Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical and Radiological Responses after Infliximab Treatment for Perianal Fistulizing Crohn's Disease

OBJECTIVES:Infliximab is an effective therapy for fistulizing Crohn's disease of the perineum. We sought to determine whether the clinical improvement after infliximab is associated with radiological closure of fistula tracts.METHODS:Clinical responses and radiological imaging studies by transperineal ultrasound were evaluated in 35 patients with Crohn's disease perianal fistulas after treatment with infliximab 5 mg/kg up to 48 wk. Paired comparison of baseline and follow-up imaging studies at 8 wk and at 56 wk or discontinuation were assessed by an imaging score of perianal fistula severity, based on the Parks criteria. Complete clinical fistula closure and radiological healing were primary outcome measures.RESULTS:At 8 wk, after two infusions of infliximab at 0 and 2 wk, clinical fistula closure occurred in 49% of patients. The radiological score at 8 wk was higher for patients with clinical fistula closure than for patients with no clinical improvement (p= 0.023) and two patients showed complete radiological healing. At 56 wk, clinical fistula closure occurred in 46% patients. Clinical fistula scores correlated with radiological scores (R2= 0.52; p < 0.001) but were not associated with fistula complexity, number of fistulas, or number of collections at baseline imaging. The proportion of patients with marked radiological improvement increased from 14% at 8 wk to 43% at 56 wks (p= 0.015) and complete radiological healing occurred in 4 (11%) patients.CONCLUSIONS:For perianal fistulizing Crohn's disease, repeat dose infliximab improves clinical and radiological outcomes, although complete radiological healing occurs in a minority of patients.
Efficacy of automated auditory brainstem response hearing screening in very preterm newborns.

OBJECTIVE To investigate the efficacy of an automated auditory brainstem response (AABR) hearing screening method in very preterm newborns in the neonatal intensive care setting. STUDY DESIGN In this prospective cohort study, 90 consecutive preterm newborns (<32 weeks' gestational age) had AABR hearing screening weekly from birth until a bilateral pass result was obtained. If the newborn had a unilateral pass result, AABR screening was repeated in the same week. Data were analyzed by using the Kaplan-Meier survival function technique, resulting in a cumulative pass rate curve for postmenstrual age. Cox's regression method was used to analyze the effect of co-variables, such as sex and growth restriction, on pass rates. RESULTS Median gestational age was 29.5 weeks (range, 25.3-31.9 weeks), and median birth weight was 1115 g (range, 600-1960 g). Mean age was 6.2 days (SD 4.3) at first test, 15.7 (SD 8.1) at second test, and 21.4 (SD 8.6) at third test. Eighty percent (CI: 70.2%-89.8%) of the newborns passed at 30.3 weeks' postmenstrual age, 90% (CI: 83.6%-96.4%) passed at 31.2 weeks, and 100% passed at 34 weeks' postmenstrual age. The attainment of these pass rates correlated to postmenstrual age was not significantly influenced by sex, growth restriction, or gestational age at birth. Postnatal pass rates (in days) were strongly influenced by gestational age. CONCLUSION AABR pass rates of >80% can be obtained from 30 weeks' postmenstrual age. Therefore AABR neonatal hearing screening can be used before discharge from a neonatal intensive care unit.
Redox imbalance of red blood cells impacts T lymphocyte homeostasis: implication in carotid atherosclerosis

Summary Oxidative stress and immune/inflammatory responses are key pathogenetic factors of atherosclerotic disease. In this contest, mechanisms that regulate survival and death of immune cells may be relevant. Previous studies have demonstrated that red blood cells (RBCs) are physiologically able to inhibit apoptosis and to promote proliferation of activated T lymphocytes from healthy subjects. The aim of the present study was to evaluate whether RBCs from patients with carotid atherosclerosis maintain their property to modulate T cell homeostasis. Peripheral blood lymphocytes (PBLs) obtained from healthy subjects were activated in vitro by phytohemagglutinin in the presence/absence of RBCs from patients with carotid atherosclerosis or of in vitro oxidised RBCs from healthy subjects. Levels of reactive oxygen species (ROS) and aging markers of RBCs as well as susceptibility to apoptosis of PBLs were evaluated by flow cytometry. PBL proliferation was evaluated by 3H-methyl-thymidine incorporation assay whereas secretion of cytokines, analysed in view of their key role in T cell function, was assessed by ELISA. Levels of ROS and phosphatidyl-serine externalisation, a sign of RBC aging, resulted significantly higher in RBCs from patients than in those from healthy subjects, whereas surface glycophorin A expression and reduced glutathione content did the opposite. Unlike RBCs obtained from healthy subjects, RBCs from patients and in vitro oxidised RBCs did not protect activated T lymphocytes from apoptosis. Hence, RBCs from patients with carotid atherosclerosis, probably due to their oxidative imbalance, impact T cell integrity and function. Our results suggest a new regulatory role for RBCs in atherosclerosis.
Advances in melanoma senescence and potential clinical application

Normal cells possess a limited proliferative life span, after which they enter a state of irreversible growth arrest, called replicative senescence, which acts as a potent barrier against transformation. Transformed cells have escaped the process of replicative senescence and theoretically can not re‐enter senescence. However, recent observations showed that transformed cells, and particularly the melanoma cells, can still undergo oncogene or stress‐induced senescence. This senescence state is accompanied by many of the markers associated with replicative senescence, such as flattened shape, increased acidic β‐galactosidase activity, characteristic changes in gene expression and growth arrest. Interestingly, in some cancers, senescence induction following chemotherapy has been correlated with a favorable patient outcome. In this review, we gathered recent results describing senescence‐like phenotype induction in melanoma cells and discuss why senescence may also be exploited as a therapeutic strategy in melanoma.
Genetic Diversity and Selection Regulates Evolution of Infectious Bronchitis Virus

SUMMARY. Conventional and molecular epidemiologic studies have confirmed the ability of infectious bronchitis virus (IBV) to rapidly evolve and successfully circumvent extensive vaccination programs implemented since the early 1950s. IBV evolution has often been explained as variation in gene frequencies as if evolution were driven by genetic drift alone. However, the mechanisms regulating the evolution of IBV include both the generation of genetic diversity and the selection process. IBV's generation of genetic diversity has been extensively investigated and ultimately involves mutations and recombination events occurring during viral replication. The relevance of the selection process has been further understood more recently by identifying genetic and phenotypic differences between IBV populations prior to, and during, replication in the natural host. Accumulating evidence suggests that multiple environmental forces within the host, including immune responses (or lack thereof) and affinity for cell receptors, as well as physical and biochemical conditions, are responsible for the selection process. Some scientists have used or adopted the related quasispecies frame to explain IBV evolution. The quasispecies frame, while providing a distinct explanation of the dynamics of populations in which mutation is a frequent event, exhibits relevant limitations which are discussed herein. Instead, it seems that IBV populations evolving by the generation of genetic variability and selection on replicons follow the evolutionary mechanisms originally proposed by Darwin. Understanding the mechanisms underlying the evolution of IBV is of basic relevance and, without doubt, essential to appropriately control and prevent the disease.
Promoter-Based Isolation and Fluorescence-Activated Sorting of Mitotic Neuronal Progenitor Cells from the Adult Mammalian Ependymal/Subependymal Zone

Neuronal precursor cells are widespread in the subependyma of the forebrain ventricular lining, and may provide a cellular substrate for brain repair. We have previously identified and isolated them from fetal brain, by sorting forebrain cells transfected with plasmid DNA encoding the gene for green fluorescent protein (hGFP), driven by the early neuronal promoter for Tα1 tubulin (P/Tα1). Fetal neuronal precursors were thereby identified and harvested with both a high degree of enrichment, and a virtual abolition of glial contaminants. We have now extended this approach to include the isolation and purification of neuronal progenitors from the adult brain. Dissociates of the lateral ventricular wall, that included the combined ependymal/subependymal zone, were obtained from 3-month-old adult rats. These cells were cultured and transfected with P/Tα1:hGFP plasmid DNA. Two days later, the cells were redissociated, sorted on the basis of Tα1-driven GFP expression, and replated. The majority of these cells expressed the early neuronal proteins Hu and TuJ1/βIII-tubulin upon FACS; within the week thereafter, most matured as morphologically-evident neurons, that coexpressed βIII-tubulin and MAP-2. Fewer than 5% expressed astrocytic markers, compared to over half of the cells in matched samples that were either not sorted, or sorted after transfection with a plasmid bearing the nonfluorescent lacZ gene under the control of P/Tα1 tubulin. Thus, the use of a fluorescent transgene under the control of an early neuron-selective promoter permits the enrichment of neuronal progenitor cells from the adult rat brain, in a form that may allow their heterologous implantation.
Overexpression of the MDRL gene in blast cells from patients with acute myelocytic leukemia is associated with decreased anthracycline accumulation that can be restored by cyclosporin‐A

Typical multi‐drug resistance (MDR) in human and animal cell lines is caused by overactivity of a unidirectional drug efflux pump. This pump is composed of a 170‐kDa transmembrane glycoprotein (P‐glycoprotein) that is encoded by the so‐called mdrl gene. The functionally relevant characteristic of MDR cells is a defect in drug accumulation that can be restored by agents which inhibit the P‐glycoprotein pump. The purpose of our study was to find out whether Pglycoprotein inhibitors could increase the daunorubicin (DNR) accumulation in acute myelocytic leukemia (AML) cells, overexpressing the mdrl gene. Using dot blot analysis with an mdrl‐specific cDNA probe, we identified leukemic cell samples, obtained from chemotherapy‐resistant AML patients, that had relatively high levels of mdrl expression. These leukemic cells showed a reduced ability to accumulate DNR in vitro, as quantitated by flow cytometry. Addition of cyclosporin‐A (Cy‐A), a drug known to inhibit the P‐glycoprotein pump, to the incubation medium resulted in an increase (up to 60%) in steady‐state drug uptake by the leukemic cells. The degree of Cy‐A‐induced increase in drug accumulation in the leukemic cells correlated approximately with the level of overexpression of the mdrl gene. Our data indicate that Cy‐A is a good candidate for combination chemotherapy with cytotoxic drugs in clinical trials, aimed at the treatment of drug resistance in AML.
Effect of period, water temperature and agitation on loss of water-soluble carbohydrates and protein from grass hay: implications for equine feeding management

The effects of different water-soaking treatments on removal of water-soluble carbohydrates (WSC), WSC constituents and protein from four UK hays were determined. Hays were soaked in water for up to 16 hours at mean temperatures of 8°C, 16°C, in hot tap water (initially 49°C) or agitated and rinsed in clean water at 16°C. Initial hay WSC contents ranged from 154 to 216 g/kg dry matter. Losses of WSC from hays after 16 hours soaking at 8°C, 16°C, 16°C plus agitation and 49°C averaged 28, 46, 49 and 44 per cent, respectively. Corresponding percentage losses of fructan were 16, 37, 39 and 33. Percentage losses of sucrose averaged 55 (8°C), 86 (16°C), 91 (16°C+agitation) and 82 (initial temperature 49°C), those of glucose were 60, 85, 75 and 75, and of fructose were 41, 52, 54 and 46. Hay crude protein contents were not significantly changed by any of the soaking treatments. Soaking at 8°C generally resulted in reduced losses of WSC compared to when soaked at the higher temperatures. Thus, in cold weather using warmer water to soak hays may effect greater WSC loss, although very prolonged soaking at warm temperatures might encourage the proliferation of unwanted micro-organisms in the soak liquor.
Sarcoidosis incidence and prevalence: a nationwide register-based assessment in Sweden

Our objective was to estimate the contemporary incidence and prevalence of sarcoidosis using Swedish population-based register data. Adults with any sarcoidosis-coded visit were identified from the National Patient Register (hospitalisations 1964–2013 and outpatient care 2001–2013). Demographic and medication dispensing data were retrieved from national registers. We estimated the prevalence of sarcoidosis in 2013 overall and by county of residence. The incidence of sarcoidosis during 2003–2012 was estimated by sex, age, education level and year of diagnosis. Case definitions were varied to test their robustness. More than 16 000 individuals had a history of sarcoidosis in 2013. When defined as two or more sarcoidosis-coded visits, the prevalence was 160 per 100 000. Using different definitions, the prevalence ranged from 152 (requiring a specialist visit) to 215 per 100 000 (only one visit required). The highest prevalence was observed in northern less densely populated counties. The incidence was 11.5 per 100 000 per year and varied by −10% to +30% depending on case definition. The incidence peaked in males aged 30–50 years and in females aged 50–60 years, but did not differ by education level and was stable over time. This study represents the largest epidemiological investigation of sarcoidosis using population-based individual-level data. Age at diagnosis in men was 10 years younger than in women and geographical variation was observed. Sarcoidosis occurrence varied by region, age and sex; age at onset was 10 years younger in males than in females http://ow.ly/mKyN300E4Kp
Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases

ABSTRACT Periodontal diseases, such as chronic periodontitis, share common inflammatory risk factors with other systemic and chronic inflammatory disorders. Mucosal tissues, such as oral epithelia, are exposed to environmental stressors, such as tobacco and oral bacteria, that might be involved in promoting a systemic inflammatory state. Conversely, chronic disorders can also affect oral health. This review will summarize recent evidence for the interrelationship between chronic periodontitis and other prevalent chronic diseases such as cardiovascular diseases, diabetes, cancer and chronic respiratory diseases. The association with pregnancy is also included due to possible obstetric complications. We will focus on inflammatory cytokines such as TNF-alpha, IL-1, and IL-6, because they have been shown to be increased in patients with chronic periodontitis, in patients with chronic systemic diseases, and in patients with both chronic periodontitis and other chronic diseases. Therefore, an imbalance towards a proinflammatory immune response could underline a bidirectional link between chronic periodontitis and other chronic diseases. Finally, we highlight that a close coordination between dental and other health professionals could promote oral health and prevent or ameliorate other chronic diseases.
Experimental Characterization and Mathematical Modeling of P2X7 Receptor Channel Gating

The P2X7 receptor is a trimeric channel with three binding sites for ATP, but how the occupancy of these sites affects gating is still not understood. Here we show that naive receptors activated and deactivated monophasically at low and biphasically at higher agonist concentrations. Both phases of response were abolished by application of Az10606120, a P2X7R-specific antagonist. The slow secondary growth of current in the biphasic response coincided temporally with pore dilation. Repetitive stimulation with the same agonist concentration caused sensitization of receptors, which manifested as a progressive increase in the current amplitude, accompanied by a slower deactivation rate. Once a steady level of the secondary current was reached, responses at high agonist concentrations were no longer biphasic but monophasic. Sensitization of receptors was independent of Na+ and Ca2+ influx and ∼30 min washout was needed to reestablish the initial gating properties. T15E- and T15K-P2X7 mutants showed increased sensitivity for agonists, responded with monophasic currents at all agonist concentrations, activated immediately with dilated pores, and deactivated slowly. The complex pattern of gating exhibited by wild-type channels can be accounted for by a Markov state model that includes negative cooperativity of agonist binding to unsensitized receptors caused by the occupancy of one or two binding sites, opening of the channel pore to a low conductance state when two sites are bound, and sensitization with pore dilation to a high conductance state when three sites are occupied.
Management of facial nerve paralysis in noncholesteatomatous chronic otitis media.

OBJECTIVE The objective of this study was to analyse the clinical presentations, treatment course, and outcomes for patients treated for chronic otitis media associated with facial paralysis in noncholesteatomatous ears. METHODOLOGY The present study looked at 13 patients (10 men, 3 women; ranging in age from 15 to 59 years) treated for facial paralysis due to chronic otitis media without cholesteatoma. RESULTS Six patients had dehiscence of the fallopian canal whereas the bony canal was intact in the remaining patients. Decompression of the facial nerve was not performed in 5 of the 7 ears with an intact fallopian canal. Four ears underwent total decompression from the geniculate ganglion to the stylomastoid foramen, while the remaining 4 ears underwent partial nerve decompression. However, statistical analysis did not show any difference in recovery between the patients with surgical decompression and those without decompression (p = 0.171). All the patients not receiving decompression had successful outcomes (80% classified as Grade I and 20% as Grade II). CONCLUSION All patients not receiving decompression had successful outcomes. Intravenous antibiotic treatment in conjunction with steroid therapy is the mainstay management of facial paralysis due to chronic otitis media without cholesteatoma. It is therefore not necessary to decompress the facial nerve in cases of facial paralysis in noncholesteatomatous chronic otitis media.
Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients

Objective:To demonstrate that a new immediate-release omeprazole oral suspension is effective in preventing upper gastrointestinal bleeding in critically ill patients. Design:A noninferiority analysis was used to compare rates of clinically significant upper gastrointestinal bleeding in a prospective, phase 3, double-blind trial with parallel omeprazole suspension and cimetidine treatment groups. Setting:A total of 47 intensive care units in the United States. Patients:A total of 359 critically ill patients who required mechanical ventilation for ≥48 hrs, had an Acute Physiology and Chronic Health Evaluation score of ≥11 at baseline, had an intact stomach with a nasogastric or orogastric tube in place, and had at least one additional risk factor for upper gastrointestinal bleeding. Interventions:Patients were randomized to treatment with omeprazole suspension (two 40-mg doses on day 1, via orogastric or nasogastric tube, and 40 mg each day thereafter) or intravenous cimetidine (300-mg bolus and 50 mg/hr thereafter) for up to 14 days. Gastric aspirates were sampled for bleeding and pH. Medication doses were doubled for failure of pH control (two successive aspirates with pH ≤ 4). Measurements and Main Results:Clinically significant upper gastrointestinal bleeding (bright red blood not clearing after 5–10 mins of lavage or persistent Gastroccult-positive “coffee-grounds” material for 8 hrs on days 1–2 or for 2–4 hrs on days 3–14 and not clearing with ≥100 mL of lavage) was the primary end point of the trial. The rate of clinically significant bleeding in the per-protocol population was 4.5% with omeprazole suspension and 6.8% with cimetidine, meeting the criteria for the noninferiority of omeprazole suspension. Median gastric pH was ≥6 on all trial days with omeprazole suspension treatment and on 50% of days with cimetidine treatment (p < .001, all trial days). In the omeprazole suspension group, median gastric pH was >4 on each trial day in 95% of patients. Conclusions:Immediate-release omeprazole suspension is effective in preventing upper gastrointestinal bleeding and more effective than intravenous cimetidine in maintaining gastric pH of >4 in critically ill patients.
Growth hormone, insulinlike growth factor‐1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease

The liver is the major source of circulating insulinlike growth factor‐I (IGF‐I) and has been suggested as a major source of at least two of the major binding proteins that modify its bioavailability. We aimed to assess the direct effects of liver dysfunction on serum levels of IGF‐1 and its major binding proteins by measuring fasting levels of growth hormone, IGF‐1, IGFBP‐1, IGFBP‐3, insulin, C peptide, and glucose in 35 patients with cirrhosis and during an oral glucose tolerance test in 16 of those patients. Serum levels of growth hormone (GH) were high in the patients: median, 12.0 mU/L (range, 1 to 87) compared with normals, 0.95 mU/L (0.1 to 20) (P < .0005) and serum IGF‐1 levels were low: 81 ng/mL (38 to 153) versus 193 ng/mL (151 to 235) (P < .0001). Serum IGFBP‐3 levels were low in the patients: 1.59 mg/L (0.46 to 4.43) compared with normals, 5.41 (4.34 to 6.11) (P < .0001), and there was a significant negative correlation between IGFBP‐3 levels and Childs Pugh score (r = .63 P < .0001). Fasting IGFBP‐1 levels were significantly higher in the patients 31 ng/mL (11 to 92) than normals, 14 (7 to 20) (P < .0001). There was no correlation between fasting insulin and IGFBP‐1 levels despite high fasting insulin levels. A decrease in IGFBP‐1 levels was seen during the glucose tolerance test (GTT) in all patients. In conclusion, there are significant changes in the levels of two of the major IGF‐1 binding proteins that may further limit the bioavailability of already low circulating IGF‐1 levels. Substrate availability appears to be a stronger influence on fasting IGFBP‐1 levels than does insulin, and the close correlation of IGFBP‐3 with liver function indicates a dominant regulatory role of the hepatocyte.