Fibroblast growth factor 10 induces proliferation and differentiation of human primary cultured keratinocytes.
Fibroblast growth factor 10 is a novel member of the fibroblast growth factor family, which is involved in morphogenesis and epithelial proliferation. It is highly homologous to the keratinocyte growth factor (or fibroblast growth factor 7), a key mediator of keratinocyte growth and differentiation. Both fibroblast growth factor 10 and keratinocyte growth factor bind with high affinity to the tyrosine kinase keratinocyte growth factor receptor. Here we analyzed the effect of fibroblast growth factor 10 on primary cultures of human keratinocytes, grown in chemically defined medium, and we compared the proliferative and differentiative cell responses to fibroblast growth factor 10 with those induced by keratinocyte growth factor and epidermal growth factor. Cell counting, 5-bromo-2'-deoxyuridine incorporation, and western blot analysis showed that fibroblast growth factor 10, similarly to keratinocyte growth factor, not only is a potent mitogen for human keratinocytes, but also promotes the expression of both early differentiation markers K1 and K10 and late differentiation marker filaggrin in response to the Ca2+ signal, and seems to sustain the proliferative activity in suprabasal stratified cells. Immunoprecipitation/western blot analysis revealed that fibroblast growth factor 10, similarly to keratinocyte growth factor, is able to induce tyrosine phosphorylation of keratinocyte growth factor receptor and of cellular substrates such as PLCgamma.


A deletion mutant of Pseudomonas exotoxin-A fused to recombinant human interleukin-9 (rhIL-9-ETA') shows specific cytotoxicity against IL-9-receptor-expressing cell lines.
The receptor for human interleukin-9 (hIL-9) might be a target for selective immunotherapy. It is expressed on a variety of malignant cells, including Hodgkin's lymphoma, non-Hodgkin lymphoma and acute myeloid leukemia (AML). We therefore constructed a new chimeric toxin by fusing hIL-9-cDNA to modified Pseudomonas aeruginosa exotoxin A (ETA'). The binding properties of the new recombinant protein, rhIL-9-ETA', were assessed on different cell lines expressing the hIL-9 receptor. The antitumor potency of rhIL-9-ETA' was evaluated against the Hodgkin-derived cell lines L540Cy, KM-H2 and L1236, the Burkitt lymphoma cell line Daudi, the erythroleukemia cell line K562, and the mastocytoma cell line P815-hIL9R, transfected with hIL-9 receptor cDNA. Recombinant hIL-9-ETA' exhibited potent specific cytotoxic effects against P815-hIL9R, K562 and L1236 cells, inhibiting protein synthesis by 50% (IC50) at concentrations of 0.05, 0.58 and 3 micrograms/ml respectively. The cytotoxic effect was abrogated after addition of polyclonal antibodies against the human IL-9. rhIL-9-ETA' might be of potential use against hIL-9R-expressing malignancies.


Immigration and recommended care after a suicide attempt in Europe: equity or bias?
This report describes the investigation of care recommendations in the medical system across European countries to immigrants who attempted suicide. Data from seven European countries with 8865 local and 2921 immigrant person-cases were derived from the WHO/EURO Multicentre Study on Suicidal Behaviour and ensuing MONSUE (Monitoring Suicidal Behaviour in Europe) project. The relationship between immigrant status and type of aftercare recommended was analysed with binary logistic regression, adjusting for gender, age, method of attempt and the Centre collecting the data. Clear disparities were identified in the care recommendation practices toward immigrants, compared with hosts, over and above differing policies by the European Centres.


Urethral sphincter EMG-controlled dorsal penile/clitoral nerve stimulation to treat neurogenic detrusor overactivity.
The goal of this study was to investigate whether real-time external urethral sphincter (EUS) EMG-controlled dorsal genital nerve (DGN) stimulation can suppress undesired detrusor bladder contractions in patients with both neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia (DSD). Detrusor pressure (Pdet) and EUS EMG were recorded in 12 neurogenic patients who underwent two filling cystometries. The first one was without stimulation and was intended to confirm the NDO and DSD and to set the EMG detection threshold. The second one was with real-time EMG-controlled stimulation of DGNs. Two detection methods were analyzed to detect bladder contractions. The first method was a Kurtosis-scaled root mean square (RMS) detector and was used on-line. The second was a simple RMS detector and was used off-line. Of 12 patients included, 10 patients showed both NDO and DSD. In nine of these ten patients relevant EMG concomitant to detrusor activity was detected and stimulation could suppress at least one detrusor contraction. The second filling compared to the first one showed an increase of 84% in bladder capacity (p = 0.002) and a decrease of 106% in Pdet (p = 0.002). Nine false-positive detections occurred during the ten fillings with electrical stimulation. The mean increases of both time and Pdet between stimulation and bladder contraction onsets for method 1 were 1.8 s and 4 cmH(2)O and for method 2 were 0.9 s and 2 cmH(2)O, respectively. This study shows that EUS EMG can be used in real time to detect the onset of a bladder contraction. In combination with DGN stimulation has been shown to be feasible to suppress undesired bladder contractions and in turn to increase bladder capacity in subjects with both NDO and DSD.


Diuretic-resistant congestive heart failure treated successfully with peritoneal ultrafiltration.
We present a case of successful peritoneal ultrafiltration (pUF) treatment in a 60 year-old patient diagnosed with diuretic-resistant congestive heart failure fulfilling the criteria for type 2 cardio-renal syndrome. Six months of pUF treatment with one daily dialysis exchange with icodextrin as an osmotic agent resulted in better functional status (from IV to II/III NYHA class), quality of life and improvement of haemodynamic parameters measured by impedance cardiography. During the follow-up (six months), pUF was well tolerated by the patient and he did not require hospitalisation for decompensated heart failure.


Pesticides Curbing Soil Fertility: Effect of Complexation of Free Metal Ions.
Researchers have suggested that the reason behind infertility is pernicious effect of broad spectrum pesticides on non target, beneficial microorganism of soil. Here, studying the chelating effect of selective organophosphate and carbamate pesticides with essential metal ions, at all possible combinations of three different pH (4 ± 0.05, 7 ± 0.05 and 9 ± 0.05) and three different temperatures (15 ± 0.5°C, 30 ± 0.5°C and 45 ± 0.5°C), shows very fast rate of reaction which further increases with increase of pH and temperature. Carbonyl oxygen of carbamate and phosphate oxygen of organophosphate were found to be common ligating sites among all the complexes. Formed metal complexes were found to be highly stable and water insoluble on interaction with essential metal ions in solvent medium as well as over silica. Density functional theory (DFT) calculations not only reinforced the experimental observations, but, after a wide computational conformational analysis, unraveled the nature of the high stable undesired species that consist of pesticides complexed by metal ions from the soil. All in all, apart from the direct toxicity of pesticides, the indirect effect by means of complexation of free metal ions impoverishes the soil.


Naturalistic Developmental Behavioral Interventions: Empirically Validated Treatments for Autism Spectrum Disorder.
Earlier autism diagnosis, the importance of early intervention, and development of specific interventions for young children have contributed to the emergence of similar, empirically supported, autism interventions that represent the merging of applied behavioral and developmental sciences. "Naturalistic Developmental Behavioral Interventions (NDBI)" are implemented in natural settings, involve shared control between child and therapist, utilize natural contingencies, and use a variety of behavioral strategies to teach developmentally appropriate and prerequisite skills. We describe the development of NDBIs, their theoretical bases, empirical support, requisite characteristics, common features, and suggest future research needs. We wish to bring parsimony to a field that includes interventions with different names but common features thus improving understanding and choice-making among families, service providers and referring agencies.


Milk versus medicine for the treatment of iron deficiency anaemia in hospitalised infants.
To compare iron fortified follow-on milk (iron follow-on), iron fortified partially modified cows' milk (iron milk), and iron medicine for the treatment of iron deficiency anaemia (IDA) in hospitalised infants. In a randomised controlled trial, infants aged 9-23 months with IDA and who were hospitalised with an acute illness received iron follow-on (12 mg/l ferrous iron), iron milk (12.9 mg/l ferrous iron), or iron medicine (ferrous gluconate at 3 mg/kg of elemental iron once daily). All interventions were given for three months. Changes in measures of iron status three months after hospital discharge were determined. A total of 234 infants were randomised. Iron status was measured at follow up in 59 (70%) iron medicine, 49 (66%) iron follow-on, and 54 (70%) iron milk treated infants. There was a significant (mean, 95% CI) increase in haemoglobin (15 g/l, 13 to 16) and iron saturation (9%, 8 to 10) and decrease in ferritin (-53 microg/l, -74 to -31) in all three groups. Mean cell volume increased in iron follow-on (2 fl, 1 to 3) and iron milk (1 fl, 0.1 to 3) treated infants, but not in the iron medicine group (1 fl, -1 to 2). The proportion with IDA decreased in all three groups: iron medicine 93% to 7%, iron follow-on 83% to 8%, and iron milk 96% to 30%. Adverse effects, primarily gastrointestinal, occurred in 23% of the iron medicine, 14% of the iron follow-on, and 13% of the iron milk group. Iron fortified follow-on milk, iron fortified partially modified cows' milk, and iron medicine all effectively treat IDA in infancy.


Diagnosing between papillary carcinoma and reactive papillary changes in an infarcted thyroid nodule after fine needle aspiration and accompanied by a synchronous brain stem astrocytoma.
A 22-year-old patient underwent fine needle aspiration of a nodule at the outer center of the right lobe of the thyroid, and it was reported to be Bethesda system category IV, Hurthle cell follicular neoplasia. The patient, who persented to Onsekiz Mart University Research and Application Hospital, underwent surgery. During right total thyroidectomy, an almost totally infarcted nodule and papillary structures around these infarcted areas were detected. Herein, we report on diagnostic challenges faced in confirming whether the infarcted nodule was a case of reactive papillary changes or an underdiagnosed papillary carcinoma and how the challenges were overcome using immunohistochemistry analysis and molecular genetic testing. In addition, we examined the case along with a literature review because an accompanying synchronous brain stem astrocytoma was detected in the patient after thyroidectomy.


[In Process Citation].
Membranous nephropathy is one of the most common glomerular diseases and leading causes of nephrotic syndrome in Caucasian adults. Known as a clinico-pathologic entity for over 50 years, it is defined by thickening of the glomerular capillary membrane with subepithelial immuncomplexes. Secondary forms (e. g. hepatitis B, autoimmune disease or medication-induced) are distinguished from idiopathic forms. Despite spontaneous remissions in about 30 % of cases, one third of idiopathic forms progress to end-stage renal disease after 10 years. Seminal research progress of the last decade has allowed the identification of autoantibodies directed against podocytary elements leading to secondary damage to the filtration barrier. The so-called idiopathic membranous nephropathy has thus become a prototype of autoimmune disease. The autoantibodies detectable in 70 - 80 % of cases of idiopathic membranous nephropathy are directed against the M-type phospholipase A2-receptor on the podocyte membrane and correlate with disease activity. These epochal findings influence on diagnostic and therapeutic strategies establishing a rationale for the use of B cell-directed therapy on top of optimal supportive therapy.


Meta-analysis of the impact of stocking rate on the productivity of pasture-based milk production systems.
The objective of this study is to quantify the milk production response per cow and per hectare (ha) for an incremental stocking rate (SR) change, based on a meta-analysis of published research papers. Suitable experiments for inclusion in the database required a comparison of at least two SRs under the same experimental conditions in addition to details on experimental length and milk production results per cow and per ha. Each additional increased SR treatment was also described in terms of the relative milk production change per cow and per ha compared to the lower base SR (b_SR). A database containing 109 experiments of various lengths with 131 comparisons of SR was sub-divided into Type I experiments (common experimental lengths) and Type II experiments (variable experimental lengths). Actual and proportional changes in milk production according to SR change were analysed using linear mixed model procedures with study included as a random effect in the model. Low residual standard errors indicated a good precision of the predictive equations with the exception of proportional change in milk production per cow. For all milk yield variables analysed, the results illustrate that while production per cow is reduced, a strong positive relationship exists between SR and milk production per ha. An SR increase of one cow/ha resulted in a decrease in daily milk yield per cow of 7.4% and 8.7% for Type I and Type II data, respectively, whereas milk yield per ha increased by 20.1% and 19.6%, respectively. Within the Type II data set, a one cow/ha increase in SR also resulted in a 15.1% reduction in lactation length (equivalent to 42 days). The low predictability of proportional change in milk production per cow according to the classical SR definition of cows per ha over a defined period suggests that SR may be more appropriately defined in terms of the change in available feed offered per animal within each treatment.


Digestive manifestations in COVID-19: Prevalence and prognostic impact.
Since its declaration in december 2019, a novel coronavirus, the SARS-CoV-2 was rapidly responsible for a major pandemic. COVID-19 is mainly manifested by respiratory symptoms,however, digestive manifestations have been reported, raising the hypothesis of the viral digestive tropism. Specify the digestive manifestations due to the SARS-CoV-2, and their impact on the disease prognosis and describe the COVID-19 effect in patients with underlying digestive disease. Ageneral review of the medical literature was conducted via Medline® database, through various combinations of the following keywords :SARS-CoV-2, COVID-19, gastrointestinal tract, digestive system, inflammatory bowel diseases, liver, liver injury, chronic liver disease, neoplasms. The most relevant articles were selected. The SARS-CoV-2 tropism for the digestive tract has been confirmed by the identification of the enterocyte as a target cell of the virus. Viral particles and RNA detection in stool of infected patients has raised the potential for feco-oral transmission of the virus. Gastrointestinal manifestations were frequent and may even be revealing or isolated. Diarrhea was the most characteristic symptom. Frequent liver involvement is associated with a more severe form of the disease. Patients with digestive cancer and chronic liver disease are at risk for a severe form of SARS-CoV-2 infection. The clinician is required to know this type of manifestations in order to limit the delay in diagnosis and to better assess the prognosis.


Complementary feeding patterns in a developing country: a cross-sectional study across Lebanon.
This first, large-scale study on complementary feeding in Lebanon analysed the timing and types of food introduced to infants according to mothers' demographic and socioeconomic and infants' characteristics. A cross-sectional survey over 10 months found that the majority of infants were introduced to solid foods at or after 4 months of age. A large number of infants were given liquids other than breast or formula milk earlier. Women in employment outside the home were almost twice as likely to introduce solid foods before age 4 months. The most common starting food was cereals. More than half the children consumed starchy foods and fruits every day, but not meats and fish.


[Surgical repair of atrial septal defect in 1011 consecutive patients].
The immediate postoperative complications of 1011 consecutive patients undergoing surgical repair of atrial septal defects between 1980 and 1998 at Marie Lannelongue Hospital were analysedwith the ultimate objective of comparing their incidence with that of percutaneous closure. Five patients died (0.49%) of low cardiac output (N=3), pulmonary oedema (N=1) or pulmonary hypertension (N=1). A total of 356 patients (35.2%) had 448 postoperative complications. There were 77% minor and 23% major complications. The minor complications included arrhythmias and conduction defects (N=130), respiratory complications (N=90) and pericardial effusions (N=64). The main major complications were cardiac failure (N=27), cardiac tamponade (N=13), neurological complications (N=8) and reoperation (N=28). Of the survivors, 95.6% of patients were discharged from hospital with no residual problem and 41 (4.4%) had sequellae: arrhythmias (N=29, including one pacemaker implantation), neurological complications (N=4), acquired mitral regurgitation (N=2), phrenic nerve paralysis (N=1) and minimal residual shunt (N=10). Factors correlated with surgical morbidity were age, the severity of pulmonary hypertension, the type of atrial septal defect (less morbidity with ostium secundum defects), the presence of associated malformations, the surgical approach (less morbidity with the right postero-lateral thoracic approach). This study demonstrated the incompressible risk of open heart cardiac surgery. It will form a basis for a comparative study of the two modern methods of treating atrial septal defect: surgical and percutaneous closure.


Regulatory Problems in Very Preterm and Full-Term Infants Over the First 18 Months.
This study is an investigation of differences in regulatory problems (RPs; crying, sleeping, feeding) expressed by infants born very preterm (VP; <32 wk gestation) or with very low birth weight (VLBW; <1500 g) and infants born at full term (FT) during the first 18 months of life. It investigates the prevalence of single and multiple RPs, their persistence and how early in infancy RPs still found at 18 months of age can be predicted. This prospective longitudinal study of 73 VP/VLBW and 105 FT infants utilized a standard interview of mothers to assess regulatory problems among the infants at term, 3, 6, and 18 months of age. Few differences were found between VP/VLBW and FT infants in the first 6 months. At 18 months, VP/VLBW infants had more single sleeping (RR = 2.2, CI = 1.3-3.7), feeding (RR = 1.4, CI = 1.03-1.8), and multiple RPs (RR = 1.7, CI = 1.02-2.8) than FT infants. In VP/VLBW infants, RPs as early as 3 months and in FT infants RPs as early as 6 months predicted RPs at 18 months. Those infants who had persistent RPs in the first 6 months of life were more likely to still have RPs at 18 months. VP/VLBW children are at slightly increased risk for RPs at term and in the second year of life. Clinicians should be aware that RPs that persist across the first 6 months point to increased risk of continuing RPs into toddlerhood in both VP/VLBW and FT infants.


Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part I: Cattle and swine.
Physiologically based pharmacokinetic (PBPK) models for chemicals in food animals are a useful tool in estimating chemical tissue residues and withdrawal intervals. Physiological parameters such as organ weights and blood flows are an important component of a PBPK model. The objective of this study was to compile PBPK-related physiological parameter data in food animals, including cattle and swine. Comprehensive literature searches were performed in PubMed, Google Scholar, ScienceDirect, and ProQuest. Relevant literature was reviewed and tables of relevant parameters such as relative organ weights (% of body weight) and relative blood flows (% of cardiac output) were compiled for different production classes of cattle and swine. The mean and standard deviation of each parameter were calculated to characterize their variability and uncertainty and to allow investigators to conduct population PBPK analysis via Monte Carlo simulations. Regression equations using weight or age were created for parameters having sufficient data. These compiled data provide a comprehensive physiological parameter database for developing PBPK models of chemicals in cattle and swine to support animal-derived food safety assessment. This work also provides a basis to compile data in other food animal species, including goats, sheep, chickens, and turkeys.


Predicting factors for outcome of tube thoracostomy in complicated parapneumonic effusion for empyema.
To determine the predicting factors for outcome of tube thoracostomy in patients with complicated parapneumonic effusion (CPE) or empyema. Retrospective chart review over a 55-month period at a tertiary referred medical center. The medical charts of patients with empyema or CPE were reviewed. Data including age, gender, clinical symptoms, important underlying diseases, leukocyte count, duration of preadmission symptoms, interval from first procedure to second procedure, the time from first procedure to discharge (recovery time), the amount of effusion drained, administration of intrapleural streptokinase, chest tube size and position, loculation of pleural effusion, and characteristics and culture results of pleural effusion were recorded and compared between groups of patients with successful and failed outcome of tube thoracostomy drainage. One hundred twenty-one patients were selected for study. One hundred of these patients had received tube thoracostomy drainage with 53 successful outcomes and 47 failed outcomes of chest tube drainage. Nineteen patients received decortication directly, and the other two received antibiotics alone. Univariate analysis showed that pleural effusion leukocyte count, effusion amount, and loculation of pleural effusion were significantly related to the outcome of chest tube drainage. Multiple logistic regression analysis demonstrated that loculation and pleural effusion leukocyte count < or = 6,400/uL were the only independent predicting factors related to failure of tube thoracostomy drainage. Loculation and pleural effusion leukocyte count < or = 6,400/microL were independent predicting factors of poor outcome of tube thoracostomy drainage. These results suggest that if the initial attempt at chest tube drainage fails, early surgical intervention should be considered in good surgical candidates with loculated empyema or pleural effusion with leukocyte count < or = 6,400/microL.


Synthetic access to calix[3]pyrroles via meso-expansion: hosts with diverse guest chemistry.
Calix[3]pyrroles were synthesized for the first time. These macrocycles display versatile guest binding ability based on the bridges connecting the two α-positions of the tripyrrane moiety e.g. with an ethene bridge they showed colorimetric sensing of fluoride and cyanide ions, whereas with a phenylene spacer they exhibited fluorometric sensing of fluoride ions only, and the macrocycle with an ethylene unit acted as a host towards the water molecule with unique penta-coordinated oxygen in the solid state.


Inflammatory health effects of indoor and outdoor particulate matter.
Inflammation is a common and essential event in the pathogenesis of diverse diseases. Decades of research has converged on an understanding that all combustion-derived particulate matter (PM) is inflammatory to some extent in the lungs and also systemically, substantially explaining a significant portion of the massive cardiopulmonary disease burden associated with these exposures. In general, this means that efforts to do the following can all be beneficial: reduce particulates at the source, decrease the inflammatory potential of PM output, and, where PM inhalation is unavoidable, administer anti-inflammatory treatment. A range of research, including basic illumination of inflammatory pathways, assessment of disease burden in large cohorts, tailored treatment trials, and epidemiologic, animal, and in vitro studies, is highlighted in this review. However, meaningful translation of this research to decrease the burden of disease and deliver a clear and cohesive message to guide daily clinical practice remains rudimentary. Ongoing efforts to better understand substantial differences in the concentration and type of PM to which the global community is exposed and then distill how that influences inflammation promises to have real-world benefit. This review addresses this complex topic in 3 sections, including ambient PM (typically associated with ground-level transportation), wildfire-induced PM, and PM from indoor biomass burning. Recognizing the overlap between these domains, we also describe differences and suggest future directions to better inform clinical practice and public health.


Membrane currents in canine bronchial artery and their regulation by excitatory agonists.
The bronchial vasculature plays an important role in airway physiology and pathophysiology. We investigated the ion currents in canine bronchial smooth muscle cells using patch-clamp techniques. Sustained outward K(+) current evoked by step depolarizations was significantly inhibited by tetraethylamonium (1 and 10 mM) or by charybdotoxin (10(-6) M) but was not significantly affected by 4-aminopyridine (1 or 5 mM), suggesting that it was primarily a Ca(2+)-activated K(+) current. Consistent with this, the K(+) current was markedly increased by raising external Ca(2+) to 4 mM but was decreased by nifedipine (10(-6) M) or by removing external Ca(2+). When K(+) currents were blocked (by Cs(+) in the pipette), step depolarizations evoked transient inward currents with characteristics of L-type Ca(2+) current as follows: 1) activation that was voltage dependent (threshold and maximal at -50 and -10 mV, respectively); 2) inactivation that was time dependent and voltage dependent (voltage causing 50% maximal inactivation of -26 +/- 22 mV); and 3) blockade by nifedipine (10(-6) M). The thromboxane mimetic U-46619 (10(-6) M) caused a marked augmentation of outward K(+) current (as did 10 mM caffeine) lasting only 10-20 s; this was followed by significant suppression of the K(+) current lasting several minutes. Phenylephrine (10(-4) M) also suppressed the K(+) current to a similar degree but did not cause the initial transient augmentation. None of these three agonists elicited inward current of any kind. We conclude that bronchial arterial smooth muscle expresses Ca(2+)-dependent K(+) channels and voltage-dependent Ca(2+) channels and that its excitation does not involve activation of Cl(-) channels.


Estimating Survival After Salvage Surgery for Recurrent Oral Cavity Cancer.
Locoregional recurrence of oral cavity squamous cell carcinoma (OCSCC) continues to be a life-threatening and difficult clinical situation. Salvage surgery can result in significant morbidities, and survival following recurrence is poor. To outline prognostic factors influencing overall survival (OS) following salvage surgery for OCSCC to guide management of treatment for patients with locoregionally recurrent disease. The medical records of 293 patients presenting to the London Health Sciences Center with locoregionally recurrent OCSCC between October 5, 1999, and May 2, 2011, were retrospectively reviewed. The primary outcome was OS from salvage treatment to last follow-up or death. Univariate analyses were carried out using the Cox proportional hazards regression model. A recursive partitioning analysis was used to create risk groups based on prognosis. Analysis was conducted from December 8, 2015, to February 26, 2016. Of the 293 patients evaluated, 59 (20%) had recurrence identified after their initial OCSCC treatment; 39 (66%) were men, and the mean (SD) age at diagnosis was 62.2 (11.8) years. Thirty-nine (66%) of these patients underwent salvage surgery for locoregional recurrence with curative intent. Five-year OS from the time of salvage surgery was 43%. Recursive partitioning analysis identified 3 risk groups: (1) high risk (patients who received adjuvant chemoradiotherapy or radiotherapy after initial surgery) with 5-year OS rate of 10% (hazard ratio [HR], 9.41; 95% CI, 2.68-33.04), (2) intermediate risk (previous surgery alone, age ≥62 years) with a 5-year OS rate of 39% (HR, 2.95; 95% CI, 0.86-10.09), and (3) low risk (previous surgery alone, age <62 years) with 5-year OS rate of 74%. This recursive partitioning analysis identified 3 prognostic groups in patients undergoing salvage surgery for recurrent OCSCC. The marked differences in survival between these groups should be taken into consideration when counselling and managing treatment for patients with locoregionally recurrent disease.


Continuous subcutaneous insulin infusion. American Diabetes Association.
Use of continuous subcutaneous insulin infusion requires continuing available care by skilled professionals, careful selection of patients, meticulous patient monitoring, and provisions for recording and reporting experiences. Insulin pumps prescribed by a physician within these guidelines are a part of treatment and should be covered by usual payment mechanisms.


Mesenchymal stem cell therapy for cardiac repair.
Stem cell therapy for repair of damaged cardiac tissue is an attractive option to improve the health of the growing number of heart failure patients. Mesenchymal stem cells (MSCs) possess unique properties that may make them a better option for cardiac repair than other cell types. Unlike other adult stem cells, they appear to escape allorecognition by the immune system and they have immune-modulating properties, thus making it possible to consider them for use as an allogeneic cell therapy product. There is a large and growing body of preclinical and early clinical experience with MSC therapy that shows great promise in realizing the potential of stem cell therapy to effect repair of damaged cardiac tissue. This review discusses the mechanism of action of MSC therapy and summarizes the current literature in the field.


Two-year changes in bone and body composition in young children with a history of prolonged milk avoidance.
No previous longitudinal studies of calcium intake, anthropometry and bone health in young children with a history of avoiding cow's milk have been undertaken. We report the 2-year changes of a group of 46 Caucasian children (28 girls, l8 boys) aged 8.1+/-2.0 years (mean +/- SD) who had low calcium intakes at baseline and were short in stature, with elevated body mass index, poor skeletons and lower Z scores for both areal bone mineral density (BMD, in grams per square centimeter) and volumetric density (bone mineral apparent density, BMAD, in grams per cubic centimeter), compared with a reference population of milk drinkers. At follow-up, adverse symptoms to milk had diminished and modest increases in milk consumption and calcium intake had occurred. Total body bone mineral content (BMC) and bone area assessed by dual energy X-ray absorptiometry had increased (P<0.05), and calcium intake from all sources was associated with both these measures (P<0.05). However, although some catch-up in height had taken place, the group remained significantly shorter than the reference population (Z scores -0.39+/-1.14), with elevated body mass index (Z scores 0.46+/-1.0). The ultradistal radius BMC Z scores remained low (-0.31+/-0.98). The Z scores for BMD had improved to lie within the normal range at predominantly cortical sites (33% radius, neck of femur and hip trochanter) but had worsened at predominantly trabecular sites (ultradistal radius and lumbar spine), where values lay below those of the reference group (P<0.05). Similarly, although volumetric BMAD Z scores at the 33% radius had normalized, BMAD Z scores at the lumbar spine remained below the reference population at follow-up (-0.67+/-1.12, P<0.001). Our results demonstrate persisting height reduction, overweight and osteopenia at the ultradistal radius and lumbar spine in young milk avoiders over 2 years of follow-up.


Evaluation of trends in the use of intensity-modulated radiotherapy for head and neck cancer from 2000 through 2005: socioeconomic disparity and geographic variation in a large population-based cohort.
The current study was conducted to evaluate trends in utilization of intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). Identified were 5487 patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with a diagnosis of HNC (aged>or=65 years) between 2000 and 2005, who received any type of radiotherapy (RT). Multivariate logistic regression analyses were performed to assess the influence of patient, tumor, treatment, and sociodemographic characteristics on receipt of IMRT versus conventional radiotherapy techniques. Overall, 21.3% of patients in the cohort received IMRT as the technique of irradiation. The use of IMRT increased significantly, with 1.3% of patients receiving it in 2000 compared with 46.1% in 2005 (P<.0001 for trend). Patients treated with RT in 2005 were 68 times more likely to receive IMRT than those treated in 2000. There was significant geographic variation observed in use of IMRT, ranging from 11.3% of cases in Kentucky to 40.4% of cases in Hawaii. Patients in the census tracks comprising the lowest quartile for socioeconomic status were 33% less likely to receive IMRT than patients in the highest quartile, even when adjusting for geographic area and year of diagnosis. The use of IMRT has rapidly become widespread for the delivery of RT for patients with HNC. However, there was significant geographic variation noted in the utilization of IMRT. Patients in census tracks comprising the lowest socioeconomic quartile were less likely to receive IMRT than their more affluent counterparts.


Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines.
Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.


Effect of Lacticaseibacillus paracasei strain Shirota supplementation on clinical responses and gut microbiome in Parkinson's disease.
Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor issues and a range of non-motor symptoms. Microbial therapy may be a useful approach for the treatment of PD. However, comprehensive analyses of the impact of probiotic supplementation on motor and non-motor symptoms are still lacking and the mechanisms whereby the treatment works remain unclear. This study investigated Lacticaseibacillus paracasei strain Shirota (LcS) supplementation on clinical responses, gut microbiota and faecal metabolites in PD patients. Patients (n = 128) were randomised to receive either probiotics (LcS-fermented milk, containing 1 × 1010 living LcS cells) or placebo for 12 weeks. All participants were examined and the basic clinical features were recorded using questionnaires. Fecal and blood samples were collected at the baseline and after 12 weeks for further omics analysis. We found that LcS intervention significantly alleviated patients' constipation-related symptoms and non-motor symptoms. We found no significant shifts in the composition of gut microbiota or faecal metabolites. Several taxa were differentially abundant between the groups, especially with regard to LcS intake, which increased the abundance of the genus Lacticaseibacillus in the probiotic group compared with those at the baseline and in the placebo group. The faecal concentration of L-tyrosine was significantly decreased and the plasma concentration of L-tyrosine was increased in the probiotic group compared with the placebo group. Our study demonstrated that although supplementation with LcS did not induce major changes in the global gut microbiome, the probiotic had favorable effects in managing constipation and other non-motor symptoms in PD patients. This study was registered at the Chinese Clinical Trial Registry: ChiCTR1800016795.


Legume genomics: understanding biology through DNA and RNA sequencing.
The legume family (Leguminosae) consists of approx. 17 000 species. A few of these species, including, but not limited to, Phaseolus vulgaris, Cicer arietinum and Cajanus cajan, are important dietary components, providing protein for approx. 300 million people worldwide. Additional species, including soybean (Glycine max) and alfalfa (Medicago sativa), are important crops utilized mainly in animal feed. In addition, legumes are important contributors to biological nitrogen, forming symbiotic relationships with rhizobia to fix atmospheric N2 and providing up to 30 % of available nitrogen for the next season of crops. The application of high-throughput genomic technologies including genome sequencing projects, genome re-sequencing (DNA-seq) and transcriptome sequencing (RNA-seq) by the legume research community has provided major insights into genome evolution, genomic architecture and domestication. This review presents an overview of the current state of legume genomics and explores the role that next-generation sequencing technologies play in advancing legume genomics. The adoption of next-generation sequencing and implementation of associated bioinformatic tools has allowed researchers to turn each species of interest into their own model organism. To illustrate the power of next-generation sequencing, an in-depth overview of the transcriptomes of both soybean and white lupin (Lupinus albus) is provided. The soybean transcriptome focuses on analysing seed development in two near-isogenic lines, examining the role of transporters, oil biosynthesis and nitrogen utilization. The white lupin transcriptome analysis examines how phosphate deficiency alters gene expression patterns, inducing the formation of cluster roots. Such studies illustrate the power of next-generation sequencing and bioinformatic analyses in elucidating the gene networks underlying biological processes.


Neutral evolution of model proteins: diffusion in sequence space and overdispersion.
We stimulate the evolution of model protein sequences subject to mutations. A mutation is considered neutral if it conserves (1) the structure of the ground state, (2) its thermodynamic stability and (3) its kinetic accessibility. All other mutations are considered lethal and are rejected. We adopt a lattice model, amenable to a reliable solution of the protein folding problem. We prove the existence of extended neutral networks in sequence space-sequences can evolve until their similarity with the starting point is almost the same as for random sequences. Furthermore, we find that the rate of neutral mutations has a broad distribution in sequence space. Due to this fact, the substitution process is overdispersed (the ratio between variance and mean is larger than 1). This result is in contrast with the simplest model of neutral evolution, which assumes a Poisson process for substitutions, and in qualitative agreement with the biological data.


PI3K-AKT signaling is a downstream effector of retinoid prevention of murine basal cell carcinogenesis.
Basal cell carcinoma (BCC) is the most common human cancer. We have demonstrated previously that topical application of the retinoid prodrug tazarotene profoundly inhibits murine BCC carcinogenesis via retinoic acid receptor γ-mediated regulation of tumor cell transcription. Because topical retinoids can cause adverse cutaneous effects and because tumors can develop resistance to retinoids, we have investigated mechanisms downstream of tazarotene's antitumor effect in this model. Specifically we have used (i) global expression profiling to identify and (ii) functional cell-based assays to validate the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway as a downstream target pathway of tazarotene's action. Crucially, we have demonstrated that pharmacologic inhibition of this downstream pathway profoundly reduces murine BCC cell proliferation and tumorigenesis both in vitro and in vivo. These data identify PI3K/AKT/mTOR signaling as a highly attractive target for BCC chemoprevention and indicate more generally that this pathway may be, in some contexts, an important mediator of retinoid anticancer effects.


Effects of betahistine on patient-reported outcomes in routine practice in patients with vestibular vertigo and appraisal of tolerability: experience in the OSVaLD study.
This was a 3-month multicentre, open-label post-marketing surveillance study of betahistine (24 mg b.i.d. or 16 mg t.i.d.) in patients with vertigo of peripheral vestibular origin. Study endpoints comprised on-treatment changes in the Dizziness Handicap Index (DHI), Hospital Anxiety and Depression Score (HADS) and the Short-Form (SF)-36v2. Total DHI score improved 37.2 points (of a 100-point scale) following betahistine treatment. Corresponding improvements occurred in all three DHI scale domains (all p < 0.001 vs baseline). Betahistine therapy was also accompanied by progressive, significant improvements in both HADS-A and HADS-D scores (p < 0.001), and improvements in the distribution profiles of anxiety and depression scores. Significant improvements in the Physical Component Summary and Mental Component Summary scores of the SF-36v2 were recorded during betahistine treatment. Betahistine was generally well tolerated. A total of 76 adverse drug reactions (ADRs) were recorded in 49 patients (2.4%), of which 75 were classified as mild or moderate and 54 were possibly related to betahistine. ADRs led to study drug discontinuation in 17 patients. These data illustrate that treatment with betahistine 48 mg/day in patients with recurrent peripheral vestibular vertigo is associated with improvements in objective measures of health-related quality of life and satisfactory tolerability.


Validation of three Arabic health literacy assessment tools in Lebanon.
Health literacy is an important predictor of health status, health behaviours, and other health outcomes. However, research on health literacy in the Arab world is scarce and no health literacy tool has been validated to test the health literacy level of the Lebanese population so far. The aim of this study was to validate Arabic translations of three commonly used health literacy assessment tools, the S-TOFHLA, the REALM-R, and the Brief Health Literacy Screening items. The tools were linguistically and culturally adapted to the Lebanese context, and 250 face-to-face interviews were conducted in an outpatient clinic in Beirut, Lebanon, between April and June 2015. The General Self-Efficacy Scale and socio-demographic questions such as gender, age, origin, education and chronic condition were included to assess predictive validity. Reliability of the instruments was found to be low to high (Cronbach's α =0 .94 for the S-TOFHLA, Cronbach's α = 0.46 for the REALM-R). Younger and highly educated participants scored higher on the S-TOFHLA. The Brief Health Literacy Screening items were significantly correlated with age, education, self-efficacy and the S-TOFHLA, reinforcing the convergent and predictive validity of the two tools. Results indicate that the S-TOFHLA and the three screening questions are a valuable tool to measure health literacy in Lebanon and, allowing for minimal adaptations according to each country's healthcare system, in the entire Arabic-speaking area.


A framework for analyzing the determinants of obstetric fistula formation.
Obstetric fistula, a devastating complication of prolonged obstructed labor, was once common in the Western world but now occurs almost exclusively in resource-poor countries. Although much has been written about the surgical repair of obstetric fistulas, prevention of fistulas has garnered comparatively little attention. Because obstetric fistulas result from obstructed labor (one of the common causes of maternal death in impoverished countries), this study assesses the obstetric fistula problem using a framework originally developed to analyze the determinants of maternal mortality. The framework identifies and explicates three sets of determinants of obstetric fistulas: the general socioeconomic milieu in which such injuries occur (the status of women, their families, and their communities); intermediate factors (health, reproductive status, and use of health care resources); and the acute clinical factors that determine the ultimate outcome of any particular case of obstructed labor. Interventions most likely to work rapidly in fistula prevention are those that have a direct impact on acute clinical situations, but these interventions will only be effective when general socioeconomic and cultural conditions promote an enabling environment for health care delivery and use. Sustained efforts that impact all three levels of determining factors will be necessary to eradicate obstetric fistula.


Assessing CD 10 Expression Level and Its Prognostic Impact in Egyptian Patients with Urothelial Carcinoma.
CD10 is expressed in urothelial carcinoma cells and cancer associated fibroblasts (CAF). In the current study, CD10 immunohistochemical staining (IHC) and CD10 mRNA expression in urothelial carcinoma of bladder (UCB) were assessed, and its relationship with tumor progression and prognosis was investigated. In this study, 106 formalin fixed paraffin-embedded (FFPE) tissue of UCB, obtained through radical cystectomy specimen, and 10 matched normal tissue samples were included.CD10 expression was evaluated by immunohistochemistry and real time PCR techniques. CD10 expression in tumor cells and associated stromal fibroblasts was significantly associated with high tumor grade and advanced stage. Significant correlation was found between CD10 tumor expression and lymphovascular invasion (LVI) (P<0.001) as well as perineural invasion (PNI). CD10 expression in stromal fibroblasts was significantly associated with squamous differentiation of tumor cells, lymph node metastasis (LNM), and tumor necrosis. Positive CD10 expression in both tumor cells and associated stromal fibroblasts was associated with shorter OS . CD10 mRNA was overexpressed in tumors in comparison with the matched normal tissues. CD10 mRNA was significantly higher in invasive tumor, advanced stage tumor, and high grade tumor. There was significant correlation between CD10 mRNA tumor expression and LVI, PNI, and tumor recurrence. Increased expression of CD10 in the tumor and CAF was strongly correlated with tumor progression, invasion, metastasis, shorter OS, and RFS in urothelial carcinoma patients. CD10 mRNA showed significantly higher expression in tumor tissue than in matched normal tissue. CD10 mRNA was associated with depth of invasion, TNM stage, tumor grade, vascular tumor invasion, and tumor recurrence.


Serum homocysteine level in pediatric patients with COVID-19 and its correlation with the disease severity.
Thrombosis and embolism are possible complications in coronavirus disease 2019 (COVID)-19-positive pediatric patients. Although the risk is lesser in children than it is in adults, it does exist during acute infection and multi-inflammatory syndrome in children. Biomarkers such asd-dimer, prothrombin time, and fibrinogen degradation products are ineffective at detecting disease severity. Homocysteine (Hcy) is a prothrombotic factor that has been reported to be higher in adult COVID-19 patients, leading to speculation that it could be used as a biomarker for disease severity. To detect the correlation between serum total homocysteine (tHcy) level and the severity of COVID-19 in pediatrics. A cross-sectional study was conducted on 40 children with COVID-19 and 40 healthy control subjects. Serum tHcy was measured by enzyme-linked immunosorbent assay and correlated with the clinical, laboratory, and radiological parameters of the patients. The median serum tHcy level in COVID-19 patients was 27.5 (interquartile range [IQR]: 23-31.75) μmol/L, while that in the controls was 1.8 (IQR: 1.6-1.875) μmol/L. There was a statistically significant increase in the tHcy level in cases compared to controls (p < 0.001). There was a statistically significant positive correlation between serum tHcy and d-dimer, ferritin, alanine transaminase, aspartate transaminase, blood urea nitrogen, and a highly significant positive correlation between tHcy and COVID-19 reporting and data system score, pediatric intensive care unit admission, and the disease severity classification. Hcy could be a biomarker of importance in predicting the severity of COVID-19 in pediatrics.


The Value of 18F-FDG PET/CT in Detecting Bone Marrow Involvement in Childhood Cancers.
The aim of this study was to assess the utility of F-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared with bone marrow biopsy (BMB) in the initial staging of pediatric patients with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), Ewing sarcoma (ES), and neuroblastoma (NB). A total of 94 patients (57 boys, 37 girls, median age 7 y, range 1 to 18 y) with newly diagnosed NHL, HL, ES, and NB between July 2014 and December 2017, who underwent BMB and F-FDG PET/CT before chemotherapy were included in this study. There were 36 patients with NHL, 27 HL, 16 ES, and 15 NB. F-FDG PET/CT and BMB results were reviewed and compared retrospectively. Retrospective analysis of data from 94 pediatric patients (57 boys, 37 girls, median age 7 y, range 1 to 18 y) was performed. Of the 94 patients, 29 had BMI on F-FDG PET/CT. BMB was positive in 14, negative in 13, and insufficient in 2 of these 29 patients. In 65 patients negative on F-FDG PET/CT, BMB was also negative in 54 and insufficient in 7. For the whole group, sensitivity, specificity, and positive and negative predictive values of F-FDG PET/CT in detecting bone marrow metastasis at the time of diagnosis were 90.6%, 100%, 100%, and 95.4% and those of BMB were 53.1%, 87.1%, 94.4%, and 80.6%, respectively. Our study demonstrates that F-FDG PET/CT predicts BMI better than BMB. F-FDG PET/CT may be used at initial staging of pediatric patients with NHL, HL, ES, and NB.


Epidemiologic survey of thrombocytopenia in dogs: a report on 987 cases.
Thrombocytopenia was documented in 987 of 18,910 (5.2%) dogs admitted to North Carolina State University, College of Veterinary Medicine, Veterinary Teaching Hospital, between 1983 and 1989. Classifying thrombocytopenic dogs by etiologic groups revealed the following proportionate ratios: 5% (48/987) immune-mediated thrombocytopenia; 13% (130/987) neoplasia-associated thrombocytopenia; 23% (224/987) inflammatory/infectious thrombocytopenia; and 59% (585/987) miscellaneous thrombocytopenia. Dogs with immune-mediated thrombocytopenia had significantly (P < 0.05) lower platelet counts (mean 36,760 +/- 50,288 microliter) than dogs in the other three groups, and Doberman Pinschers were overrepresented in all groups except the immune-mediated thrombocytopenic group. We conclude that thrombocytopenia is a prevalent and potentially important diagnostic finding in a variety of disease states.


Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape.
HCV infection is a leading cause of chronic liver disease and a major indication for liver transplantation. Although direct-acting antivirals (DAAs) have much improved the treatment of chronic HCV infection, alternative strategies are needed for patients with treatment failure. As an essential HCV entry factor, the tight junction protein claudin-1 (CLDN1) is a promising antiviral target. However, genotype-dependent escape via CLDN6 and CLDN9 has been described in some cell lines as a possible limitation facing CLDN1-targeted therapies. Here, we evaluated the clinical potential of therapeutic strategies targeting CLDN1. We generated a humanised anti-CLDN1 monoclonal antibody (mAb) (H3L3) suitable for clinical development and characterised its anti-HCV activity using cell culture models, a large panel of primary human hepatocytes (PHH) from 12 different donors, and human liver chimeric mice. H3L3 pan-genotypically inhibited HCV pseudoparticle entry into PHH, irrespective of donor. Escape was likely precluded by low surface expression of CLDN6 and CLDN9 on PHH. Co-treatment of a panel of PHH with a CLDN6-specific mAb did not enhance the antiviral effect of H3L3, confirming that CLDN6 does not function as an entry factor in PHH from multiple donors. H3L3 also inhibited DAA-resistant strains of HCV and synergised with current DAAs. Finally, H3L3 cured persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy. Overall, these findings underscore the clinical potential of CLDN1-targeted therapies and describe the functional characterisation of a humanised anti-CLDN1 antibody suitable for further clinical development to complement existing therapeutic strategies for HCV.


Effect of a Health Care System Respiratory Fluoroquinolone Restriction Program To Alter Utilization and Impact Rates of Clostridium difficile Infection.
Fluoroquinolones are one of the most commonly prescribed antibiotic classes in the United States despite their association with adverse consequences, including Clostridium difficile infection (CDI). We sought to evaluate the impact of a health care system antimicrobial stewardship-initiated respiratory fluoroquinolone restriction program on utilization, appropriateness of quinolone-based therapy based on institutional guidelines, and CDI rates. After implementation, respiratory fluoroquinolone utilization decreased from a monthly mean and standard deviation (SD) of 41.0 (SD = 4.4) days of therapy (DOT) per 1,000 patient days (PD) preintervention to 21.5 (SD = 6.4) DOT/1,000 PD and 4.8 (SD = 3.6) DOT/1,000 PD posteducation and postrestriction, respectively. Using segmented regression analysis, both education (14.5 DOT/1,000 PD per month decrease; P = 0.023) and restriction (24.5 DOT/1,000 PD per month decrease; P < 0.0001) were associated with decreased utilization. In addition, the CDI rates decreased significantly (P = 0.044) from preintervention using education (3.43 cases/10,000 PD) and restriction (2.2 cases/10,000 PD). Mean monthly CDI cases/10,000 PD decreased from 4.0 (SD = 2.1) preintervention to 2.2 (SD = 1.35) postrestriction. A significant increase in appropriate respiratory fluoroquinolone use occurred postrestriction versus preintervention in patients administered at least one dose (74/130 [57%] versus 74/232 [32%]; P < 0.001), as well as in those receiving two or more doses (47/65 [72%] versus 67/191 [35%]; P < 0.001). A significant reduction in the annual acquisition cost of moxifloxacin, the formulary respiratory fluoroquinolone, was observed postrestriction compared to preintervention within the health care system ($123,882 versus $12,273; P = 0.002). Implementation of a stewardship-initiated respiratory fluoroquinolone restriction program can increase appropriate use while reducing overall utilization, acquisition cost, and CDI rates within a health care system.


Phase separation behavior of whey protein isolate particle dispersions in the presence of xanthan.
In this study, phase separation of colloidal whey protein isolate (WPI) particle dispersions was studied using a rod-like polysaccharide xanthan. Effects of different xanthan concentration, particle volume fraction, and temperature were analyzed by visual observations, turbidity measurements, and particle mobility tracking method. Particle mobility was determined using a diffusing wave spectroscopy (DWS) set up. Xanthan concentration was kept low in order not to increase the viscosity of dispersions, so that the phase separation could be observed easily. Visual observations showed that there was a minimum concentration of xanthan to induce phase separation at a constant particle volume fraction, and xanthan concentration was found to have an important effect on the degree of phase separation. The temperature was also found to have an effect on depletion mechanism. Phase separation was mainly a result of different sizes of WPI particles, and xanthan induced the depletion interaction between WPI particles, as supported by the data obtained from DWS. The results of this study explained both the mechanism and the stability range of particle dispersions in the presence of xanthan, which is important for the design of stable systems, including colloidal particles.


Genome-Wide Identification and Characterization of the Soybean DEAD-Box Gene Family and Expression Response to Rhizobia.
DEAD-box proteins are a large family of RNA helicases that play important roles in almost all cellular RNA processes in model plants. However, little is known about this family of proteins in crops such as soybean. Here, we identified 80 DEAD-box family genes in the Glycine max (soybean) genome. These DEAD-box genes were distributed on 19 chromosomes, and some genes were clustered together. The majority of DEAD-box family proteins were highly conserved in Arabidopsis and soybean, but Glyma.08G231300 and Glyma.14G115100 were specific to soybean. The promoters of these DEAD-box genes share cis-acting elements involved in plant responses to MeJA, salicylic acid (SA), low temperature and biotic as well as abiotic stresses; interestingly, half of the genes contain nodulation-related cis elements in their promoters. Microarray data analysis revealed that the DEAD-box genes were differentially expressed in the root and nodule. Notably, 31 genes were induced by rhizobia and/or were highly expressed in the nodule. Real-time quantitative PCR analysis validated the expression patterns of some DEAD-box genes, and among them, Glyma.08G231300 and Glyma.14G115100 were induced by rhizobia in root hair. Thus, we provide a comprehensive view of the DEAD-box family genes in soybean and highlight the crucial role of these genes in symbiotic nodulation.


Insight into the Antifungal Mechanism of Action of Human RNase N-terminus Derived Peptides.
Candida albicans is a polymorphic fungus responsible for mucosal and skin infections. Candida cells establish themselves into biofilm communities resistant to most currently available antifungal agents. An increase of severe infections ensuing in fungal septic shock in elderly or immunosuppressed patients, along with the emergence of drug-resistant strains, urge the need for the development of alternative antifungal agents. In the search for novel antifungal drugs our laboratory demonstrated that two human ribonucleases from the vertebrate-specific RNaseA superfamily, hRNase3 and hRNase7, display a high anticandidal activity. In a previous work, we proved that the N-terminal region of the RNases was sufficient to reproduce most of the parental protein bactericidal activity. Next, we explored their potency against a fungal pathogen. Here, we have tested the N-terminal derived peptides that correspond to the eight human canonical RNases (RN1-8) against planktonic cells and biofilms of C. albicans. RN3 and RN7 peptides displayed the most potent inhibitory effect with a mechanism of action characterized by cell-wall binding, membrane permeabilization and biofilm eradication activities. Both peptides are able to eradicate planktonic and sessile cells, and to alter their gene expression, reinforcing its role as a lead candidate to develop novel antifungal and antibiofilm therapies.


Getting to Know Your Neighbor: Protein Structure Prediction Comes of Age with Contextual Machine Learning.
The folding of a protein structure is a process governed by both local and nonlocal interactions. While incorporating local dependencies into a machine learning algorithm for protein structure prediction is simple and has been exploited for some time, the modeling of long-range dependences which result from structurally-neighboring residues has only recently begun to be addressed. Structural properties designed to localize the prediction space from direct tertiary structure prediction, such as secondary structure, contact maps, and intrinsic disorder, among others, have begun to greatly benefit from machine learning models capable of modeling a widened, potentially global protein context. This has led to a direct enhancement of the quality of predicted tertiary structures through both the optimization of structural constraints and improved reliability of alignments to structural templates. These improvements have stemmed from the application of recurrent and convolutional neural network architectures effective not only at innate sequential context propagation but also deep feature extraction due to novel skip connections and normalization techniques allowing for greatly enhanced error back-propagation. The recent results from independent blind testing in Critical Assessment of protein Structure Prediction 13 have signaled the beginning of a new generation of protein structure prediction through the utilization of these contextual techniques. The ripples from advancements in the determination of one-dimensional and two-dimensional structural properties have us moving ever closer to the solution of the protein structure prediction problem.


Variability and predictability of performance times of elite cross-country skiers.
Analyses of elite competitive performance provide useful information for research and practical applications. Here the authors analyze performance times of cross-country skiers at international competitions (World Cup, World Championship, and Olympics) in classical and free styles of women's and men's distance and sprint events, each with a total of 410-569 athletes competing in 1-44 races at 15-25 venues from seasons 2002 to 2011. A linear mixed model of race times for each event provided estimates of within-athlete race-to-race variability expressed as a coefficient of variation (CV) after adjustment for fixed or random effects of snow conditions, altitude, race length, and competition terrain. Within-athlete variability was similar for men and women over various events for all athletes (CV of 1.5-1.8%) and for the annual top-10 athletes (1.1-1.4%). Observed effects of snow conditions and altitude on mean time were substantial (~2%) but mostly unclear, owing to large effects of terrain (CV of 4-10% in top-10 analyses). Predictability of performance was extremely high for all athletes (intraclass correlations of .90-.96) but only trivial to poor for top-10 athletes (men .00-.03, women .03-.35). The race-to-race variability of top-ranked skiers is similar to that of other elite endurance athletes. Estimates of the smallest worthwhile performance enhancement (0.3× within-athlete variability) will help researchers and practitioners evaluate strategies affecting performance of elite skiers.


Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection.
Transendothelial migration of neutrophils in postcapillary venules is a key event in the inflammatory response against pathogens and tissue damage. The precise regulation of this process is incompletely understood. We report that perivascular macrophages are critical for neutrophil migration into skin infected with the pathogen Staphylococcus aureus. Using multiphoton intravital microscopy we showed that neutrophils extravasate from inflamed dermal venules in close proximity to perivascular macrophages, which are a major source of neutrophil chemoattractants. The virulence factor α-hemolysin produced by S. aureus lyses perivascular macrophages, which leads to decreased neutrophil transmigration. Our data illustrate a previously unrecognized role for perivascular macrophages in neutrophil recruitment to inflamed skin and indicate that S. aureus uses hemolysin-dependent killing of these cells as an immune evasion strategy.


A Novel Deep Learning Algorithm for Human Papillomavirus Infection Prediction in Head and Neck Cancers Using Routine Histology Images.
The etiology of head and neck squamous cell carcinoma (HNSCC) involves multiple carcinogens, such as alcohol, tobacco, and infection with human papillomavirus (HPV). Because HPV infection influences the prognosis, treatment, and survival of patients with HNSCC, it is important to determine the HPV status of these tumors. In this article, we propose a novel deep learning pipeline for HPV infection status prediction with state-of-the-art performance in HPV detection using only whole-slide images of routine hematoxylin and eosin-stained HNSCC sections. We show that our Digital-HPV score generated from hematoxylin and eosin slides produces statistically significant patient stratifications in terms of overall and disease-specific survival. In addition, quantitative profiling of the spatial tumor microenvironment and analysis of the immune profiles show relatively high levels of lymphocytic infiltration in tumor and tumor-associated stroma. High levels of B cells and T cells and low macrophage levels were also identified in HPV-positive patients compared to HPV-negative patients, confirming different immune response patterns elicited by HPV infection in patients with HNSCC.


Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy.
Evidence from human and animal studies suggests that maternal nutrition can induce developmental programming of adult hypertension in offspring. We have previously described a model of maternal dietary imbalance in Sprague-Dawley rats whereby administration of a maternal diet rich in animal lard programmes the development of increased blood pressure, insulin resistance, dyslipidaemia, obesity and mesenteric artery endothelial dysfunction in adult offspring. To further characterize the mechanism of hypertension in this model we have examined vascular and renal structure in adult offspring of Sprague-Dawley rats fed a control diet (OC) or lard-rich diet (OHF) during pregnancy and suckling followed by a control diet post-weaning. To gain further insight, we assessed aortic reactivity and elasticity in an organ bath preparation and renal renin and Na+,K+-ATPase activity. Plasma aldosterone concentration was also measured. Stereological examination of the aorta in OHF demonstrated reduced endothelial cell volume and smooth muscle cell number compared with OC. Adult OHF animals showed increased aortic stiffness and reduced endothelium-dependent relaxation. Renal stereology showed no differences in kidney weight, glomerular number or volume in OHF compared with OC, but renin and Na+,K+-ATPase activity were significantly reduced in OHF compared with controls. Programmed alterations to aortic structure and function are consistent with previous observations that exposure to maternal high fat diets produces systemic vascular changes in the offspring. Despite normal renal stereology, altered renal Na+,K+-ATPase and renin activity offers further insight into the mechanism underlying the increased blood pressure characteristic of this model.


Systemic effects of nocturnal hypoxemia in patients with chronic obstructive pulmonary disease without obstructive sleep apnea syndrome.
To study the effects of nocturnal hypoxemia in patients with chronic obstructive pulmonary disease without obstructive sleep apnea syndrome. We studied 21 patients-10 desaturators and 11 nondesaturators-submitted to arterial blood gas analysis, polysomnography, spirometry, cardiopulmonary exercise testing (cycle ergometer), and hand-grip dynamometry, as well as measurements of maximal inspiratory pressure, maximal expiratory pressure, and C-reactive protein (CRP) levels. Patients with arterial oxygen tension > 60 mmHg were included; those with an apnea-hypopnea index > 5 events/hour of sleep were excluded. Maximal oxygen uptake, maximal power, systolic blood pressure, diastolic blood pressure (DBP), and maximal heart rate were measured during exercise in order to detect hemodynamic alterations. Patients presenting CRP levels above 3 mg/L were considered CRP-positive. Minimal peripheral oxygen saturation during sleep was significantly higher among nondesaturators (p = 0.03). More desaturators presented CRP > 3 mg/L (p < 0.05). No differences were observed in terms of any variables, However, mean peripheral oxygen saturation during sleep correlated with DBP and maximal inspiratory pressure (p < 0.001 and p = 0.001, respectively). Although nocturnal hypoxemia does not reduce exercise capacity or hand-grip strength in patients with mild/moderate COPD, its effect on maximal exercise DBP seems to depend on the degree of hypoxemia. In addition, there is a positive relationship between maximal inspiratory pressure and mean peripheral oxygen saturation during sleep, as well as evidence of pronounced inflammatory activation in patients with nocturnal hypoxemia.


A panel of serum biomarkers differentiates IgA nephropathy from other renal diseases.
There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN. We compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients. Each serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria. Serum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases.


General practitioners' experiences of managing patients with chronic leg ulceration.
To understand general practitioners' experiences of managing patients with chronic leg ulceration, thus informing future strategies to improve leg ulcer care in general practice, Australia. Qualitative study using phenomenology and in-depth interviewing. Maximum variation sample of 12 GPs working in the Perth and Hills Division of General Practice between September and December 2004. Themes in participants' experiences of leg ulcer care. Participants regarded leg ulcer management as an integral part of general practice. They expressed a desire to maintain their involvement, yet relied on nursing assistance. They perceived that ulcer care was usually straightforward and successful. Approaches to management appeared to differ significantly from that outlined in current guidelines. Instead, participants valued accessibility of care for the patient, awareness of patient context and regular review. Occasional problems with non-healing ulcers were experienced, and, in these situations, specialist opinion was appreciated. This study highlights fundamental differences between GP and specialist conceptualisation of leg ulcer care. For GPs, it identifies key areas of ulcer management that could be improved. For specialists, it suggests that widespread implementation of traditional guidelines may not be appropriate or acceptable. New approaches to leg ulcer management in general practice are likely to need a combination of education, human resources and practical support.


[Effect of Ginkgo biloba extract on biological endocrine parameters].
In order to find out whether Ginkgo biloba extract has an influence on endocrine balance, 7 male volunteers (mean age: 26.1 years) received twice the usual dose of the drug for 8 weeks. Different hormonal assays and stimulation tests with LHRH and TRH were performed before, and 4 and 8 weeks after treatment. No significant change or tendency to change was observed. The other, usual blood tests also were unmodified.


Social profile and habits of oral cancer patients in Ibadan.
The aim of this study was to compare the socioeconomic profile and social habits of oral cancer patients and those of control subjects in order to investigate the relative importance of these risk factors in the occurrence of oral cancer. Thirty-two histologically diagnosed oral carcinoma patients and 30 normal patients were recruited at the dental centre University College Hospital, Ibadan. A 33-item questionnaire was administered to the two groups. The data obtained was analyzed using student t test and chi square as appropriate as well as odds ratio. Incomes less than 50,000 naira per annum, absence of fruit in every diet and tobacco use, were associated with 5.7, 3.0 and 4.05 increased risk of oral cancer respectively. Low income, fruit depleted diet and tobacco use seems to be the most important risk factors for oral cancer development in the studied environment.


Autocrine nerve growth factor is essential for cell survival and viral maturation in HHV-8-infected primary effusion lymphoma cells.
High levels of nerve growth factor (NGF) are found in sera from individuals infected with human herpesvirus 8 (HHV-8). BC-1 and BCBL-1 cells are primary effusion lymphoma-derived B-cell lines; BC-1 cells are infected by HHV-8 and the Epstein-Barr virus (EBV), and BCBL-1 cells are infected only by HHV-8. Both cells express NGF receptors and produce NGF, whereas RAMOS cells (a B-cell line that is negative for HHV-8 and EBV) express NGF receptors but do not produce detectable NGF. Neutralization of endogenous NGF results in cell growth inhibition and apoptosis in BCBL-1 cells and, to a minor extent, in BC-1 cells. When the HHV-8 lytic cycle is induced in BCBL-1 cells by tetradecanoyl phorbol acetate (TPA), an initial reduction of endogenous NGF production is observed, and many cells undergo apoptosis. However, at 48 hours, TPA-treated cells produce significantly more NGF than untreated controls, and a subsequent recovery of cell viability is observed. Consistent with this finding, the addition of exogenous NGF or anti-NGF antibodies to TPA-treated cells reduces or increases, respectively, the rate of apoptosis in response to TPA. Finally, electron microscopy of TPA-treated BCBL-1 cells shows that the addition of exogenous NGF increases the number of cells producing and releasing complete virions as compared with the controls (25% versus 5%). On the contrary, NGF neutralization leads to the production of defective viral progeny in about 2% of cells. These data indicate that NGF is essential for both cell survival and virus maturation in HHV-8-infected cell lines. (Blood. 2000;95:2905-2912)


Serological and molecular survey of brucellosis and chlamydiosis in dromedary camels from Tunisia.
The present sero-epidemiological survey was designed and conducted to scrutinize the current status of camel-related brucellosis and chlamydiosis in Tunisia. Whole blood and serum samples were collected from 470 dromedaries (Camelus dromedarius) from eight different Tunisian governorates. Serum samples were subjected to indirect enzyme-linked immunosorbent assay (iELISA). The detection of Brucella and Chlamydia DNA was performed using conventional PCR targeting the bcsp-31 and 16 S rRNA gene, respectively. Overall, 10/470(2.12%) and 27/470 (5.75%) camels were revealed seropositive to Brucella and Chlamydia, respectively. Multivariate logistic regression analysis showed different risk factors associated with these infections. Meaningful high rates of seropositivity of brucellosis (9.5%; p = 0.000; OR=64.193) and chlamydiosis (22.6%; p = 0.000; OR=42.860) were noted among camels showing previous abortions in particular for aged females. Besides, Chlamydia seropositivity is significantly important during winter (12.5%; p = 0.009; OR= 27.533), and in camels raised in small farms (11.4%, p = 0.000, OR=86.052). Molecular analysis revealed no positivity from all analyzed blood samples. These findings indicate the involvement of camels in the epidemiology of these abortive infectious diseases. This raises awareness and serious public health concern for infectious camel diseases in order to develop further diagnostic improvements and effective control strategies.


Fine mapping of an immunodominant domain in the transmembrane glycoprotein of human immunodeficiency virus.
Sera from virtually all individuals infected with human immunodeficiency virus contain antibodies against the viral envelope glycoproteins. By using a series of synthetic peptide antigens, we identified an immunodominant domain at amino acid position 598-609 of gp41. The minimal essential epitope is a 7-amino-acid sequence (amino acids 603-609) containing two cysteine residues. Both cysteine residues are required for the antigenic conformation of the sequence, possibly due to creation of a cyclic structure via disulfide bond formation.


Unveiling a Photoinduced Hydrogen Evolution Reaction Mechanism via the Concerted Formation of Uranyl Peroxide.
We present a density functional theory study for the photochemical water oxidation reaction promoted by uranyl nitrate upon sunlight radiation. First, we explored the most stable uranyl complex in the absence of light. The reaction in a dark environmen proceeds through the condensation of uranyl monomers to form dimeric hydroxo-bridged species, which is the first step toward a hydrogen evolution reaction (HER). We found a triplet-state-driven mechanism that leads to the formation of uranyl peroxide and hydrogen gas. To describe in detail this reaction path, we characterized the singlet and triplet low-lying states of the dimeric hydroxo-bridged species, including minima, transition states, minimal energy crossing points, and adiabatic energies. Our computational results provide mechanistic insights that are in good agreement with the experimental data available.


Role of preoperative chemotherapy in squamous cell carcinoma of esophagus in kashmir, a cancer belt - a pilot study.
Esophageal carcinoma is the fifth leading gastrointestinal malignancy and is one of the leading causes of cancer related death. Despite improvements in surgical technique over the last few decades, the outcome has been dismal, with overall 5 year survival not exceeding 15%-25%. To evaluate the effect of preoperative chemotherapy on resectability, complication rate and overall survival in patients with squamous cell carcinoma esophagus. 50 patients with histologically confirmed squamous cell carcinoma (SCC), with localised or loco-regional disease (stage 4 excluded) were divided into 2 groups. Group A patients were subjected to 2-3 cycles of pre-operative chemotherapy (5FU-CDDP), whereas Group B patients were directly operated on. 3 (12%) patients in group A showed complete pathological response to chemotherapy and 18 (72%) showed a partial response, with four patients (16%) showing resistance to chemotherapy. There was no statistically significant difference in terms of response to chemotherapy with respect to degree of differentiation of tumor. There was no significant difference in the overall resectability rates between the two groups (p > 0.05), but R0 resection was achieved in 20 (80%) of group A and only 10 (40%) of group B, the difference being statistically significant (p < 0.05). The rate of overall complications was also much higher in the control group. Initially there was no significant difference in the survival between the two groups, but later (20 months) the study group showed a slight non-significant advantage. Preoperative chemotherapy significantly increases the rate of R0 resection without significantly increasing postoperative morbidity and mortality in patients with squamous cell carcinoma of esophagus. However, to assess the impact on survival the study period needs to be extended.


Environmental lead exposure: a public health problem of global dimensions.
Lead is the most abundant of the heavy metals in the Earth's crust. It has been used since prehistoric times, and has become widely distributed and mobilized in the environment. Exposure to and uptake of this non-essential element have consequently increased. Both occupational and environmental exposures to lead remain a serious problem in many developing and industrializing countries, as well as in some developed countries. In most developed countries, however, introduction of lead into the human environment has decreased in recent years, largely due to public health campaigns and a decline in its commercial usage, particularly in petrol. Acute lead poisoning has become rare in such countries, but chronic exposure to low levels of the metal is still a public health issue, especially among some minorities and socioeconomically disadvantaged groups. In developing countries, awareness of the public health impact of exposure to lead is growing but relatively few of these countries have introduced policies and regulations for significantly combating the problem. This article reviews the nature and importance of environmental exposure to lead in developing and developed countries, outlining past actions, and indicating requirements for future policy responses and interventions.


Lethal DNA damage caused by ion-induced shock waves in cells.
The elucidation of fundamental mechanisms underlying ion-induced radiation damage of biological systems is crucial for advancing radiotherapy with ion beams and for radiation protection in space. The study of ion-induced biodamage using the phenomenon-based multiscale approach (MSA) to the physics of radiation damage with ions has led to the prediction of nanoscale shock waves created by ions in a biological medium at the high linear energy transfer (LET). The high-LET regime corresponds to the keV and higher-energy losses by ions per nanometer, which is typical for ions heavier than carbon at the Bragg peak region in biological media. This paper reveals that the thermomechanical stress of the DNA molecule caused by the ion-induced shock wave becomes the dominant mechanism of complex DNA damage at the high-LET ion irradiation. Damage of the DNA molecule in water caused by a projectile-ion-induced shock wave is studied by means of reactive molecular dynamics simulations. Five projectile ions (carbon, oxygen, silicon, argon, and iron) at the Bragg peak energies are considered. For the chosen segment of the DNA molecule and the collision geometry, the number of DNA strand breaks is evaluated for each projectile ion as a function of the bond dissociation energy and the distance from the ion's path to the DNA strands. Simulations reveal that argon and especially iron ions induce the breakage of multiple bonds in a DNA double convolution containing 20 DNA base pairs. The DNA damage produced in segments of such size leads to complex irreparable lesions in a cell. This makes the shock-wave-induced thermomechanical stress the dominant mechanism of complex DNA damage at the high-LET ion irradiation. A detailed theory for evaluating the DNA damage caused by ions at high-LET is formulated and integrated into the MSA formalism. The theoretical analysis reveals that a single ion hitting a cell nucleus at high-LET is sufficient to produce highly complex, lethal damages to a cell by the shock-wave-induced thermomechanical stress. Accounting for the shock-wave-induced thermomechanical mechanism of DNA damage provides an explanation for the "overkill" effect observed experimentally in the dependence of cell survival probabilities on the radiation dose delivered with iron ions. This important observation provides strong experimental evidence of the ion-induced shock-wave effect and the related mechanism of radiation damage in cells.


Peripheral blood leucocyte subclasses as potential biomarkers of adipose tissue inflammation and obesity subphenotypes in humans.
While obesity is clearly accepted as a major risk factor for cardio-metabolic morbidity, it is also apparent that some obese patients largely escape this association, forming a unique obese subphenotype(s). Current approaches to define such subphenotypes include clinical biomarkers that largely reflect already manifested comorbidities, such as markers of dyslipidaemia, hyperglycaemia and impaired regulation of vascular tone, and anthropometric or imaging-based assessment of adipose tissue distribution. Low-grade inflammation, evident both systemically and within adipose tissue (particularly intra-abdominal fat depots), seems to characterize the more cardio-metabolically morbid forms of obesity. Indeed, several systemic inflammatory markers (C-reactive protein), adipokines (retinol-binding protein 4, adiponectin) and cytokines have been shown to correlate in humans with adipose tissue inflammation and with obesity-associated health risks. Circulating leucocytes constitute a diverse group of cells that form a major arm of the immune system. They are both major sources of cytokines and likely also of infiltrating adipose tissue immune cells in obesity. In the present review, we summarize currently available literature on 'classical' blood white cell classes and on more specific leucocyte subclasses present in the circulation in human obesity. We critically raise the possibility that leucocytes may constitute clinically available markers for the more morbidity-associated obesity subphenotype(s), and when available, for intra-abdominal adipose tissue inflammation.


Microbial community compositions in the gastrointestinal tract of Chinese Mongolian sheep using Illumina MiSeq sequencing revealed high microbial diversity.
Chinese Mongolian sheep are an important ruminant raised for wool and meat production. However, little is known about the microbiota of the gastrointestinal tract (GIT) of Chinese Mongolian sheep. To increase our understanding of the microbial community composition in the GIT of Chinese Mongolian sheep, microbiota of five sheep is investigate for the first time using the Illumina MiSeq platform. High microbial diversity was obtained from the GIT, and the microbiota exhibited a higher biodiversity in the stomach and large intestine than in the small intestine. Firmicutes (44.62%), Bacteroidetes (38.49%), and Proteobacteria (4.11%) were the three most abundant phyla present in the GIT of the sheep. The present study also revealed the core genera of Prevotella, Bacteroides, Ruminococcus, Oscillospira, Treponema, and Desulfovibrio in the GIT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States indicated that the metabolic pathway related to carbohydrate metabolism was the richest in the sheep GIT. In addition, a series of metabolic pathways related to plant secondary metabolism was most abundant in the stomach and large intestine than in the small intestine. Overall, the present study provides insight into the microbial community composition in GIT of the Chinese Mongolian sheep which is highly diverse and needs to be studied further to exploit the complex interactions with the host.


Efficient nonlocal means for denoising of textural patterns.
This paper contributes two novel techniques in the context of image restoration by nonlocal filtering. First, we introduce an efficient implementation of the nonlocal means filter based on arranging the data in a cluster tree. The structuring of data allows for a fast and accurate preselection of similar patches. In contrast to previous approaches, the preselection is based on the same distance measure as used by the filter itself. It allows for large speedups, especially when the search for similar patches covers the whole image domain, i.e., when the filter is truly nonlocal. However, also in the windowed version of the filter, the cluster tree approach compares favorably to previous techniques in respect of quality versus computational cost. Second, we suggest an iterative version of the filter that is derived from a variational principle and is designed to yield nontrivial steady states. It reveals to be particularly useful in order to restore regular, textured patterns.


Long-term disease activity and disability progression in relapsing-remitting multiple sclerosis patients on natalizumab.
Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited. To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab. Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab. EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6-6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00-1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06-2.72, p = 0.028). The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression.


The size of metastatic foci and lymph nodes yielding false-negative and false-positive lymph node staging with positron emission tomography in patients with lung cancer.
We examined the sizes of lymph nodes and metastatic foci within the lymph nodes that affect false-positive and false-negative lymph node staging by positron emission tomography in lung cancer. Preoperative positron emission tomography and computed tomography scans were performed for 564 lymph node stations in 80 patients with peripheral-type lung cancer. The sizes of both the lymph nodes and the metastatic foci within the lymph nodes were measured, and these measurements were compared with those obtained with positron emission tomography scanning. To establish general sizes of metastatic foci within the lymph nodes, 277 metastatic lymph nodes in operative specimens previously resected from another 111 patients with lung cancer were examined as a control. The sensitivity was significantly higher for positron emission tomography than for computed tomographic scanning (P =.026). The sizes of metastatic foci within lymph nodes that showed false-negative (n = 8) and true-positive (n = 28) with positron emission tomography ranged from 0.5 to 9 mm (3 +/- 1 mm) and from 4 to 18 mm (10 +/- 3 mm), respectively (P <.001). None of the metastatic foci smaller than 4 mm could be detected with positron emission tomography scanning. The review of the 277 previously resected metastatic lymph nodes showed that 89 (32%) had metastatic foci smaller than 4 mm. The sizes of true-positive (n = 28) and false-positive (n = 10) lymph nodes ranged from 6 to 15 mm (10 +/- 2 mm) and from 9 to 16 mm (12 +/- 2 mm), respectively (P <.01). None of the false-positive lymph nodes was smaller than 9 mm. Although positron emission tomography was superior to computed tomography scanning in lymph node staging in lung cancer, positron emission tomography was unable to distinguish metastatic foci smaller than 4 mm, which were not unusual sizes for lymph node metastases in lung cancer. Positive lymph nodes with positron emission tomography smaller than 9 mm are likely to be true-positive rather than false-positive.


Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism.
Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.


Quantitative estimation of attenuation in ultrasound video images: correlation with histology in diffuse liver disease.
To determine the relationship between the attenuation of backscatter intensity in B-scan images of the liver and diffuse liver disease in order to assess the usefulness of this method in providing quantitative objective characterization of diffuse liver diseases in general and in fatty liver in particular. Twenty-four healthy volunteers and 28 patients with elevated liver enzyme levels who underwent liver biopsy were included in this study. An automatic far-field slope (FFS) algorithm that estimates the decrease in amplitude of the backscattered echo as a function of beam depth was implemented on the noncompensated image that was acquired on a commercial phased-array ultrasound system fitted to a custom-built interface card. The images were processed at a work-station. All scans were acquired repeatedly, read, and graded blindly by experienced ultrasound radiologists. Histology obtained via needle biopsy was reviewed without knowledge of the ultrasound findings. Analysis of the FFS data for fatty infiltration in all patient groups yielded a sensitivity of 67%, a specificity of 77%, a positive predictive value (PPV) of 77%, negative predictive value (NPV) of 67%, and an accuracy of 71%. The mean score of the ultrasound reviewers showed a sensitivity of 82%, a specificity of 66%, a PPV% of 68%, an NPV of 81%, and an accuracy of 72%. Normal FFS values (false-negative) were found in five patients with proved fatty infiltration. All of these patients had coexistent moderate to severe hepatic inflammation. However, FFS data in patients with uncomplicated (pure) fatty infiltration revealed a sensitivity of 100%, a specificity of 80%, a PPV of 89%, an NPV of 100%, and an accuracy of 92%. The best ultrasound score yielded a sensitivity of 100%, a specificity of 60%, a PPV of 80%, an NPV of 100%, and an accuracy of 85% in the same patients. The data demonstrate an excellent sensitivity (100%) of the FFS values in patients with uncomplicated fatty infiltration. This was also the only group of patients in whom the FFS score was superior to the radiologists' best score. The FFS method can be used as a tool to follow up the response to a clinical or research treatment and to obtain standardization of pattern interpretation independently of the individual reader.


[Mycoplasma pneumoniae-associated mucositis in a 17-year-old girl].
Stevens-Johnson syndrome is an autoimmune condition characterised by erythematous target lesions on the skin with involvement of the oral and genital mucosa and conjunctivae. Recent case reports describe incomplete presentations with absence of the characteristic skin changes. This is caused by extrapulmonary manifestations of Mycoplasma pneumoniae lung infection and is now recognised as M. pneumoniae-associated mucositis (MPAM). This case report describes the clinical presentation of MPAM in a 17-year-old girl and highlights the importance of the recognition and the appropriate clinical management.