Miracle-dz/UniFAR-FTUs huggingface dataset:
Emergence of new oral antithrombotics: a critical appraisal of their clinical potential

In Western countries, venous thromboembolism (VTE) is a widespread and serious disorder, with hospital admission rates that appear to be increasing. Current anticoagulant therapies available for the prevention and treatment of VTE have several drawbacks that make them either difficult to manage effectively, due to a need for careful monitoring to control coagulation, or, in the case of parenterally administered agents, inconvenient for long-term use. To address some of these issues, new anticoagulants are in clinical development that can be orally administered and directly target specific factors in the coagulation cascade. This article reviews the rationale behind development of these novel agents and provides a critical appraisal of their clinical potential. In addition, the impact that the introduction of such agents into clinical practice would have is discussed from the patient perspective.
DELAYED HYPERSENSITIVITY TO HAPTEN-PROTEIN CONJUGATES

Further data have been presented showing that the specificity of the delayed hypersensitivity reaction in the guinea pig to hapten-protein conjugates involves to a considerable degree a contribution by the protein carrier. The carrier contribution is such that sensitization to guinea pig albumin-m-azobenzenesulfonate, for example, does not result in cross-reaction with conjugates of the same hapten with unrelated proteins such as ovalbumin or human gamma globulin, nor were cross-reactions observed between conjugates prepared with the same hapten, coupled to the same protein, but by two different chemical routes, such that the point of attachment of the hapten to the protein differed. It thus appears that in this system both hapten and carrier protein are necessary, but that neither alone is in general sufficient to stimulate the delayed sensitive cell. Desensitization experiments with cross-reacting hapten-protein conjugates have suggested the presence of a multiplicity of antigenic determinants participating in the elicitation of the delayed lesion, and of a concomitant development of a heterogeneity of specificities in the population of delayed sensitive cells in the sensitized animal. The data are discussed in terms of the apparent requirement of the delayed sensitivity mechanism for a larger functional antigenic determinant than that required for interaction with circulating antibodies. Some possible explanations for this difference, and some of its consequences, are discussed.
Concentration dependent cardiotoxicity of terodiline in patients treated for urinary incontinence.

OBJECTIVE--Terodiline, an antimuscarinic and calcium antagonist drug, was used to treat detrusor instability but was withdrawn in 1991 after provoking serious ventricular arrhythmias associated with increases in the corrected QT interval (QTc). This research was performed to relate drug induced electrocardiographic changes in asymptomatic recipients to plasma concentrations of the R(+) and S(-) terodiline enantiomers. SETTING--Urological and geriatric clinics and wards. SUBJECTS--Asymptomatic patients taking terodiline in stable dose. METHODS--Electrocardiograms (50 mm/s) were collected from patients while they were taking terodiline and compared with ECGs obtained before or after terodiline. QT interval, heart rate corrected QT interval (QTc), and QT dispersion (QTd) were measured. Drug induced electrocardiographic changes were related to plasma concentrations of R(+) and S(-) terodiline. RESULTS--During terodiline treatment mean QTc and QTd were prolonged (491(43) and 84 (35) ms 1/2) compared with measurements made off therapy (443 (33) and 42 (17) ms 1/2, paired t tests, P < 0.002 and P < 0.01 respectively) in the 12 patients in sinus rhythm. The mean (95% confidence interval) drug induced increases were 48 (23 to 74) ms 1/2 for QTc and 42 (13 to 70) ms 1/2 for QTd. These increases correlated with total plasma terodiline (QTc: r = 0.77, P < 0.006, QTd: r = 0.68, P < 0.025) and with plasma concentrations of both terodiline enantiomers. CONCLUSIONS--Terodiline increases QTc and QTd in a concentration dependent manner. It is not clear whether this is a stereoselective effect and, if so, which enantiomer is responsible. The results suggest that drug induced torsade de pointes is a type A (concentration dependent) adverse drug reaction.
Intracellular formation of ”undisruptable” dimers of inducible nitric oxide synthase

Overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathogenesis of many diseases. iNOS is active only as a homodimer. Dimerization of iNOS represents a potentially critical target for therapeutic intervention. In this study, we show that intracellular iNOS forms dimers that are ”undisruptable” by boiling, denaturants, or reducing agents. Undisruptable (UD) dimers are clearly distinguishable from the easily dissociated dimers formed by iNOS in vitro. UD dimers do not form in Escherichia coli-expressed iNOS and could not be assembled in vitro, which suggests that an in vivo cellular process is required for their formation. iNOS UD dimers are not affected by intracellular depletion of H4B. However, the mutation of Cys-115 (critical for zinc binding) greatly affects the formation of UD dimers. This study reveals insight into the mechanisms of in vivo iNOS dimer formation. UD dimers represent a class of iNOS dimers that had not been suspected. This unanticipated finding revises our understanding of the mechanisms of iNOS dimerization and lays the groundwork for future studies aimed at modulating iNOS activity in vivo.
Suppressive effect of dietary raffinose on T-helper 2 cell-mediated immunity

The effects of the dietary oligosaccharide raffinose on immune responses, with special reference to its anti-allergic functions, were examined in vivo. First, feeding a diet supplemented with 50 g raffinose/kg to BALB/c mice significantly (P<0·05) increased interleukin (IL) 12 secretion from isolated Peyer's patch (PP) cells in vitro compared with feeding control diet. When isolated PP cells were used as antigen-presenting cells (APC) for CD4+ T-splenocytes isolated from ovalbumin (OVA)-specific T-cell receptor transgenic (Tg) mice in the presence of OVA as antigen, significantly (P<0·05) higher levels of interferon-γ were observed in the cultures using APC from raffinose-fed mice than those cultures using APC from control mice. Second, the diet containing 50 g raffinose/kg or control diet was fed to OVA Tg mice, and subsequently, OVA was added to each diet to prime T cells in vivo. CD4+ T-cells from the mesenteric lymph nodes of the raffinose-fed mice secreted significantly (P<0·05) higher levels of IL-2 and significantly (P<0·05) lower levels of IL-4 following in vitro antigenic stimulation compared with those of the control mice. These present results suggest that feeding raffinose may suppress differentiation of naïve T-helper (Th) cells into Th2 cells in the mesenteric lymphoid nodes. Last, feeding raffinose suppressed rises of serum immunoglobulin E levels in the Tg mice treated with long-term ingestion of OVA. In conclusion, it is suggested that dietary raffinose suppresses serum immunoglobulin E response through suppression of Th2-type immune response against oral antigen in the lymphoid organs located in or near the intestine.
Heat shock-triggered Ca2+ mobilization accompanied by pectin methylesterase activity and cytosolic Ca2+ oscillation are crucial for plant thermotolerance

Apoplastic Ca2+ concentration controls membrane permeability, cell wall stabilization, and cell integrity; however, little is known about its role in thermotolerance in plants. Here, we report that the acquired thermotolerance of etiolated rice seedlings (Oryza sativa) was abolished by an exogenously supplied Ca2+ chelator, EGTA, related to increased cellular content leakage during heat shock (HS) treatment. Thermotolerance was restored by the addition of Ca2+ during EGTA incubation. Pectin methylesterase (EC 3.1.1.11), a cell-wall remodeling enzyme, was activated in response to HS, and its elevated activity was related to the recovery of the HS-released Ca2+ concentration. EGTA interfered with the capability of HS to increase oscillation of [Ca2+]cyt content. We assume that heat-activated PME activity is involved in cell-wall-localized Ca2+. The removal of apoplastic Ca2+ might participate in HS signaling to induce HS protein expression and cell-wall remodeling to retain plasma membrane integrity, prevent cellular content leakage and confer thermoprotection.
No effect of odor-induced memory reactivation during REM sleep on declarative memory stability

Memory reactivations in hippocampal brain areas are critically involved in memory consolidation processes during sleep. In particular, specific firing patterns of hippocampal place cells observed during learning are replayed during subsequent sleep and rest in rodents. In humans, experimentally inducing hippocampal memory reactivations during slow-wave sleep (but not during wakefulness) benefits consolidation and immediately stabilizes declarative memories against future interference. Importantly, spontaneous hippocampal replay activity can also be observed during rapid eye movement (REM) sleep and some authors have suggested that replay during REM sleep is related to processes of memory consolidation. However, the functional role of reactivations during REM sleep for memory stability is still unclear. Here, we reactivated memories during REM sleep and examined its consequences for the stability of declarative memories. After 3 h of early, slow-wave sleep (SWS) rich sleep, 16 healthy young adults learned a 2-D object location task in the presence of a contextual odor. During subsequent REM sleep, participants were either re-exposed to the odor or to an odorless vehicle, in a counterbalanced within subject design. Reactivation was followed by an interference learning task to probe memory stability after awakening. We show that odor-induced memory reactivation during REM sleep does not stabilize memories against future interference. We propose that the beneficial effect of reactivation during sleep on memory stability might be critically linked to processes characterizing SWS including, e.g., slow oscillatory activity, sleep spindles, or low cholinergic tone, which are required for a successful redistribution of memories from medial temporal lobe regions to neocortical long-term stores.
Sequence-dependent base pair stepping dynamics in XPD helicase unwinding

Helicases couple the chemical energy of ATP hydrolysis to directional translocation along nucleic acids and transient duplex separation. Understanding helicase mechanism requires that the basic physicochemical process of base pair separation be understood. This necessitates monitoring helicase activity directly, at high spatio-temporal resolution. Using optical tweezers with single base pair (bp) resolution, we analyzed DNA unwinding by XPD helicase, a Superfamily 2 (SF2) DNA helicase involved in DNA repair and transcription initiation. We show that monomeric XPD unwinds duplex DNA in 1-bp steps, yet exhibits frequent backsteps and undergoes conformational transitions manifested in 5-bp backward and forward steps. Quantifying the sequence dependence of XPD stepping dynamics with near base pair resolution, we provide the strongest and most direct evidence thus far that forward, single-base pair stepping of a helicase utilizes the spontaneous opening of the duplex. The proposed unwinding mechanism may be a universal feature of DNA helicases that move along DNA phosphodiester backbones. DOI: http://dx.doi. org/10.7554/eLife.00334. 001
Colposcopic accuracy in a residency training program: defining competency and proficiency.

BACKGROUND The determination of proficiency in procedural skills has evoked keen interest, but meaningful guidelines are limited by the absence of pertinent clinical data. Colposcopic accuracy is defined as the clinical correlation between a colposcopic impression and a histologic report. The colposcopic accuracy of physicians in a university-based family practice residency colposcopy program was evaluated. METHODS Demographic information, clinical findings, and laboratory results of patients evaluated by colposcopy were prospectively recorded. Colposcopic accuracy was calculated based on the agreement of the colposcopic impression with the histologic interpretation within one histologic grade. RESULTS Colposcopic examinations were performed on 282 patients. Histologic evidence of premalignant cervical disease was identified in 115 patients as follows: mild dysplasia, 72; moderate dysplasia, 24; and severe dysplasia, 19. The colposcopic impression agreed within one histologic grade in 188 of 205 patients for a colposcopic accuracy rate of 91.7% (95% CI = 87.1% to 95.1%). CONCLUSIONS Given an acceptable latitude of clinical correlation between the colposcopic impression and histologic interpretation, the colposcopic accuracy of family physicians compared favorably with that reported by other colposcopists. The more common colposcopic errors were overestimation of low-grade disease and underestimation of high-grade disease. Colposcopic accuracy at an essential minimal proficiency level of 80% should form the basis for assessing specialized perceptual ability and therefore determining colposcopic competency.
Increasing Pro-Environmental Behaviors by Increasing Self-Concordance: Testing an Intervention

Globally, there is a clear need to change our behavior to mitigate climate change. Many people, however, will not find the need for mitigation important enough to make their behavior more environmentally sustainable. Three studies supported the hypothesis that it is possible to overcome this issue by connecting these behaviors to goals that are important to people, even if such goals are unrelated to climate change or the environment in general. Study 1 (N = 305 working adults) showed that stronger self-concordance of behavior related to energy sustainability was related to a greater chance of signing a petition for increasing renewable energy sources. Next, 2 experimental studies (Study 2: N = 412 working and nonworking adults, and Study 3: N = 300 working adults) showed that increasing self-concordance of environmentally sustainable behaviors by asking people to cognitively connect either sustainable energy use (Study 2) or commuting behaviors (Study 3) to their personal goals increased intentions to engage in these behaviors compared to a control condition (Study 2 and Study 3) and compared to persuasion attempts based on climate change mitigation (Study 3). These findings occurred even after controlling for political orientation and environmental concerns. This research has significant practical implications for workplaces, particularly for those in which employees or managers place a low priority on environmental and climate change considerations.
Perceptions of Private Medical Practitioners on Tuberculosis Notification: A Study from Chennai, South India

Background The Government of India declared TB as a notifiable disease in 2012. There is a paucity of information on the government's mandatory TB notification order from the perspective of private medical practitioners (PPs). Objective To understand the awareness, perception and barriers on TB notification among PPs in Chennai, India. Methods Total of 190 PPs were approached in their clinics by trained field staff who collected data using a semi-structured and pre-coded questionnaire after getting informed consent. The data collected included PPs' specialization, TB management practices, awareness about the TB notification order, barriers in its implementation and their suggestions to improve notification. Results Of 190 PPs from varied specializations, 138 (73%) had diagnosed TB cases in the prior three months, of whom 78% referred these patients to government facilities. Of 138 PPs, 73% were aware of the order on mandatory TB notification, of whom 46 (33%) had ever notified a TB case. Of 120 PPs, 63% reported reasons for not notifying TB cases. The main reasons reported for not notifying were lack of time (50%), concerns regarding patients' confidentiality (24%) and fear of offending patients (11%). Of 145 PPs, 76% provided feedback about information they felt uncomfortable reporting during notification. PPs felt most uncomfortable reporting patient's government-issued Aadhar number (77%), followed by patient's phone number (37%) and residential address (26%). The preferred means of notification was through mobile phone communication (24%), SMS (18%) and e-mail (17%). Conclusion This study highlights that one-fourth of PPs were not aware of the TB notification order and not all those who were aware were notifying. While it is important to sensitize PPs on the importance of TB notification it is also important to understand the barriers faced by PPs and to make the process user-friendly in order to increase TB notification.
Leucine-Rich Repeat Kinase 2 Is Associated With the Endoplasmic Reticulum in Dopaminergic Neurons and Accumulates in the Core of Lewy Bodies in Parkinson Disease

Mutation of the leucine-rich repeat kinase 2 (LRRK2) gene is the most frequent genetic cause of Parkinson disease (PD). To understand the role of LRRK2 in the neuropathology of PD, we investigated the protein expression in a healthy brain and brains from patients with PD and its subcellular localization in dopaminergic neurons. LRRK2 was found to be widely expressed in healthy adult brain, including areas involved in PD. By double fluorescent staining, we found that endogenous LRRK2 is colocalized with the endoplasmic reticulum (ER) markers Neurotrace and KDEL in human dopaminergic neurons. Labeling of brain sections with anti-LRRK2 and anti-&agr;-synuclein antibodies revealed localization of LRRK2 in the core of 24% of Lewybodies (LBs) in the substantia nigra and 11% of LBs in the locuscoeruleus in idiopathic PD patients. The percentage was increased to 50% in both areas in a patient with the G2019S LRRK2 mutation. The finding of ER localization suggests the possibility that LRRK2 is involved in the ER stress response and could account for the susceptibility to neuronal degeneration of LRRK2 mutation carriers. The localization of LRRK2 protein in the core of a subset of LBsdemonstrates the contribution of LRRK2 to LB formation and diseasepathogenesis.
Evaluation of Different Management Modules for Leaf Curl Disease of Chilli in Kymore Plateau and Satpura Hill Zone of Madhya Pradesh, India

Chilli (Capsicum annum L.) is an important cash crop of India. Besides traditional use of chilli as vegetables, spices, condiments, sauces and pickles, it is also used in pharmaceuticals, cosmetic and beverages (Tiwari et al., 2005). Chilli has very excellent nutritive value especially for vitamin A and C. Each 100 gram chilli contains 160 calorie energy, 36 gram carbohydrates, 16 gram proteins, 480 milligram fat, 3.1 mg calcium, 640 IU vitamin A and 40 mg vitamin C (Narayanan et al., 1999). The major chilli producing countries in the world are China, Turkey, Mexico, Spain, USA, Indonesia, Nigeria, Egypt, Korea, Italy and India. In India chillies are grown in 794.1 million ha area with 1304.4 million tonnes production and 1643 Kg/ha green chilli yield during 2012-13. Madhya Pradesh is one of the International Journal of Current Microbiology and Applied Sciences ISSN: 2319-7706 Volume 7 Number 01 (2018) Journal homepage: http://www.ijcmas. com
Improving automatic music genre classification with hybrid content-based feature vectors

Current research on the task of automatic music genre classification has been focusing on new classification approaches based on combining information from other sources than the music signal. The reason for this is that the use of content-based approaches, i.e. using features extracted directly from the audio signal, seems to have reached a glass ceiling. In this work we show that by using different types of content-based features together it is possible to substantially improve the classification accuracy. This is an interesting result as different types of content-based features aim, at a conceptual level, to capture the same type of information. In order to identify which types of content-based features are responsible for the predictive accuracy gain, we also used a feature selection (FS) approach based on a genetic algorithm (GA). The analysis of the results in two databases shows that the use of the GA for FS succeeds in selecting a representative subset without significant loss in accuracy. It also shows that all the different types of content-based features employed are important for the improvement of the accuracy in classifying music genres.
Effects of Acetabular Rim Trimming on Hip Joint Contact Pressures

Background: In patients with femoroacetabular impingement (FAI), acetabular rim trimming removes the offending area of the acetabular deformity in patients with pincer-type and mixed-type FAI to improve hip joint kinematics. Although the rationale for arthroscopic acetabular rim trimming in patients with FAI is well established, the amount of rim resection has not been quantified, and the threshold at which excessive rim resection results in abnormal hip contact pressures has not been described. Purpose: To investigate the changes in contact areas, contact pressures, and peak forces within the hip joint with sequential acetabular rim trimming. Study Design: Controlled laboratory study. Methods: Six fresh-frozen, nondysplastic, human cadaveric hemipelvises were analyzed utilizing thin-film piezoresistive load sensors to measure the contact area, contact pressure, and peak force after anterosuperior acetabular rim trimming at depths of 0 mm (intact), 2 mm, 4 mm, 6 mm, and 8 mm. Each specimen was examined at 20° of extension and 60° of flexion. Analysis was performed on 2 regions of interest: the acetabular rim and the acetabular base (deep part of the acetabulum). After each experimental condition, the acetabulum was normalized with respect to the intact state to account for specimen variability. Statistical analysis was conducted through 1-way analysis of variance with post hoc Games-Howell tests. Results: At the acetabular base, there were significant increases in the contact area after 4-mm resection (60°: 169.12% ± 30.64%; P = .0138), contact pressure after 6-mm resection (60°: 292.76% ± 79.07%; P = .009), and peak force after 6-mm resection (60°: 166.00% ± 34.40%; P = .027). At the acetabular rim, there were significant decreases in the contact area after 6-mm resection (60°: 66.32% ± 18.80%; P = .0354) (20°: 65.47% ± 15.87%; P = .0127), contact pressure after 6-mm resection (60°: 50.77% ± 11.49%; P < .001) (20°: 58.01% ± 23.10%; P = .0335), and peak force after 6-mm resection (60°: 60.67% ± 9.29%; P < .001) (20°: 74.44% ± 9.84%; P = .007). Conclusion: Resecting more than 4 to 6 mm of the acetabular rim during hip arthroscopic surgery to address a pincer deformity may dramatically increase contact pressures by 3-fold at the acetabular base. The study suggests that excessive rim resection may lead to increased loads in the hip joint and may predispose to premature joint degeneration. Clinical Relevance: Resecting more than 4 to 6 mm of the acetabular rim may significantly alter hip joint biomechanics, increasing joint reactive forces and subsequent chondrolabral degeneration.