Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterization of Within-Subject Responses to Fluticasone and Montelukast in Childhood Asthma

Purpose of the Study. Asthmatic individuals vary in their responses to inhaled corticosteroids (ICSs) and leukotriene antagonists (LTRAs). The authors of this study sought to determine if responses are concordant for both types of drugs and sought markers for responses. Study Population. Children (aged 6–17 years) with mild-to-moderate asthma. They had asthma symptoms or bronchodilator use on average at least 3 days/week over the preceding 4 weeks and improvement in forced expiratory volume in 1 second (FEV1) of ≥12% after maximal bronchodilation or methacholine PC20 (provocative concentration causing a 20% decrease in FEV1) of ≤12.5 mg/mL. Children with severe asthma were excluded, as were those with recent use of corticosteroid or LTRA. Methods. After a 5- to 10-day characterization phase, participants were randomly assigned to 1 of 2 crossover treatment sequences with 8-week periods of either active ICS (fluticasone 100 μg twice daily) or an age-appropriate dose of montelukast. During the active-treatment period for one drug, the participant received a placebo for the alternative drug. Baseline-only characterization included various asthma biomarkers. The primary outcome measure was percentage change in prebronchodilator FEV1 from baseline to the end of the treatment period. “Response” was defined as improvement in FEV1 of at least 7.5%. Results. Fifty-five percent of the 126 participants showed no response to either drug, whereas 23% responded to fluticasone alone, 17% responded to both, and 5% responded to montelukast alone. Compared with those who responded to neither drug, those who responded to fluticasone alone had higher exhaled nitric oxide, serum immunoglobulin E, serum eosinophilic cationic protein, and total eosinophil count, along with lower methacholine PC20 and lower pulmonary function. Favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use and response, along with higher exhaled nitric oxide and serum eosinophilic cationic protein levels and lower methacholine PC20 and pulmonary function. Conclusions. Responses to fluticasone and montelukast vary. Children with low pulmonary function or high levels of biomarkers should start with ICSs. In children with less severe disease, it would be reasonable to start with either ICSs or LTRAs. Asthma therapy might soon move from the current approach, which is based on mean responses in populations, to one predicated on a given person’s asthma phenotype and genotype. Reviewer Comments. The vast majority of asthmatic patients in a primary care practice can maintain excellent control with one or the other of the above-mentioned drugs as simple monotherapy. History is paramount in assessing asthma severity, especially because the above-described biomarkers are largely unavailable to the pediatrician. It is tantalizing to consider a time when we will be able to more accurately target successful treatment in advance.
Targeting Group II Metabotropic Glutamate (mGlu) Receptors for the Treatment of Psychosis Associated with Alzheimer's Disease: Selective Activation of mGlu2 Receptors Amplifies β-Amyloid Toxicity in Cultured Neurons, Whereas Dual Activation of mGlu2 and mGlu3 Receptors Is Neuroprotective

Dual orthosteric agonists of metabotropic glutamate 2 (mGlu2) and mGlu3 receptors are being developed as novel antipsychotic agents devoid of the adverse effects of conventional antipsychotics. Therefore, these drugs could be helpful for the treatment of psychotic symptoms associated with Alzheimer's disease (AD). In experimental animals, the antipsychotic activity of mGlu2/3 receptor agonists is largely mediated by the activation of mGlu2 receptors and is mimicked by selective positive allosteric modulators (PAMs) of mGlu2 receptors. We investigated the distinct influence of mGlu2 and mGlu3 receptors in mixed and pure neuronal cultures exposed to synthetic β-amyloid protein (Aβ) to model neurodegeneration occurring in AD. The mGlu2 receptor PAM, N-4′-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride (LY566332), devoid of toxicity per se, amplified Aβ-induced neurodegeneration, and this effect was prevented by the mGlu2/3 receptor antagonist (2S,1′S,2′S)-2-(9-xanthylmethyl)-2-(2′-carboxycyclopropyl)glycine (LY341495). LY566332 potentiated Aβ toxicity regardless of the presence of glial mGlu3 receptors, but it was inactive when neurons lacked mGlu2 receptors. The dual mGlu2/3 receptor agonist, (−)-2-oxa-4-aminobicyclo[3.1. 0]exhane-4,6-dicarboxylic acid (LY379268), was neuroprotective in mixed cultures via a paracrine mechanism mediated by transforming growth factor-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβ neurotoxicity was mediated entirely by glial mGlu3 receptors. The selective noncompetitive mGlu3 receptor antagonist, (3S)-1-(5-bromopyrimidin-2-yl)-N-(2,4-dichlorobenzyl)pyrrolidin-3-amine methanesulfonate hydrate (LY2389575), amplified Aβ toxicity on its own, and, interestingly, unmasked a neurotoxic activity of LY379268, which probably was mediated by the activation of mGlu2 receptors. These data indicate that selective potentiation of mGlu2 receptors enhances neuronal vulnerability to Aβ, whereas dual activation of mGlu2 and mGlu3 receptors is protective against Aβ-induced toxicity.
Is This Patient Malnourished

PATIENTS Case 1 Ten days prior to being seen a 65-year-old man suffered a Wallenberg stroke involving the lateral medulla. This left him with difficulty swallowing. Since that time he had been treated with intravenous fluids, and attempts at eating led to mild aspiration with pneumonia. In that period he lost 6% of his usual body weight and was continuing to lose weight. He felt weak and was able to ambulate only with difficulty, both because of his stroke-related ataxia and generalized weakness. On physical examination there was an obvious squared-off appearance to his shoulders from subcutaneous tissue and muscle wasting. There was no edema. Case 2 A 63-year-old man was admitted to the hospital for gastric resection of an obstructing gastric carcinoma. He was well until 6 weeks prior to admission when he began to notice the rapid onset of early satiety. This progressed to the point where he
Cone beam computed tomography images fusion in predicting lung ablation volumes: a feasibility study

Background Recently different software with the ability to plan ablation volumes have been developed in order to minimize the number of attempts of positioning electrodes and to improve a safe overall tumor coverage. Purpose To assess the feasibility of three-dimensional cone beam computed tomography (3D CBCT) fusion imaging with “virtual probe” positioning, to predict ablation volume in lung tumors treated percutaneously. Material and Methods Pre-procedural computed tomography contrast-enhanced scans (CECT) were merged with a CBCT volume obtained to plan the ablation. An offline tumor segmentation was performed to determine the number of antennae and their positioning within the tumor. The volume of ablation obtained, evaluated on CECT performed after 1 month, was compared with the pre-procedural predicted one. Feasibility was assessed on the basis of accuracy evaluation (visual evaluation [VE] and quantitative evaluation [QE]), technical success (TS), and technical effectiveness (TE). Results Seven of the patients with lung tumor treated by percutaneous thermal ablation were selected and treated on the basis of the 3D CBCT fusion imaging. In all cases the volume of ablation predicted was in accordance with that obtained. The difference in volume between predicted ablation volumes and obtained ones on CECT at 1 month was 1.8 cm3 (SD ± 2, min. 0.4, max. 0.9) for MW and 0.9 cm3 (SD ± 1.1, min. 0.1, max. 0.7) for RF. Conclusion Use of pre-procedural 3D CBCT fusion imaging could be useful to define expected ablation volumes. However, more patients are needed to ensure stronger evidence.
Determinants of physicians' prevention‐related practice: a comparison between Aarhus, Denmark, and Mainz, Germany

Aims The study describes the self‐reported interest of physicians in prevention‐related practice with alcohol misusers in Aarhus in Denmark and Mainz in Germany, and identifies determinants of this interest. Methods The study took the form of a postal anonymous survey, carried out between 25 January and 15 February 2000, of general practitioners (GPs) and hospital practitioners (HPs). The identified sample was n=572, and the response rate 66% (n=374). Results A minority of physicians in Aarhus (35%) and a majority of physicians in Mainz (60%) were personally interested in preventive work. In both cities, a self‐reported interest in preventive work was significantly correlated to having taken an advanced course on alcohol misuse within the last 12 months and having a personal belief in the ability of physicians to influence patients' attitudes to alcohol. Being a GP in Aarhus and being female in Mainz were significantly related to reporting interest in preventive work, too. Physicians' age and drinking 5+ drinks monthly were not found to be dependent on interest in prevention. Conclusion These findings provide an empirical baseline for a future comparative research on a physician's personal interest in prevention, which is of critical importance for the design of effective culturally relevant prevention interventions.
Tuberculosis, diabetes mellitus, and Malaysia

Tuberculosis (TB) remained a leading cause of mortality in Malaysia and it had been reported that TB was among the top five transmissible diseases. [1,2] In Malaysia, national TB control program was introduced in 1961and it played vital role in controlling TB. [2] However, a gradual increase in the number of TB notification was observed in the last decade. The incidence of TB in 1997 was 63.6/100,000 populations when compared to 61.0/100,000 population in 1996[3] and it reached to 64.7/100,000 in year 2000. [4] In Malaysia, the highest incidence of (TB) was in the states of Sabah, Wilayah Persekutuan, Sarawakn and Pinang. [4] Sabah accounted for 29% of the total newly identified cases at national level and annual notification rate were also highest than other states of Malaysia. [5,6] The directly observed treatment, short-course (DOTS) therapy was first employed in Malaysia during 1999, and free medication were provided to the patients. However, overall cases of all forms of TB had been augmented from 15,057 in year 2000 to 22,710 cases in 2012. [1,7,8]
Revision Anterior Cruciate Ligament Reconstruction: Techniques and Tips—The Vail Experience

Revision reconstruction of the anterior cruciate ligament (ACL) is becoming increasingly more common as the number of primary reconstructions increases. The authors present an algorithm that makes it possible to perform revision surgery with predictable results. Basic principles, including recognition of the factors which may contribute to the failure process and patient selection, are presented as part of the algorithm. The operative technique emphasized uses a patellar tendon autograft or allograft in most circumstances. This technique focuses on the goal of recreating normal anatomy. Our extensive experience with revision of failed prosthetic grafts is also discussed. In general, we report outcome scores which are only slightly inferior to those obtained from primary reconstructions.
Peak Expiratory Flow Rate In Cigarette Smokers

Objective: To compare lung function between smokers and non-smokers using Peak Expiratory Flow Rate (PEFR). Methods: This study examines the peak expiratory flow rate (PEFR) of three hundred and forty cigarette smokers, age and sex-matched with PEFR of equal number of non-smokers. Results: The mean PEFR of all smokers (males and females) was 225.0 + 62.79 L/min. (P Conclusion: Long duration of smoking is associated with significant reduction in lung function. This can be detected with this simple but reliable test of PEFR even in rural clinics. Key words: Peak Expiratory Flow Rate: Cigarette Smokers. Highland Medical Research Journal Vol.1(2) 2002: 36-37
Evidence for weapon-related traumas in medieval Japan: observations of the human crania from Seiyokan

The Seiyokan site is located in Kamakura, Japan, and has yielded 91 human skeletons belonging to the 14-15th centuries AD. The purposes of this study are to examine the human crania from the archeological site at Seiyokan, to analyze the presence, distribution, and variability of their weapon-related traumas, and finally to better understand violence in medieval Japan from osteological evidence. The results demonstrate that the traumas on the crania have morphological features consistent with human-induced cut marks. The presence of cut marks on the Seiyokan crania, which strongly suggests the prevalence of violence in medieval Japan, is in accord with the historical background--that a militarily organized society was founded by force and that the rise to political power of the warrior class and the establishment of a military government resulted in continuous disturbances, armed conflicts, and violent death.
State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training

The list of diseases with a known inflammatory etiology is growing. Cardiovascular disease, osteoporosis, diabetes, geriatric cachexia, and Alzheimer's disease have all been shown to be linked to or exacerbated by aberrantly regulated inflammatory processes. Nevertheless, there is mounting evidence that those who are physically active, or who become physically active, have a reduction in biomarkers associated with chronic inflammation. There was strong early consensus that exercise-induced reductions in inflammation were explained by body mass index or body fatness, but recent studies provide support for the contention that exercise has body fat—independent anti-inflammatory effects. With few exceptions, the anti-inflammatory effects of exercise appear to occur regardless of age or the presence of chronic diseases. What remains unclear are the mechanisms by which exercise training induces these anti-inflammatory effects, but there are several intriguing possibilities, including release of endogenous products, such as heat shock proteins; selective reduction of visceral adipose tissue mass or reducing infiltration of adipocytes by macrophages; shift in immune cell phenotype; cross-tolerizing effects; or exercise-induced shifts in accessory proteins of toll-like receptor signaling. However, future research endeavors are likely to uncover additional potential mechanisms, and it could be some time before functional mechanisms are made clear. In summary, the potential anti-inflammatory influences of exercise training may provide a low-cost, readily available, and effective treatment for low-grade systemic inflammation and could contribute signifiecantly to the positive effects of exercise training on chronic disease.
Renal contrast microangiography with synchrotron radiation: a novel method for visualizing structures within nephrons in vivo

Background No non-invasive method of observing renal microcirculation in vivo has been established as yet. Although angiography is considered to be ideally suited for the purpose, conventional X-rays cannot be used to image structures smaller than 100 µm. Purpose To develop a method for visualizing the renal arterioles, glomeruli, and proximal tubules of rats in vivo making use of synchrotron radiation. Material and Methods Male Wistar rats were anesthetized, and a catheter was inserted via laparotomy into the abdominal aorta with its tip placed above the renal arteries. The rats were paralyzed with a neuromuscular blocking agent and mechanically ventilated. An inorganic iodine contrast medium was injected via the catheter. The SR derived X-rays transmitted through the subjects were recorded with a CCD camera. Two-dimensional images with a pixel size of 9 µm were obtained. The exposure time was fixed at 50 ms, with a maximum acquisition rate of three images/s. Results Renal arterioles as small as 18 µm in diameter, glomeruli with an average diameter of 173 ± 21 µm, as well as proximal tubules, were clearly visualized. In addition, glomerular density at the peripheral renal cortex was measurable. Conclusion Rat renal microcirculation could be successfully observed in real-time, without exteriorization of the kidney in this study.
The Relationship Between Parameters Measured by Optical Coherence Tomography and Visual Field Indices

Purpose: To evaluate the diagnostic ability of optic disc topographic parameters and the retinal nerve fiber layer (RNFL) thickness parameter measured by optical coherence tomography (OCT) and to determine the association of these structural parameters with visual field indices. Methods: Fifty-six glaucomatous eyes and 65 healthy control eyes were enrolled in this retrospective cross-sectional study. Each subject had a 24-2 full threshold test on a Humphrey visual field analyzer and an optical coherence tomographic evaluation. The parameters from the fast RNFL thickness algorithm and the fast optic disc algorithm were analyzed by an ROC curve, and we sought to determine the association of these parameters with visual field indices by linear and logarithmic regression. Results: The area under the receiver operating characteristic curve (AUROC) value of the fast optic disc algorithm parameters ranged from 0.78 to 0.79 and that of the fast RNFL thickness algorithm parameters ranged from 0.74 to 0.81. The associations between the parameters from the fast optic disc algorithm and from the fast RNFL thickness algorithm with visual field indices were statistically significant (P
Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds

Transient receptor potential canonical (TRPC) proteins form Ca2+-permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca2+ influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca2+ signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca2+-dependent transcription factor, cAMP response element–binding protein. These findings suggest that Ca2+ signaling mediated by activation of DAG-activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a new class of synthetic neurotrophic drugs.
Heart rate and respiration influence on macroscopic blood and CSF flows

Background Changes in blood volume in the intracranial arteries and the resulting oscillations of brain parenchyma have been presumed as main initiating factors of cerebrospinal fluid (CSF) pulsations. However, respiration has been recently supposed to influence CSF dynamics via thoracic pressure changes. Purpose To measure blood and CSF cervical flow and quantify the contribution of cardiac and respiratory cycles on the subsequent signal evolution. Material and Methods Sixteen volunteers were enrolled. All participant underwent two-dimensional fast field echo echo planar imaging (FFE-EPI). Regions of interest were placed on internal carotids, jugular veins, and rachidian canal to extract temporal profiles. Spectral analysis was performed to extract respiratory and cardiac frequencies. The contribution of respiration and cardiac activity was assessed to signal evolution by applying a multiple linear model. Results Mean respiratory frequency was 14.6 ± 3.9 cycles per min and mean heart rate was 66.8 ± 9 cycles per min. Cardiac contribution was higher than breathing for internal carotids, explaining 74.68% and 10.27% of the signal variance, respectively. For the jugular veins, respiratory component was higher than the cardiac one contributing 44.28% and 6.53% of the signal variance, respectively. For CSF, breathing and cardiac component contributed less than half of signal variance (12.61% and 23.23%, respectively). Conclusion Respiration and cardiac activity both influence fluid flow at the cervical level. Arterial inflow is driven by the cardiac pool whereas venous blood aspiration seems more due to thoracic pressure changes. CSF dynamics acts as a buffer between these two blood compartments.
Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

The ATP-binding cassette (ABC) transporter multidrug resistance protein 1 (MRP1/ABCC1) is responsible for the cellular export of a chemically diverse array of xenobiotics and endogenous compounds. Arsenic, a human carcinogen, is a high-affinity MRP1 substrate as arsenic triglutathione [As(GS)3]. In this study, marked differences in As(GS)3 transport kinetics were observed between MRP1-enriched membrane vesicles prepared from human embryonic kidney 293 (HEK) (Km 3.8 µM and Vmax 307 pmol/mg per minute) and HeLa (Km 0.32 µM and Vmax 42 pmol/mg per minute) cells. Mutant MRP1 lacking N-linked glycosylation [Asn19/23/1006Gln; sugar-free (SF)-MRP1] expressed in either HEK293 or HeLa cells had low Km and Vmax values for As(GS)3, similar to HeLa wild-type (WT) MRP1. When prepared in the presence of phosphatase inhibitors, both WT- and SF-MRP1-enriched membrane vesicles had a high Km value for As(GS)3 (3–6 µM), regardless of the cell line. Kinetic parameters of As(GS)3 for HEK-Asn19/23Gln-MRP1 were similar to those of HeLa/HEK-SF-MRP1 and HeLa-WT-MRP1, whereas those of single glycosylation mutants were like those of HEK-WT-MRP1. Mutation of 19 potential MRP1 phosphorylation sites revealed that HEK-Tyr920Phe/Ser921Ala-MRP1 transported As(GS)3 like HeLa-WT-MRP1, whereas individual HEK-Tyr920Phe- and -Ser921Ala-MRP1 mutants were similar to HEK-WT-MRP1. Together, these results suggest that Asn19/Asn23 glycosylation and Tyr920/Ser921 phosphorylation are responsible for altering the kinetics of MRP1-mediated As(GS)3 transport. The kinetics of As(GS)3 transport by HEK-Asn19/23Gln/Tyr920Glu/Ser921Glu were similar to HEK-WT-MRP1, indicating that the phosphorylation-mimicking substitutions abrogated the influence of Asn19/23Gln glycosylation. Overall, these data suggest that cross-talk between MRP1 glycosylation and phosphorylation occurs and that phosphorylation of Tyr920 and Ser921 can switch MRP1 to a lower-affinity, higher-capacity As(GS)3 transporter, allowing arsenic detoxification over a broad concentration range.