Miracle-dz/UniFAR-FTUs huggingface dataset:
Apixaban in patients with atrial fibrillation.

BACKGROUND Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).
Combined use of proacrosion immunocytochemistry and autosomal DNA in situ hybridisation for evaluvation of human ejaculated germ cells

Summary The recently reported human pregnancies and births after fertilising oocytes with round spermatids recovered from the ejaculate of men with non-obstructive azoospermia have underscored the need for a more accurate evaluation of the nuclear and cytoplasmic maturation status of ejaculated germ cells. In this study we describe our first experience with a method combining the immunocytochemical visualisation of proacrosin with autosomal DNA fluorescence in situ hybridisation (FISH) to assess ejaculated germ cells from patients with a spermiogenesis defect. The proacrosin immunoreactivity, analysed with the use of the monoclonal antibody 4D4, has been detected in cells of round spermatid size presenting a haploid FISH figure as well as in larger cells whose ploidy corresponds to primary and secondary spermatocytes. These observations are in agreement with previously published results obtained, with the use of the same antibody, by immunocytochemical analysis of histological sections of testicular tissue. All the cells of round spermatid size possessing proacrosin immunoreactivity were found to be haploid by FISH. On the other hand, some of the haploid cells of round spermatid size did not possess proacrosin immunoreactivity. The structural pattern of proacrosin immunoreactivity was highly variable both in spermatids and in younger spermatogenic cells. These data show that cell size is the main criterion to be used for the identification of ejaculated round spermatids, whereas the presence of the developing acrosome represents only an auxiliary criterion. The scoring of acrosomal development in ejaculated spermatids may be useful as part of pre-treatment diagnosis before the inclusion of infertile couples in a spermatid conception programme.
Altered Thymic and Peripheral T-Lymphocyte Repertoire Preceding Onset of Diabetes in NOD Mice

Insulitis occurs by 5 wk of age in all NOD mice. However, diabetes is detectable only after 3–5 mo of age and only in ∼50% of females and 10% of males in our colony. Therefore, it is predictable that changes in the T-lymphocyte repertoire of diabetes-prone mice occur and predispose them to disease. We demonstrate here that an altered (with respect to control BALB/cJ mice) thymic T-lymphocyte maturation reflected by a depletion (∼12%) of CD4+CD8+ T lymphocytes and a reciprocal increase in CD4−CD8− T lymphocytes precedes the onset of diabetes. This depletion was detected only ∼3 mo after insulitis and is manifested by a specific loss (∼3%) of immature T lymphocytes bearing Vβ8lo (lo is a relative level of expression) T-lymphocyte receptor. By onset of diabetes, an even greater decrease (∼35%) of CD4+CD8+ and a reciprocal increase of CD4−CD8− T lymphocytes were apparent and accompanied by the same depletion (3%) of Vβ8lo T lymphocytes. Administration of cyclophosphamide (CY), which accelerates the appearance of diabetes in NOD mice, caused similar depletions of CD4+CD8+ and Vβ8lo thymic T lymphocytes. The same alterations in the distribution of these thymic T-lymphocyte subsets were evident even earlier in insulitis- and diabetes-free NON mice, indicating that these changes in thymic T-lymphocyte development may be necessary but not sufficient to give rise to diabetes. Despite the common genetic origin of NOD and NON mice, differences at their MHC-linked and -unlinked loci may account for their differential susceptibility to diabetes. Analyses of peripheral lymph node (LN) T lymphocytes showed a decrease (6–10%) in the frequency of the CD4+ T-lymphocyte subset and a concomitant reduction (3–4%) in CD4+Vβ8+ T lymphocytes in spontaneously and CY-induced diabetic NOD mice. Interestingly, the latter reduction resulted primarily from a depletion of CD4+Vβ8. 1+ LN T lymphocytes in diabetic mice and was not detectable either in prediabetic NOD mice at 16 wk of age or in nondiabetic NON mice. These data suggest that depletion of CD4+ regulatory T lymphocytes and/or the rerouting of CD4+Vβ8. 1+ effector T lymphocytes from the peripheral LN to the pancreas during progression to disease onset mediate the pathogenesis of diabetes.
Blindness and Eye Disease in Cambodia

Purpose: To assess the prevalence and etiology of blindness and low vision and to assess the prevalence of common eye diseases in central Cambodia. Methods: In this cross-sectional, population-based study, 6,558 residents of Kandal Province, Cambodia were registered, and 5,803 (88.5%) were interviewed and examined. This house-to-house survey was conducted by a team consisting of a senior ophthalmologist, a Cambodian eye doctor, and eight Cambodian eyecare workers. Results: The prevalence of bilateral blindness (visual acuity <3/60) is 1.1% (95% confidence interval [CI], 0.9–1.4), and an additional 4.4% (95% CI, 3.9–5.0) have low vision (visual acuity < 6/18, ≥3/60 in the better eye). The major causes of bilateral blindness are cataract (67.4%), phthisis (6.1%), uncorrected refractive error (6.1%), corneal scar (5.3%), uncorrected aphakia (3.0%), trachoma corneal scar (3.0%), optic atrophy (3.0%), and others (6.1%). The major causes of low vision are uncorrected refractive error (49.8%) and cataract (42.7%). The prevalence of unilateral blindness is 1.2% (95% CI, 0.9–1.4), often caused by cataract, corneal scar, or phthisis. Trauma due to landmine explosions and war-related injuries was frequently the underlying etiology in subjects with phthisis, corneal scarring, or other pathology.Conclusions: The prevalence of blindness and low vision in Cambodia is relatively high compared to other developing countries. Most of the causes of blindness and low vision are treatable or preventable. Landmines and other war-related injuries are an important cause of ocular injury. These results will assist in developing a national plan for the prevention of blindness in Cambodia.
Aberrant Glycosylation of E-cadherin Enhances Cell-Cell Binding to Suppress Metastasis*

Introduction of the β1-4 N-acetylglucosaminyltransferase (GnT-III) gene was reported to suppress metastasis in highly metastatic B16-hm murine melanoma cells (Yoshimura, M., Nishikawa, A., Ihara, Y., Taniguchi, S., and Taniguchi, N. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 8754-8758). In this study, the effect of GnT-III gene transfer on E-cadherin was studied, since E-cadherin acts as a suppressor of metastasis. E-cadherin expression at cell-cell contacts of B16-hm cells expressing high GnT-III activity was greater than controls without affecting transcription. Lectin blotting showed that E-cadherin from GnT-III transfectants was glycosylated by ectopically expressed GnT-III. The glycosylated E-cadherin exhibited the delayed turnover and the decreased release from cell surface, as compared with the native E-cadherin, resulting in the elevated expression at the cell-cell border of GnT-III transfectants. Furthermore, cell-cell aggregation was enhanced in GnT-III transfectants, indicating that the glycosylated E-cadherin is biologically functional. These results suggest that the glycosylated E-cadherin contributes to the suppression of metastasis by the introduction of GnT-III gene into melanoma cells.
Role for NADPH/NADH Oxidase in the Modulation of Vascular Tone a

Abstract: The endothelium modulates vascular tone by producing vasodilator andvasoconstrictor substances. Of these, the best characterized and potentially most important are nitric oxide (NO•) and O2−•. These small molecules exhibit opposing effects on vascular tone and chemically react with each other in a fashion that negates their individual effects and leads to the production of potentially toxic substances, such as peroxynitrite (ONOO−). These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. The precise O2−• source within vascular tissue remains to be determined. Recent work demonstrated that in endothelial cells as well as in vascular smooth muscle cells, a membrane‐associated NAD(P)H‐dependent oxidase represents the most significant O2−• source. Interestingly, this oxidase is activated upon stimulation with angiotensin II, suggesting that under all conditions of an activated circulating and/or local renin‐angiotensin system endothelial dysfunction secondary to increased vascular O2−• production is expected.
Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort

Objective:Differences in antiretroviral distribution into the central nervous system (CNS) may impact neurocognitive status. We assessed the relationship between estimates of antiretroviral therapy penetration into the CNS, using a published ranking system, and neurocognitive status in HIV-positive participants with plasma HIV-1 RNA (vRNA) suppression. Design:Participants with at least 6 weeks ongoing antiretroviral drug use and vRNA less than 50 copies/ml (N = 2636; 83% male, median baseline CD4 T cells: 244 cells/μl) had at least one neuroscreen assessment [Trail Making Test, Part A and B; Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol] at 10 413 neurovisits. Neuroscreen test scores were demographically adjusted and converted to Z-scores (NPZ3: lower scores imply more impairment). Central nervous system penetration effectiveness (CPE) ranks of 0.0 (low), 0.5 (medium), or 1.0 (high) were assigned to antiretrovirals and summed per regimen, per neurovisit. Methods:Multivariate linear regression models using generalized estimating equations assessed NPZ3 scores with respect to antiretroviral regimen. Covariates were retained if P ≤ 0.1. Results:A final model demonstrated that better NPZ3 scores were associated with higher CPE among participants taking more than three antiretroviral drugs (+0.07 per one unit increase in CPE score; P = 0.004) but not among participants with three or less antiretroviral drugs in the regimen (+0.01; P = 0.5). Results were adjusted for demographics, injection drug use, hepatitis C virus serostatus, CD4 cell count (current and nadir), baseline vRNA, antiretroviral experience, and years since first antiretroviral drug use. Conclusion:Use of antiretroviral drugs with better estimated CNS penetration may be associated with better neurocognitive functioning; some people may require more than three antiretroviral drugs to treat HIV in the CNS. Clinically this means antiretroviral regimens could be designed to optimize estimated CNS penetration without sacrificing virologic and immunologic benefits.
Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference

Background: The function of renin angiotensin system (RAS) is gender-related, and this system affects cisplatin (CP)-induced nephrotoxicity. In this study, we compared the effect of enalapril as an angiotensin-converting enzyme (ACE) inhibitor on CP-induced nephrotoxicity between male and female rats. Materials and Methods: Sixty-two adult male and female Wistar rats were divided into eight groups. Both genders received CP (2.5 mg/kg, i.p.) and enalapril (30 mg/kg, i.p.) for 7 days in compared with CP alone or enalapril alone or vehicle alone treated groups. At the end of the experiment, blood samples were obtained, and the kidney tissue was investigated for histopathological changes. Results: CP increased the serum levels of blood urea nitrogen and creatinine as well as kidney weight and kidney tissue damage score in both genders (P < 0.05). However, not only enalapril failed to ameliorate the aforementioned parameters in both genders, but also it intensified nephrotoxicity in females (P < 0.05). In addition, enalapril enhanced body weight loss induced by CP in females (P < 0.05). CP alone decreased kidney level of nitrite in both genders (P < 0.05) and enalapril could not reverse this decreasing. The combination of enalapril and CP significantly increased serum level of nitrite in females, but this was not observed in males (P < 0.05). Conclusion: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response.
Utility of hERG Assays as Surrogate Markers of Delayed Cardiac Repolarization and QT Safety

HERG (human-ether-a-go-go-related gene) encodes for a cardiac potassium channel that plays a critical role in defining ventricular repolarization. Noncardiovascular drugs associated with a rare but potentially lethal ventricular arrhythmia (Torsades de Pointes) have been linked to delayed cardiac repolarization and block of hERG current. This brief overview will discuss the role of hERG current in cardiac electrophysiology, its involvement in drug-induced delayed repolarization, and approaches used to define drug effects on hERG current. In addition, examples of hERG blocking drugs acting differently (i.e., overt and covert hERG blockade due to multichannel block) together with the utility and limitations of hERG assays as tools to predict the risk of delayed repolarization and proarrhythmia are discussed.
Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and S6K1

Coordinating Metabolism Growth factors help to coordinate metabolism with growth in part by stimulating the activity of the protein kinase mTORC1 (mechanistic target of rapamycin complex 1). Ben-Sahra et al. (p. 1323, published online 21 February) and Robitaille et al. (p. 1320, published online 21 February) independently identified a key target of mTORC1—carbamolyl-phosphate synthase 2, or CAD, the rate-limiting enzyme for de novo synthesis of pyrimidines. Metabolomic profiling and phosphoproteomic analyses of normal cells and cells lacking signaling by mTORC1 converged on CAD as a key point at which growth-promoting signals also ramp up production of nucleic acids. In addition to its role in stimulating protein and lipid synthesis, the kinase mammalian target of rapamycin stimulates nucleotide biosynthesis. Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.
Furthering our understanding of SUDEP: the role of animal models

ABSTRACT Sudden and unexpected death in epilepsy (SUDEP) is the most common type of death among patients with epilepsy. Here, we address the importance of the experimental models in search of the mechanisms underlying SUDEP. Most studies have investigated the cardiovascular responses in animal models of epilepsy. However, there are few proposed SUDEP models in literature. Hypoventilation, apnea, respiratory distress, pulmonary hypertension, autonomic dysregulation and arrhythmia are common findings in epilepsy models. Impairments on adenosinergic and serotonergic systems, brainstem spreading depolarization, seizure-activation of neural substrates related to cardiorespiratory control, altered autonomic control, and mutations on sodium and potassium channels are hypothesis suggested. Overall, current research highlights the evident multifactorial nature of SUDEP, which involves acute and chronic aspects ranging from systemic to molecular alterations. Thus, we are convinced that elucidation and prevention of SUDEP can be achieved only through the interaction between basic and clinical science.
Longitudinal Studies Of Virulence Factors of Pseudomonas Aeruginosa in Cystic Fibrosis

&NA; Among 111 strains of Pseudomonas aeruginosa from 49 children with cystic fibrosis, duration of colonization correlated with bacterial phenotype. We confirmed that P. aeruginosa from chronically colonized patients tended to be less motile, produce lower levels of protease and elastase, to be more sensitive to normal serum and to be polyagglutinating or untypable with standard antisera. We also showed that phospholipase and heat‐stable hemolysin, concerned in metabolism of inorganic phosphate, and exotoxin A, were lower in these isolates. In longitudinal studies there was a decrease in virulence properties when isolates from the same patient were compared. No reversion from altered phenotype to ‘wild‐type’ characteristics was found.
Effects of age, step direction, and reaction condition on the ability to step quickly.

BACKGROUND The ability to take a step quickly is important for balance maintenance during activities of daily living. The purpose of this study was to investigate the effects of age, reaction condition, and step direction on the ability to take a volitional step as fast as possible. METHODS The performance of a voluntary step task was measured in young adult (mean age 20, SD 0.9 years), young-old adult (mean age 67, SD 3.7 years), and old adult (mean age 78, SD 2.3 years) healthy female participants. Each participant stepped as fast as possible in eight directions in response to a visual cue in a simple or choice reaction time condition. The effects of age, reaction condition, and step direction and their interactions on the primary outcome variables of response time, step liftoff, and step landing time were examined. RESULTS The normal aging process progressively increased the response, liftoff, and landing times. The choice reaction time condition, compared to the simple, had significantly increased response, liftoff, and landing times. Step direction significantly affected the liftoff and landing times, with lateral, diagonal, and anterior and posterioir (A-P) times increasing, respectively. CONCLUSIONS We found substantial declines in the ability to step rapidly in healthy adults as age increased. When a decision was required regarding the step direction, the step performance also declined. Step direction also significantly affected step performance. The assessment of voluntary step performance, which may be an indicator of balance ability, should include dimensions of both direction and the choice condition.
Factors affecting subject catalog search success

The study examined the effects of two variables on success in searching an academic library subject catalog that uses Library of Congress subject headings. The vari‐ables were “subject familiarity,” and “catalog familiar‐ity,” representing patron knowledge of a subject field and of the principles of the subject heading system, re‐spectively. Testing was done in a laboratory setting which reproduced a real search situation. The n varied with the particular test, but about 20 university students in each of the following majors participated: psychology, economics, librarianship. Success was measured as degree of match between search term and term used by the library for desired books on the subject. Catalog familiarity was found to have a very signifi‐cant beneficial effect on search matching success, and subject familiarity a slight, but not significant, detri‐mental effect. An interview substudy of subject experts suggested causes for the failure of subject expertise to help in catalog search term formulation. Surprising results were that overall matching success was strikingly low. Since the methodology used enabled a more precise determination of match success than has been typical of catalog use studies, it appears that people may be less successful than we have thought in using subject catalogs.
11 Kidney Manifestation of Systemic Lupus Erythematosus

Kidney disease secondary to SLE can affects up to 50% of patients with SLE and largely mediated by deposition of immune complex in the kidneys (1) (2). The clinical diagnosis of lupus nephritis is usually made following a diagnostic kidney biopsy in the presence of proteinuria and/or hematouria,positive serology,and extrarenal manifestation of SLE. The presence of kidney disease is the most important predictor of morbidity and mortality in the patients with SLE. Several demographic,serologic,and genetic risk factors are associated with an increased risk for developing kidney disease. Patient with lupus nephritis are more likely than SLE patients without kidney involvement to have a family history of SLE,anemia,high antidsDNA antibody titer,and hypocomplementemia. Children with SLE develop nephritis more frequently than adults and so do males.