Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological protection of NSAID- induced intestinal permeability in the rat: effect of tempo and metronidazole as potential free radical scavengers

Recently, NSAID-induced changes in both the structure and function of the distal intestine have been found to occur more frequently and with greater toxicological significance than previously thought. We have previously validated a suitable animal model to evaluate intestinal permeability changes using orally administered 51Cr- EDTA that correlates with intestinal ulceration. In this study we investigated the suitability of metronidazole and the nitroxide stable free radical scavenger (tempo) as protective agents against NSAID-induced intestinal per meability. Male Sprague-Dawley rats were dosed with two doses of metronidazole (50 mg/kg, 12 and 1 h pre-NSAID) or a single 100 mg/kg dose of tempo 1 h prior to NSAIDs. The urinary excretion of the orally administered marker 51Cr-EDTA was measured. Both tempo and metronidazole dramatically reduced indomethacin (20 mg/kg) and flur biprofen (10 mg/kg)-induced intestinal permeability. All the animals exposed to indomethacin alone died within 48-96 h and presented with histological evidence of drug- induced enteropathy, ulceration and frank peritonitis. Protection by tempo and metronidazole suggests that free radicals and/or bacteria may be important mediators in the pathogenesis of intestinal mucosal damage induced by NSAIDs. Nitric oxide donor compounds used concomi tantly with NSAIDs may protect gastrointestinal tract.
Global estimation of myelination in the developing brain on the basis of magnetization transfer imaging: a preliminary study.

BACKGROUND AND PURPOSE In the developing brain, myelination occurs in an orderly and predetermined sequence. The aim of this study was to determine whether such changes can be tracked using volumetric magnetization transfer imaging. METHODS Three-dimensional magnetization transfer imaging was performed in 50 children (age range, 0.6-190 months) with no evidence of developmental delay or structural abnormalities. Volumetric magnetization transfer ratio (MTR) parameters generated of the whole brain were mean MTR and height and location of the MTR histogram peak. Relationships between volumetric MTR parameters and age were assessed using nonlinear regression analysis. RESULTS With age, all volumetric MTR parameters changed exponentially in a way that was best expressed by the function y = a + b.exp(-x/c) (P < .0001). The peak height of the MTR histogram was the parameter that changed most predictably and that continued to change for the longest period of time. CONCLUSION With this preliminary study, we show that by using volumetric MTR analysis, it is possible to monitor changes in the developing brain, presumably the myelination progress. This method has a potential role for detecting myelination disorders in the pediatric population, for studying the natural history of these diseases, and for monitoring the effects of treatment.
Teleradiotherapy of joints in rheumatoid arthritis: lack of efficacy

Background: Low dose radiotherapy is commonly used for painful rheumatic conditions in clinical practice. Teleradiotherapy may be a cheap, painless procedure which is applicable to many joints at a time. Objective: To determine if the local application of x rays to inflamed joints in rheumatoid arthritis (RA) affects the signs and symptoms of inflammation. Methods: In a randomised, controlled, double blind study, roentgen irradiation was administered in a total dose of 20 Gy during 2 weeks to single joints in six patients with RA who were receiving constant and stable pharmacological treatment with DMARDs and NSAIDs. Single inflamed joints on the contralateral side of the body were used as controls and received sham irradiation. Swelling and tenderness was assessed by blinded investigators before and until 3 months after the irradiation; general disease activity and pain scales were included in the assessment. Results: No change in the scores for tenderness, swelling, pain, or disease activity was seen. The trial was stopped for ethical reasons. Conclusion: Local roentgen treatment of RA at a substantial dose of 20 Gy was ineffective in this pilot trial.
The supply of dentists and access to care in rural Kansas.

CONTEXT Rural deficits in dental care and oral health are well documented and are typically attributed to the low number of dentists practicing in rural areas, but the relationships between rural residence, dental supply, and access to care have not been firmly established, impeding the development of effective public policy. PURPOSE The purpose of this study is to develop a conceptual framework for observed variations in dental supply, oral health, and access to dental care in rural versus nonrural areas, and to test key empirical implications of this framework (eg, whether lower levels of utilization are associated with the lack of dentists and/or other aspects of residence in a rural area). METHODS This study employs descriptive statistics, bivariate analyses, and multiple logistic regression to describe the relationship between oral health, access to care, and the supply of dentists in rural versus nonrural populations. Data analyzed includes Kansas' dental licensure records and the 2002 Behavioral Risk Factor Surveillance System. FINDINGS Bivariate results confirm that dental supply, access to care, and oral health are lower for populations living in rural areas. Multivariate models indicate that dentist supply has a positive and independent association with utilization, but that rurality is not associated with utilization and oral health after controlling for demographics and dentist supply. CONCLUSIONS Findings are consistent with a conceptual framework linking the geography of rural residence, individual preferences for services such as dental care, and the financial disincentives for dentists to locate in rural areas.
Oxidative stress and mitochondrial impairment can be separated from lipofuscin accumulation in aged human skeletal muscle

According to the free radical theory of aging, reactive oxygen species (ROS) act as a driving force of the aging process, and it is generally believed that mitochondrial dysfunction is a major source of increased oxidative stress in tissues with high content of mitochondria, such as muscle or brain. However, recent experiments in mouse models of premature aging have questioned the role of mitochondrial ROS production in premature aging. To address the role of mitochondrial impairment and ROS production for aging in human muscles, we have analyzed mitochondrial properties in muscle fibres isolated from the vastus lateralis of young and elderly donors. Mitochondrial respiratory functions were addressed by high‐resolution respirometry, and ROS production was analyzed by in situ staining with the redox‐sensitive dye dihydroethidium. We found that aged human skeletal muscles contain fully functional mitochondria and that the level of ROS production is higher in young compared to aged muscle. Accordingly, we could not find any increase in oxidative modification of proteins in muscle from elderly donors. However, the accumulation of lipofuscin was identified as a robust marker of human muscle aging. The data support a model, where ROS‐induced molecular damage is continuously removed, preventing the accumulation of dysfunctional mitochondria despite ongoing ROS production.
Foxo3 Is Essential for the Regulation of Ataxia Telangiectasia Mutated and Oxidative Stress-mediated Homeostasis of Hematopoietic Stem Cells*

Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROS-independent modulations of ATM and p16INK4a and ROS-mediated activation of p53/p21CIP1/WAF1/Sdi1 tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.
A Bayesian semiparametric model for bivariate sparse longitudinal data

Mixed‐effects models have recently become popular for analyzing sparse longitudinal data that arise naturally in biological, agricultural and biomedical studies. Traditional approaches assume independent residuals over time and explain the longitudinal dependence by random effects. However, when bivariate or multivariate traits are measured longitudinally, this fundamental assumption is likely to be violated because of intertrait dependence over time. We provide a more general framework where the dependence of the observations from the same subject over time is not assumed to be explained completely by the random effects of the model. We propose a novel, mixed model‐based approach and estimate the error–covariance structure nonparametrically under a generalized linear model framework. We use penalized splines to model the general effect of time, and we consider a Dirichlet process mixture of normal prior for the random‐effects distribution. We analyze blood pressure data from the Framingham Heart Study where body mass index, gender and time are treated as covariates. We compare our method with traditional methods including parametric modeling of the random effects and independent residual errors over time. We conduct extensive simulation studies to investigate the practical usefulness of the proposed method. The current approach is very helpful in analyzing bivariate irregular longitudinal traits. Copyright © 2013 John Wiley & Sons, Ltd.
Epigenetic variation in the FWA gene within the genus Arabidopsis.

fwa is a late flowering epi-mutant in Arabidopsis thaliana. FWA is silenced by DNA methylation in vegetative tissue but is demethylated in the central cell of the female ovule and continues to be expressed in the endosperm from the maternal copy. FWA is stably silenced in A. thaliana, but in related Arabidopsis species, FWA expression and DNA methylation levels vary in vegetative tissue. In this study, we show that variation in FWA expression in field isolates having identical DNA sequences is associated with changes in DNA methylation and may change over time. Vegetative FWA expression is correlated with decreased methylation at non-CG sites in the region upstream of the transcription start site in species related to A. thaliana and we conclude that methylation of this region is critical for FWA silencing in these species. In A. thaliana, FWA expression is affected by methylation in regions both upstream and downstream of the transcription start site. Ectopic A. thaliana FWA expression causes a late flowering phenotype, but over-expression of Arabidopsis lyrata FWA does not. In A. thaliana, stable silencing of FWA to prevent late flowering may have evolved through the selection of large tandem repeats and spread of the critical methylated region to include these repeats.
Sex Differences in Succumbing to Sexual Temptations

Men succumb to sexual temptations (e.g., infidelity, mate poaching) more than women. Explanations for this effect vary; some researchers propose that men and women differ in sexual impulse strength, whereas others posit a difference in sexual self-control. These studies are the first to test such underlying mechanisms. In Study 1, participants reported on their impulses and intentional control exertion when they encountered a real-life tempting but forbidden potential partner. Study 2 required participants to perform a reaction-time task in which they accepted/rejected potential partners, and we used process dissociation to separate the effects of impulse and control. In both studies, men succumbed to the sexual temptations more than women, and this sex difference emerged because men experienced stronger impulses, not because they exerted less intentional control. Implications for the integration of evolutionary and self-regulatory perspectives on sex differences are discussed.
Lack of effect of single and repeated doses of levocetirizine, a new antihistamine drug, on cognitive and psychomotor functions in healthy volunteers.

AIMS Levocetirizine (R-cetirizine), is the active enantiomer of cetirizine, an antihistamine indicated in the treatment of allergic rhinitis and chronic idiopathic urticaria. The purpose of this trial was to analyse the effects of levocetirizine single and multiple doses on CNS using integrated measures of cognitive and psychometric performance. METHODS A battery of psychometric tests was used: critical flicker fusion (CFF), choice reaction time (CRT), body sway (BS), learning memory test (LMT) and subjective assessments of alertness compared with placebo. Nineteen (19) healthy male volunteers received either levocetirizine 5 mg (therapeutic dose), diphenhydramine 50 mg or placebo once daily for 5 consecutive days (3-way cross-over). Diphenhydramine was used as a positive control. CFF tests were performed on days 1 and 5 at baseline and up to 24 h following drug intake. Subjects used the Bond-Lader visual analogue scales (VAS) to assess their mood and vigilance. RESULTS In contrast to diphenhydramine, when compared with placebo, levocetirizine did not modify the CFF (primary endpoint), regardless of the dosing scheme (-1.62 Hz [-2.61, -0.64] and -0.81 Hz [-1.80, 0.19], respectively, 3 h after dosing on day 1). CRT was decreased with both levocetirizine and placebo up to 5 h after dosing on day 1 and up to 3 h after dosing on day 5. Body sway data were similar with levocetirizine and placebo but increased with diphenhydramine. LMT was similar in all three groups. No relevant difference between placebo and levocetirizine was recorded by the subjects on their assessment of alertness using the VAS, whilst decreased alertness was reported following diphenhydramine 50 mg. CONCLUSIONS This study showed that levocetirizine does not produce any deleterious effect on cognitive and psychometric functions compared with placebo in healthy male volunteers.
Analysis of US Food and Drug Administration Review Intervals for Drugs Approved during the Period 1997–2002

This research investigates US Food and Drug Administration review intervals in the United States from 1997 through 2002 for three main categories new drugs applications: new drug application (NDA), the supplemental new drug application (SNDA), and the abbreviated new drug application (ANDA). Review interval for each application was the basis for evaluation and was calculated based on the difference between approval date and the application date. The median review time for all applications was 13.5 months (1.1 years). The median review intervals for ANDAs, NDAs, and SNDAs were 19.1, 12.0, and 10.0 months (1.6, 1.0, and 0.8 years), respectively, during the period. It was found that the median review period for an ANDA was significantly longer than that for an NDA and SNDA. Comparison of application class medians revealed significant differences for all 3 pairwise comparisons (all P < 0.001, Tukey HSD). Within each application category, we compared differences between years. The year effect was not statistically significant for ANDAs or NDAs. NDA median review times were 13.7, 12.0, 12.0, 10.8, 12.5, and 11.7 months (1.14, 1.00, 1.00, 0.90, 1.04, and 0.98 years), while ANDA median review times were 20.4, 19.1, 19.9, 18.6, 18.4, and 21.5 months (1.70, 1.59, 1.66, 1.55, 1.53, and 1.79 years) for 1997, 1998, 1999, 2000, 2001, and 2002, respectively. Year differences were significant for SNDAs (P < 0.001). The primary source of this difference was a lower median review time during 1997, but there was little difference in median review times for the remaining years.
Coronary no‐reflow phenomenon: From the experimental laboratory to the cardiac catheterization laboratory

Coronary no‐reflow occurs commonly during acute percutaneous coronary intervention, particularly in patients with acute myocardial infarction and those with degenerated vein grafts. It is associated with a guarded prognosis, and thus needs to be recognized and treated promptly. The pathophysiology originates during the ischemic phase and is characterized by localized and diffuse capillary swelling and arteriolar endothelial dysfunction. In addition, leukocytes become activated and are attracted to the lumen of the capillaries, exhibit diapedesis and may contribute to cellular and intracellular edema and clogging of vessels. At the moment of perfusion, the sudden rush of leukocytes and distal atheroemboli further contributes to impaired tissue perfusion. Shortening the door‐to‐balloon time, use of glycoprotein IIb/IIIa platelet receptor inhibitors and distal protection devices are predicted to limit the development of no‐reflow during percutaneous interventions. Distal intracoronary injection of verapamil, nicardipine, adenosine, and nitroprusside may improve coronary flow in the majority of patients. Hemodynamic support of the patient may be needed in some cases until coronary flow improves. © 2008 Wiley‐Liss, Inc.
Serial measurements of high-sensitivity cardiac troponin T after exercise stress test in stable coronary artery disease

Abstract Objective: The aim was to assess serial measurements of high-sensitivity cardiac troponin T (hs-cTNT) post-exercise in patients with stable coronary artery disease (CAD). Methods: Twelve patients with positive coronary angiograms (CAD positives) and 12 controls performed an exercise stress test. Results: CAD positive had higher baseline and peak concentrations of hs-cTNT than controls. Significant increases in hs-cTNT were seen in both groups after exercise. In two-third of patients the peak in hs-cTNT was above the 99th percentile. Conclusion: hs-cTNT is higher in patients with stable coronary disease than in controls and exceeds the diagnostic cut-off value for myocardial infarction in a majority of patients with CAD after exercise.
Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2.

OBJECTIVE To examine the risk factors for mild cognitive impairment (MCI) in a longitudinal population study-the Cardiovascular Health Study Cognition Study. DESIGN We examined the factors that in the period 1991 through 1994 predicted the development of MCI in all participants of the Cardiovascular Health Study Cognition Study. Further examination was conducted in the Pittsburgh, Pa, cohort (n = 927), where participants with MCI were classified as having either the MCI amnestic-type or the MCI multiple cognitive deficits-type. SETTING Multicenter population study. PATIENTS This study includes all participants of the Cardiovascular Health Study Cognition Study (n = 3608) who had a magnetic resonance imaging (MRI) scan of the brain between 1991 and 1994, and detailed neuropsychological, neurological, and medical evaluations to identify the presence of MCI or dementia in the period 1998 to 1999. The mean time between the closest clinical examination to the MRI and the diagnostic evaluation for cognitive disorders was 5.8 years for the Cardiovascular Health Study Cognition Study cohort and 6.0 years for the Pittsburgh cohort. MAIN OUTCOME MEASURES Risk factors for MCI at the time of the MRI were identified using logistic regression, controlling for age, race, educational level, baseline Modified Mini-Mental State Examination and Digit Symbol Test scores, measurements of depression, MRI findings (atrophy, ventricular volume, white matter lesions, and infarcts), the presence of the apolipoprotein E (APOE) epsilon4 allele, hypertension, diabetes mellitus, and heart disease. RESULTS Mild cognitive impairment (n = 577) was associated with race (African American), low educational level, low Modified Mini-Mental State Examination and Digit Symbol Test scores, cortical atrophy, MRI-identified infarcts, and measurements of depression. The MCI amnestic-type was associated with MRI-identified infarcts, the presence of the APOE epsilon4 allele, and low Modified Mini-Mental State Examination scores. The MCI multiple cognitive deficits-type was associated with low Modified Mini-Mental State Examination and Digit Symbol Test scores. CONCLUSIONS The development of MCI is associated with measurements of cognition and depression, racial and constitutional factors, and cerebrovascular disease. Early cognitive deficits seem to be a common denominator for the 2 forms of MCI; the presence of cerebrovascular disease and the APOE epsilon4 allele is associated with the amnestic type of MCI.
Iron deficiency in cystic fibrosis: relationship to lung disease severity and chronic Pseudomonas aeruginosa infection.

BACKGROUND Iron deficiency (ID) is common in patients with cystic fibrosis (CF) and may be related to GI factors and chronic inflammation. Pseudomonas aeruginosa (PA) infection is predominantly responsible for chronic lung suppuration in patients with CF, but its survival is critically dependent on the availability of extracellular iron, which it obtains via highly efficient mechanisms. OBJECTIVE To determine whether ID in CF patients is directly related to the severity of suppurative lung disease. DESIGN We determined the iron status of 30 randomly selected adult CF patients (13 women) and assessed the relationship to lung disease severity and GI factors by determining their daily sputum volume, FEV(1) percent predicted, C-reactive protein (CRP) level, erythrocyte sedimentation rate, and degree of pancreatic supplementation. Additionally, we measured the sputum concentrations of iron and ferritin in a randomly selected subgroup of 13 of the 30 subjects. SETTING Adult CF Service in a tertiary-care center. RESULTS Seventy-four percent of subjects experienced ID (ie, serum iron levels < or = 12 micromol/L and/or transferrin saturation levels < or = 16%). There was no relationship found with the degree of pancreatic supplementation. The daily sputum volume was strongly associated with low serum iron levels, transferrin saturation, ferritin/CRP ratio, and FEV(1) percent predicted (p < 0.05). Serum iron levels and transferrin saturation were negatively related to CRP (r = -0.8 and r = -0.7, respectively; p < 0.01) and erythrocyte sedimentation rate (r = -0.5 and r = -0.4, respectively; p < 0.05). FEV(1) percent predicted was positively related to serum iron level (r = 0.5; p < 0.01), transferrin saturation (r = 0.4; p < 0.05), and ferritin/CRP ratio (r = 0.7; p < 0.05). Sputum iron concentration (median, 63 micromol/L; range, 17 to 134 micromol/L) and ferritin concentration (median, 5,038 microg/L; range, 894 to 6,982 microg/L) exceeded plasma levels and negatively correlated with FEV(1) percent predicted (r = -0.6 and r = -0.5, respectively; p < or = 0.05). CONCLUSION In our CF patients, ID was directly related to the increased severity of suppurative lung disease but not to the degree of pancreatic insufficiency. Iron loss into the airway may contribute to ID and may facilitate PA infection.