Miracle-dz/UniFAR-FTUs huggingface dataset:
RESPIRATORY MOVEMENT OF UPPER AIRWAY TISSUE IN OSA

1069 Movement of the OSA Upper Airway—Brown et al INTRODUCTION Obstructive sleep apnea (OSA) has a prevalence of around 4% of the middle-aged male population.1 It is a multifactorial disorder involving anatomical and neuromuscular alterations that predispose patients to recurrent hypoventilation and arousal during sleep.2 One-third of the variability of the apnea hypopnea index (AHI) is ascribed to increased mechanical load, and two-thirds to blunted neuromuscular responses.3 Passive mechanical loads are elevated in severe OSA, but some normal subjects with elevated load are able to increase neuromuscular activity and overcome airway collapse.4 Movement of the muscles in response to neuromuscular input during sleep is poorly understood. The upper airway muscles respond to changes in airway pressure during respiration,5,6 but whether neural output leads to movement or muscle stiffening is unknown. The muscles of the airway, particularly the genioglossus, receive phasic and tonic input from the respiratory control center in the brainstem,5,7 which is modulated by hypercapnia,8-10 hypoxia,11 and negative pressure.12-14 Lung volume,15,16 sex hormones,17 and temperature18 also influence central output to the dilator muscles. Because OSA patients have greater mechanical loads RESPIRATORY MOVEMENT OF UPPER AIRWAY TISSUE IN OSA
The Effects of Gender and Maturational Status on Generalized Joint Laxity in Young Athletes

Our purpose was to examine the effects of pubertal status on generalized joint laxity in a population of male and female athletes. We hypothesized that females would show higher generalized joint laxity after the onset of puberty while males would not. This cross-sectional cohort study included 275 female and 143 male middle school and high school basketball and soccer athletes. Joint laxity was assessed using the Beighton and Horan Joint Mobility Index. BHJMI scores were averaged and female and male athletes were compared by pubertal stage. Females demonstrated increased joint laxity scores between pre-pubertal and post-pubertal groups (P=0.042), while males did not. Pre-pubertal male and female athletes were not different in cumulative joint laxity scores (female pre-puberty Mean=2.00; male pre-pubertal Mean=1.66). However, following the onset of puberty females (pubertal Mean=2.96; post-pubertal Mean= 3.03) demonstrated a greater joint laxity score compared to males (pubertal Mean=1.24; post-pubertal Mean=1.30). Gender differences in BHJMI score was found at puberty and post-puberty (P<0.001). In contrast to males, females may have greater generalized joint laxity following the onset of puberty. Structural and physiological changes that occur during puberty such as alterations in passive joint restraints, may affect the type, severity and incidence of injuries in the maturing adolescent population.
BJRD15892 1..7

Objective: To evaluate the development of characteristic MRI changes in patients with primary large-vessel vasculitis (LVV) when treated with biological therapies. Methods: 12 patients with primary LVV (8 patients with Takayasu arteritis and 4 patients with giant-cell arteritis) received biological therapy with tumour necrosis factor-a blockers (n59) or an interleukin-6 inhibitor (n53). MRI investigations were performed at baseline (pre-treatment) and follow-up. All patients underwent the same MRI/MR angiography (MRA) protocol. Laboratory parameters (C-reactive protein and erythrocyte sedimentation rate) and clinical response (Birmingham Vasculitis Activity Score) were assessed. Results: Wall thickness was 4.260. 3mm pre-treatment and significantly decreased to 3.260. 3mm post treatment in 9/12 patients. Mural enhancement was increased in all 12/12 patients with LVV, and subsided with therapy in 5/12 patients. Mural oedema or ill-defined contour were less prevalent but also improved with biological treatment. C-reactive protein and erythrocyte sedimentation rate levels decreased, and clinical assessment revealed a significant improvement from pre-treatment to posttreatment. However, the course of imaging characteristics often did not parallel that of laboratory or clinical parameters. In all three patients receiving interleukin-6 blockade, laboratory markers and clinical scores normalized despite persistent vascular inflammation in one patient which was disclosed by MRI. Conclusion: Contrast-enhanced MRI/MRA may be useful when evaluating the development of disease activity in primary LVV under biological therapies. A high degree of suspicion and regular imaging follow-up is needed to detect persistent inflammation. Advances in knowledge: This is the first study investigating the applicability of different MRI/MRA parameters for monitoring biological therapy in patients with primary LVV.
A thrombin-crossreactive anti-cardiolipin antibody binds to activated protein C and inhibits the anticoagulant function of activated protein C

Objective— To test the hypotheses that some thrombin-reactive anti-cardiolipin antibodies (aCL) may bind to protein C (PC) and/or activated PC (APC), and that some of the PC- and APC-reactive aCL may inhibit PC activation and/or the function of APC. Methods— We studied the reactivity of patient-derived monoclonal aCL with PC and APC. Of the reactive antibodies, we examined their effects on PC activation and the activity of APC in plasma coagulation. Results— Five of five patient-derived thrombin-reactive monoclonal aCL bind to PC and APC. In addition, one patient-derived monoclonal anti-prothrombin antibody (aPT) that displays aCL activity and reacts with thrombin also binds to PC and APC. Of these 6 PC- and APC-reactive aCL/aPT, all failed to inhibit PC activation, but one (CL15) shortened the plasma coagulation time in the presence of exogenous APC and thus inhibited the anticoagulant function of APC. Conclusion— Most of the thrombin-reactive aCL in APS patients may bind to PC and APC. Of the APC-reactive aCL, some (like CL15) may inhibit the anticoagulant function that some of the thrombin-reactive monoclonal aCL may bind to PC and/or APC and thus interfere with PC activation and/or APC function. We now report that 6/6 thrombin-reactive monoclonal IgG aCL/aPT bind to both PC and APC, and, of these, CL15 inhibits the anticoagulant activity of APC.
Comparison of membrane insertion pathways of the apoptotic regulator Bcl-xL and the diphtheria toxin T-domain

The diphtheria toxin T-domain and the apoptotic repressor Bcl-xL are membrane proteins that adopt their final topology by switching folds from a water-soluble to a membrane-inserted state. While the exact molecular mechanisms of this transition are not clearly understood in either case, the similarity in the structures of soluble states of T-domain and Bcl-xL led to the suggestion that their membrane-insertion pathways will be similar as well. Previously we have applied an array of spectroscopic methods to characterize the pH-triggered refolding and membrane insertion of the diphtheria toxin T-domain. Here, we use the same set of methods to describe the membrane insertion pathway of Bcl-xL, which allows us to make a direct comparison between both systems with respect to thermodynamic stability in solution, pH-dependent membrane association and transmembrane insertion. Thermal denaturation measured by CD indicates that, unlike the T-domain, Bcl-xL does not undergo a pH-dependent destabilization of the structure. FRET measurements demonstrate that Bcl-xL undergoes reversible membrane association modulated by the presence of anionic lipids, suggesting that formation of the membrane-competent form occurs close to membrane interface. Membrane insertion of the main hydrophobic helical hairpin of Bcl-xL, α 5– α 6, was studied by site-selective attachment of environment-sensitive dye NBD. In contrast to the insertion of the corresponding TH8–TH9 hairpin in T-domain, insertion of α 5– α 6 was found not to depend strongly on the presence of anionic lipids. Taken together our results indicate that while Bcl-xL and the T-domain share structural similarities, their mode of conformational switching and membrane insertion pathways are distinctly different. into the bilayer in response to a given cellular signal. Examples include some bacterial toxins (1–3) and colicins (4), which are secreted to the extracellular space; and certain annexins (5) and members of the Bcl-2 proteins (6), which are synthesized as cytosolic proteins. The unique characteristic of these proteins is their ability to move from the polar environment of the aqueous medium to the non-polar milieu of the lipid bilayer, a process that clearly involves a massive refolding of the structure. The exact molecular pathways of this refolding/insertion process are not well understood, and it is not clear if different proteins follow the same pathway or share common features. In this study, we compare the membrane insertion pathways of the diphtheria toxin T-domain and the apoptotic repressor
Medical Informatics Medical Expert Systems-Knowledge Tools for Physicians

Recent advances in the field of artificial intelligence have led to the emergence of expert systems, computational tools designed to capture and make available the knowledge of experts in a field. Although much of the underlying technology available today is derived from basic research on biomedical advice systems during the 1970s, medical application packages are thus far generally unavailable from the young artificial intelligence industry. Medical expert systems will begin to appear
Method Development and Acid Degradation Study of Rivaroxaban by RP-HPLC in bulk

A simple, precise and accurate HPLC method has been developed and validated for assay of Rivaroxaban. An isocratic separation was achieved using a phenomenex C18(250×4.6 mm, 5μm),100°A particle size columns with a flow rate of 1 ml/min and using a PDA detector to monitor the elute at 250 nm. The mobile phase consisted of Methanol: Acetronitrile (50:50, v/v). The method was validated for specificity, linearity, precision, accuracy and robustness. The method was linear over the concentration range of 20-100 µg/ml (r2= 0.99995). Intraday system and method precision were determined and accuracy was 99.89 %. The method was found to be robust and suitable for assay of Rivaroxaban in a tablet formulation. Degradation products resulting from the stress studies did not interfere with the detection of Rivaroxaban and the assay is thus stability-indicating.
Poly(ADP-ribose)polymerase inhibition as a novel therapeutic approach against intraepidermal nerve fiber loss and neuropathic pain associated with advanced diabetic neuropathy: A commentary on PARP INHIBITION OR GENE DEFICIENCY COUNTERACT INTRAEPIDERMAL NERVE FIBER LOSS AND NEUROPATHIC PAIN IN ADVAN

Diabetes mellitus is the most common cause of neuropathy which is estimated to affect 20-30 million people worldwide [1]. Clinical trials in subjects with Type 1 and Type 2 diabetes indicate that intensive therapy and improved blood glucose control reduce incidence and slow progression of diabetic neuropathy, thus implicating hyperglycemia as a leading causative factor [1]. Numerous mechanisms have been proposed to link chronic hyperglycemia to diabetic cardiovascular complications, nephropathy, and impairments in motor and sensory nerve functions among other manifestations of peripheral diabetic neuropathy (PDN, reviewed in [2-4]). It has been hypothesized, that hyperglycemia-induced overproduction of superoxide by mitochondrial electron-transport chain activates multiple pathways of cell injury (e.g. protein kinase C (PKC), advanced glycosylation end product formation (AGE), hexosamine and polyol pathway fluxes, and nuclear factor-κB signaling, among many others) by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity in endothelial cells [3]. The hyperglycemia-induced enhanced mitochondrial superoxide and iNOS-derived nitric oxide (NO) formation favor the generation of reactive oxidant peroxynitrite through diffusioncontrolled reaction in the vascular endothelium and smooth muscle [4]. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms, triggering cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury [4]. Oxidative DNA damage also leads to the over-activation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP; the most abundant isoform of the PARP enzyme family), which depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport and ATP formation on one hand [5]. On the other hand, it inhibits GAPDH by poly-ADP-ribosylation and may also be involved in the regulation of various important inflammatory pathways [5]. These processes lead to acute endothelial dysfunction in diabetic vessels both in experimental animals [6-10] and in humans [11], a concept pioneered by Dr. Szabo's group (reviewed in [5]). According to the vascular concept of diabetic neuropathy [12], endothelial dysfunction in vasa nervorum (small vessels supplying nerves) results in decrease in nerve blood flow and endoneurial hypoxia, eventually culminating into functional and morphological changes in the diabetic nerves. The neurochemical concept of PDN suggests the importance of similar mechanisms in the neural elements (e.g. Schwann cells and neurons).
Studies on Quantitative Phosphopeptide Analysis by MALDI Mass Spectrometry Without Label, Chromatography or Calibration Curves

Rationale— Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry combined with isotope labeling methods are effective for protein and peptide quantification, but limited in their multiplexing capacity, cost-effectiveness and dynamic range. This study investigates MALDI MS-based quantification of peptide phosphorylation without labeling, and aims to overcome the shot-to-shot variability of MALDI using a mathematical transformation and extended data acquisition times. Methods— A linear relationship between the reciprocal of phosphopeptide mole fraction and the reciprocal of phosphorylated-to-unphosphorylated signal ratio is derived, and evaluated experimentally using three separate phosphopeptide systems containing phosphorylated serine, threonine and tyrosine residues: mixtures of phosphopeptide and its des -phospho-analog with known stoichiometry measured by vacuum MALDI-linear ion trap mass spectrometry and fit to the linear model. The model Results— Dynamic range of picomoles to femtomoles, good accuracy (deviations of 1.5–3.0% from expected values) and reproducibility (RSD = 4.3–6.3%) are achieved. Inhibition of Cyclin-dependent Kinase phosphorylation by the classical inhibitors olomoucine and r -roscovitine was evaluated and IC 50 values found to be in agreement with reported literature values. These results, achieved with single-point calibration, without isotope or chromatography, compare favorably to those arrived at using isotope dilution (p > 0.5 for accuracy). Conclusion— The mathematical relationship derived here can be applied to a method that we term Double Reciprocal Isotope-free Phosphopeptide Quantification (DRIP-Q), as a strategy for quantification of in vitro phosphorylation assays, the first MALDI-based, isotope- and calibration curve-free method of its type. These results also pave the way for further systematic studies investigating the effect of peptide composition and experimental conditions on quantitative, label-free MALDI. a linear fashion, and show experimentally that the linear relationship holds for three individual phosphopeptide systems containing phosphorylated serine, threonine and tyrosine in MALDI-linear ion trap mass spectrometry. Based on these results, we propose a MALDI-MS method for quantification of phosphorylation stoichiometry, termed Double Reciprocal Isotope-free Phosphopeptide Quantification (DRIP-Q). This method uses a single point calibration that does not require isotope labeling or chromatography and is shown to be robust and reproducible over 2 orders of magnitude in concentration levels for phosphorylation assays. The results obtained with this method are comparable to those obtained using traditional stable isotope labeling. Using simple mixtures of peptides to limit ion suppression effects, this study serves as proof of principle that MALDI-based label-free methods are feasible for quantitative phosphorylation analysis. To our knowledge, this is the first report of a calibration-curve-free MALDI-MS method for the determination of phosphorylation.
BJRD15416 1..7

Objective: CT examination prior to emergency laparotomy has become ubiquitous in contemporary clinical practice, but the relative accuracy of CT in this context has not been widely reported. The aim of this study was to determine the accuracy and strength of agreement between the perceived pre-operative CT diagnosis and operative findings. Methods: Data from patients undergoing pre-operative CT prior to emergency laparotomy from January 2013 to June 2014 in a large teaching hospital were analysed. The CT diagnosis was compared with operative findings using the x test and weighted kappa statistic (Kw). Results were further analysed related to the time of day the CT was reported, anatomical location and grade of the reporting radiologist. Results: 361 patients [median age 67 years (18–98 years); 180 males] underwent CT prior to emergency laparotomy. CT reports were deemed accurate in 318 (88.1%) cases and inaccurate in 43 (11.9%) cases, which resulted in 5 negative laparotomies in this latter cohort (11.6%, x 37.50, df 1; p,0.0001). Accuracy and strength of agreement varied with anatomical location of the pathology; upper gastrointestinal (UGI) 75.5%, Kw 0.673 (0.531–0.815; p,0.001); small bowel 89.9%, Kw 0.781 (0.687–0.875, p,0.001); lower gastrointestinal (LGI) 90.4%, Kw 0.821 (0.749–0.893; p,0.001). CT examinations reported within normal working hours had higher strength of agreement [Kw 0.832 (0.768–0.896), p,0.001] than CTs reported out of hours [Kw 0.789 (0.721–0.857), p,0.001], but there was no significant difference in overall accuracy (89.9 vs 86.0%; x 1.306, df 1, p50.253). Reporter seniority was not associated with improved diagnostic accuracy (x 1.825, df 1; p50.177). Conclusion: CT agreement with emergency operative pathology was good to excellent, but the strength of agreement varied in relation to anatomical location of pathology. Advances in knowledge:Overall accuracy was 88.1% with good to excellent agreement between pre-operative CT and emergency laparotomy findings in adult patients with non-traumatic abdominal pain in the acute setting. Diagnostic accuracy of CT reporting varies with anatomical location of pathology.
Methods and considerations for dynamic analysis of fMRI data

Functional MRI studies have recently begun to examine spontaneous changes in inter-regional interactions (functional connectivity) over seconds to minutes, and their relation to natural shifts in cognitive and physiological states. This practice opens the potential for uncovering structured, transient configurations of coordinated brain activity whose features may provide novel cognitive and clinical biomarkers. However, the analysis of these time-varying phenomena requires careful differentiation between neural and non-neural contributions to the fMRI signal, as well as thorough validation and statistical testing. In this article, we present an overview of methodological and interpretational considerations in this emerging field.
Glycosylation of A Disintegrin And Metalloprotease 17 (ADAM17) Affects its Activity and Inhibition

ADAM17 is believed to be a tractable target in various diseases including cancer and rheumatoid arthritis; however, it is not known whether glycosylation of ADAM17 expressed in healthy cells differs from the one found in a diseased tissue and, if so, whether glycosylation affects inhibitor binding. We expressed human ADAM17 in mammalian and insect cells and compared their glycosylation, substrate kinetics, and inhibition profiles. We found that ADAM17 expressed in mammalian cells was more heavily glycosylated than its insect-expressed analog. To determine whether differential glycosylation modulates enzymatic activity, we performed kinetic studies with both ADAM17 analogs and various TNF α -based substrates. The mammalian form of ADAM17 exhibited 10–30 fold lower k cat values than the insect analog, while the K M was unaffected, suggesting that glycosylation of ADAM17 can potentially play role in the regulating enzyme activity in vivo. Finally, we tested ADAM17 forms for inhibition by several well-characterized inhibitors. Active site zinc-binding small molecules did not exhibit differences between the two ADAM17 analogs, while a non-zinc-binding exosite inhibitor of ADAM17 showed significantly lower potency towards the mammalian-expressed analog. These results suggest that glycosylation of ADAM17 can affect cell signaling in disease and might provide opportunities for therapeutic intervention using exosite inhibitors. Results presented herein suggest that potential differential glycosylation of ADAM17 in diseased cells can affect processing of its cell surface substrates in vivo (cytokines, growth factors, receptors, etc.) thus leading to the changes of paracrine and autocrine signaling. Application of an exosite inhibitor revealed differences between mammalian-and insect-expressed ADAM17. This suggests that potential differences in ADAM17 glycosylation of diseased and normal cells might provide opportunities for therapeutic intervention and greater therapeutic window for targeting ADAM17 with exosite inhibitors.
Implementation of Permutation Testing to Determine Clustering of Social and Behavioral Risk Factors for Coronary Heart Disease, NHANES 2001-2004

Purpose— To determine if social and behavioral risk factors for CHD, including education, physical activity (PA), fruit/vegetable intake and smoking, cluster (i.e. co-occur more than expected due to chance) in US adults. Methods— The study included 4,305 males and 4,673 females aged ≥20 years from the National Health and Nutrition Examination Survey. Risk factors included: ≤HS diploma/GED; <150 minutes of moderate/vigorous PA per week; <3 or <2 servings of vegetables and fruit, respectively, per day; and smoking cigarettes. Indicator variables were summed into a sociobehavioral risk index (SRI, range 0 (no risk factors) to 4 (all risk factors)). Ratios of observed-to-expected prevalence (under the assumption of independence) of the SRI were assessed. Statistical significance was evaluated using randomly permuted average observed-to-expected SRI ratios and 95% CIs. Results— In males, the ratio of observed-to-expected prevalence of SRI=0 was 1.70 (permuted ratio=1.00, 95% CI: 0.92, 1.08), and SRI=4 was 2.10 (permuted ratio=1.00, 95% CI: 0.86, 1.14), demonstrating significant clustering. In females, the ratio of observed-to-expected prevalence of SRI=0 was 1.67 (permuted ratio=1.00, 95% CI: 0.92, 1.08), and SRI=4 was 1.86 (permuted ratio=1.00, 95% CI: 0.85, 1.15). Conclusions— Social and behavioral risk factors for CHD cluster in this sample of United States adults.