge, microscope, a range of stains, and a stool test for occult blood suffice. The most common serious travel-specific diseases include malaria, falciparum > tertian, dengue fever, hepatitis, and rickettsiosis. When falciparum malaria is suspected ("flu without a runny nose", and a visit to a tropical country), the patients must be hospitalized. Emergency diagnosis is done with a blood smear, "thick drop", and rapid malaria test.


Translational models for vascular cognitive impairment: a review including larger species.
Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required.


Systemic hypertension as a risk factor for open-angle glaucoma: a meta-analysis of population-based studies.
Systemic hypertension is thought to increase the risk for developing open-angle glaucoma (OAG) through several mechanisms. However, previous epidemiological studies have shown conflicting results regarding this potential association. We systematically evaluated this issue by conducting a meta-analysis of population-based studies. A comprehensive search for articles published before 31 March 2014 was performed using PubMed, Embase, and reference lists. The pooled odds ratio (OR) was calculated using the fixed- and random-effects models, and meta-regression was performed according to age. Subgroup analyses were also conducted, and publication bias was assessed using a funnel plot and Egger's regression test. This meta-analysis included 16 studies involving 60,084 individuals, with substantial homogeneity among the studies. The pooled OR for OAG was 1.22 (95% confidence interval, CI: 1.09-1.36) using the fixed-effects model and 1.22 (95% CI: 1.08-1.37) using the random-effects model in all included studies. For subgroup analyses, the pooled OR for high-tension glaucoma (HTG) was higher than that for normal-tension glaucoma (NTG) (OR=1.92 and 0.94, respectively). No significant difference was detected between Asian and Western populations, and no publication bias was detected in either analysis. Systemic hypertension increases the risk for developing OAG, especially in those with HTG.


Role of endocytosis in cellular uptake of sex steroids.
Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.


[Differences and similarities between the competencies of a nursing supervisor and an advanced clinical nurse specialist].
With the aim of contributing to the development of a more specific professional regulation, the present study was to identify differences and similarities between the competencies of the nursing supervisor and clinical nurse specialist in an intensive care unit. A critical analysis of the literature published between 2003 and 2013 was conducted, identified through systematic searches in electronic databases, health management and practitioner journals and reference lists of the 17 items included. «Management and administration» and «direct clinical practice» were identified as specific competencies of nursing supervisor and clinical nurse specialist respectively. «Collaboration», «leadership» and «research» emerged as competencies shared by both profiles, but with different a operationalization way of conducting it. These findings imply that regulation, education and implementation of these profiles must address their specific skills as the distinctive approach taken in operationalizing shared.


Emerging Challenges and Threats for Dental Health Care Sector Attributable to COVID-19: Tale of a Developing Country.
Prevention and control of infection in dentistry is an essential matter that has gained immense attention in recent years. There exist a lack of scientific data about the cross-transmission and its associated risk, especially in the dental health care setting of Pakistan. This article will evaluate the emerging challenges and threats for the dental community in Pakistan attributable to the COVID-19 outbreak. There is a significant knowledge gap regarding the state- and institutional-level of infection prevention and control (IPC) policies and practices. In addition, not much is known about the development, implementation, and monitoring of IPC policies and its challenges.


Increased activity of platelet-activating factor acetylhydrolase in low-density lipoprotein subfractions induces enhanced lysophosphatidylcholine production during oxidation in patients with heterozygous familial hypercholesterolaemia.
Patients with heterozygous familial hypercholesterolaemia (FH) have elevated plasma concentrations of low-density lipoprotein (LDL) and develop premature atherosclerosis. There is increasing evidence that oxidative modification of LDL is important for the pathogenesis of atherosclerosis, and the LDL-associated platelet-activating factor acetylhydrolase (PAF-AH) seems to play a key role in LDL oxidation by hydrolysing the oxidized phospholipids of phosphatidylcholine (PC) and producing lysophosphatidylcholine (lyso-PC). We measured the total serum and high-density lipoprotein (HDL) levels of PAF-AH activity and studied the distribution of PAF-AH activity among three LDL subfractions isolated by gradient ultracentrifugation in 15 patients with heterozygous FH and 13 normolipidaemic control subjects. We also determined the lyso-PC production in each LDL subfraction during Cu2(+)-induced oxidation in vitro. The total serum PAF-AH activity in heterozygous FH patients was significantly higher than in control subjects, whereas the HDL-associated PAF-AH activity, expressed as a percentage of total serum PAF-AH activity, was significantly lower in the FH patients than in control subjects (13.9 +/- 6.6% vs. 30.6 +/- 4.4%, P < 0.001). Among the LDL subfractions, the PAF-AH activity in both normolipidaemic control subjects and FH patients, expressed as nmol mg-1 protein min-1, was significantly higher in the LDL3 subfraction (33.1 +/- 4.8 and 53.4 +/- 11.5 respectively) than in the LDL2 (18.6 +/- 5.3 and 26.8 +/- 10.4 respectively, P < 0.0001 for both comparisons) and LDL1 subfractions (5.1 +/- 1.5 and 7.8 +/- 2.6, respectively, P < 0.0001 for both comparisons). Additionally, the enzyme activity in each LDL subfraction of the heterozygous FH patients was significantly higher than in control subjects (P < 0.02 for LDL1, P < 0.03 for LDL2 and P < 0.0001 for LDL3). No difference was observed in the susceptibility to oxidation of each LDL subfraction among the heterozygous FH patients and the normolipidaemic control subjects. During oxidation, the PAF-AH activity decreased, whereas the lyso-PC levels significantly increased in all subfractions of both groups. The lyso-PC/sphingomyelin molar ratio in each LDL subfraction of the FH patients 3 h after the onset of the oxidation was significantly higher than in control subjects [0.38 +/- 0.05 and 0.27 +/- 0.04, respectively, for LDL1 (P < 0.006), 0.47 +/- 0.08 and 0.39 +/- 0.03, respectively, for LDL2 (P < 0.04), 0.55 +/- 0.11 and 0.42 +/- 0.06, respectively, for LDL3 (P < 0.02)]. Our results show that heterozygous FH patients exhibit higher PAF-AH activity than control subjects in all LDL subfractions, resulting in higher lyso-PC production during oxidation, which confers on these subfractions higher biological potency. This phenomenon, in combination with the diminished anti-atherogenic and antioxidant capability of HDL in these patients due to the relatively low HDL-cholesterol levels compared with LDL-cholesterol levels and, consequently, the relatively low HDL-associated PAF-AH activity, could contribute to the higher atherogenicity and incidence of coronary artery disease observed in FH patients.


Deep clustering of protein folding simulations.
We examine the problem of clustering biomolecular simulations using deep learning techniques. Since biomolecular simulation datasets are inherently high dimensional, it is often necessary to build low dimensional representations that can be used to extract quantitative insights into the atomistic mechanisms that underlie complex biological processes. We use a convolutional variational autoencoder (CVAE) to learn low dimensional, biophysically relevant latent features from long time-scale protein folding simulations in an unsupervised manner. We demonstrate our approach on three model protein folding systems, namely Fs-peptide (14 μs aggregate sampling), villin head piece (single trajectory of 125 μs) and β- β- α (BBA) protein (223 + 102 μs sampling across two independent trajectories). In these systems, we show that the CVAE latent features learned correspond to distinct conformational substates along the protein folding pathways. The CVAE model predicts, on average, nearly 89% of all contacts within the folding trajectories correctly, while being able to extract folded, unfolded and potentially misfolded states in an unsupervised manner. Further, the CVAE model can be used to learn latent features of protein folding that can be applied to other independent trajectories, making it particularly attractive for identifying intrinsic features that correspond to conformational substates that share similar structural features. Together, we show that the CVAE model can quantitatively describe complex biophysical processes such as protein folding.


Impaired binding of low density lipoprotein to hepatic membranes from uremic guinea pigs.
Chronic renal failure is associated with abnormalities in lipoprotein metabolism that may contribute to premature atherosclerosis and early mortality in patients on dialysis. In previous studies, we found that plasma clearance of radiolabelled low density lipoprotein (LDL) was retarded in nephrectomized guinea pigs left with one-sixth of normal functioning renal mass. To elucidate potential mechanisms of delayed LDL clearance, we compared binding of LDL to hepatic membranes from both normal and uremic guinea pigs. One hundred micrograms of the 8000-100,000 X g hepatic microsomal protein was incubated with 125I-labelled normal guinea pig LDL (10-150 micrograms/mL) for 1 h at 37 degrees C, and the membrane washed and pelleted by centrifugation in a Beckman Ti 42.2 rotor. Parallel incubations with excess unlabelled LDL were done to determine specific binding. LDL specific binding to uremic hepatic membranes was significantly impaired compared with normal ones. The major abnormality, as determined by Scatchard transformation of the binding data, was a reduction of the apparent maximal binding of LDL to uremic membranes, with an average Bmax of 4.1 micrograms/mg protein compared with 6.6 micrograms/mg protein for normal hepatic microsomes. The affinity of LDL for uremic liver membranes was only slightly diminished with a mean apparent Kd of 35.2 micrograms/mL in comparison with 21.8 micrograms/mL for normal liver membranes. These results provide a biochemical explanation for the diminished LDL clearance in uremia and may account for the dyslipidemia of renal failure.


Retinal vein occlusion: pathophysiology and treatment options.
This paper reviews the current thinking about retinal vein occlusion. It gives an overview of its pathophysiology and discusses the evidence behind the various established and emerging treatment paradigms.


De novo postallogeneic hematopoietic stem cell transplant membranous nephropathy.
We report membranous nephropathy in a 61-year-old man after allogeneic hematopoietic stem cell transplant without chronic graft-versus-host disease. A diagnosis of acute myeloid leukemia was made, and the patient received hematopoietic stem cell transplants, twice, from different donors. The first donor was his brother and the second donor was an unrelated man. Human leukocyte antigens between donors and recipient were fully matched. His clinical course was stable without acute or chronic graft-versus-host disease or relapse of acute myeloid leukemia with tacrolimus after the second hematopoietic stem cell transplant. Six months after the second hematopoietic stem cell transplant, tacrolimus was decreased gradually and discontinued because of tacrolimus-induced liver dysfunction. Three months after discontinuing the tacrolimus, the patient developed edema in his leg. The results of a blood analysis showed that plasma albumin level was 21 g/L and plasma total cholesterol level was 11.5 mmol/L, while results from a urinalysis showed proteinuria of 5.6 g/d without hematuria. No abnormalities in the skin, mucosal tissues, and other organs suggestive of chronic graft-versus-host disease were seen. A renal biopsy was done to investigate the cause, which revealed renal disease. Electron microscopic analysis showed dense deposits in the subepithelial region in all glomeruli. Immunofluorescence analysis showed the deposition of IgG4 and C3c in the subepithelial space of all glomeruli. Membranous nephropathy was diagnosed. He then was administered prednisolone at a dosage of 45 mg/d (0.7 mg/kg/d). After prednisolone treatment, urine protein and hypoalbuminemia were markedly improved, and his leg edema disappeared. These results suggest that this membranous nephropathy may have been de novo membranous nephropathy after hematopoietic stem cell transplant because it developed after hematopoietic stem cell transplants without chronic graft-versus-host disease.