Miracle-dz/UniFAR-FTUs huggingface dataset:
Paradoxical tolerance to cocaine after initial supersensitivity in drug‐use‐prone animals

There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a “drug‐use‐prone” phenotype that is defined by rapid acquisition of cocaine self‐administration. Here, we showed that response to novelty can also predict the neurochemical and behavioral effects of acute and repeated cocaine in rats. We used cocaine self‐administration under a fixed‐ratio 1 schedule followed by fast‐scan cyclic voltammetry in brain slices to measure subsecond dopamine (DA) release and uptake parameters in drug‐use‐prone and ‐resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had DA transporters that were more sensitive to cocaine‐induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self‐administration more rapidly and, after 5 days of extended access cocaine self‐administration, high‐responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self‐administration. Thus, we showed that tolerance to the cocaine‐induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.
Impact of an exergame intervention on habitual physical activity and diet in active young adults

Active video games or “exergames” (EG) may provide an effective method by which to increase physical activity (PA) levels of sedentary individuals although the energy cost is less than the real version of the sport or activities. However, if already active individuals increased their usage of EG, a resultant displacement of time spent engaged in real PA may reduce total PA derived energy expenditure. Of additional concern is the reported increase in energy intake (EI) associated with more frequent use of video games (Chaput et al., 2011. Am J Clin Nutr 93: 1196–1203). To date, no study has examined the impact of an EG intervention in already active young adults. To determine the effects of a short-term EG intervention on habitual PA and EI in active young adults. Twenty active young adults (10 males; age 21 ± 4 yrs; body mass 65.2 ± 5.9 kg) who did not regularly use EG each underwent two 5 day monitoring periods conducted in a randomised cross-over design. In one period each participant was required to complete 60 min∙day-1 of structured EG activity using a Microsoft X-box 360 Kinect and in the other they were instructed to maintain their normal PA level and diet (control). EI and PA were assessed daily during both monitoring periods using a food diary and an Actigraph GT3X+ accelerometer respectively. Time spent in each PA intensity classification was established using device software and habitual PA during the EG period was calculated by removing time spent in the EG session from the data set. Mean daily EI, PA, and habitual PA were compared between conditions using a paired t-test. EI was not different between control and EG conditions (2234 ± 278 kcal∙day-1 vs. 2193 ± 323 kcal∙day-1 respectively; P=0.22). Less time was spent engaged in sedentary behaviour during the EG period compared to the control period (391 ± 126 min∙day-1 vs. 463 ± 125 min∙day-1 respectively; P<0.001) and more time was spent engaged in moderate-vigorous PA (132 ± 36 min∙day-1 vs. 92 ± 30 min∙day-1 respectively; P<0.001). Habitual moderate-vigorous PA during the EG period (100 ± 34 min∙day-1) was not different to the control period (P=0.26). Daily use of EG augmented moderate-vigorous PA and reduced sedentary behaviour with no impact on EI in active young adults. EG therefore remains a viable option to increase PA in this population.
Synchronisation hubs in the visual cortex may arise from strong rhythmic inhibition during gamma oscillations

Neurons in the visual cortex exhibit heterogeneity in feature selectivity and the tendency to generate action potentials synchronously with other nearby neurons. By examining visual responses from cat area 17 we found that, during gamma oscillations, there was a positive correlation between each unit's sharpness of orientation tuning, strength of oscillations, and propensity towards synchronisation with other units. Using a computational model, we demonstrated that heterogeneity in the strength of rhythmic inhibitory inputs can account for the correlations between these three properties. Neurons subject to strong inhibition tend to oscillate strongly in response to both optimal and suboptimal stimuli and synchronise promiscuously with other neurons, even if they have different orientation preferences. Moreover, these strongly inhibited neurons can exhibit sharp orientation selectivity provided that the inhibition they receive is broadly tuned relative to their excitatory inputs. These results predict that the strength and orientation tuning of synaptic inhibition are heterogeneous across area 17 neurons, which could have important implications for these neurons' sensory processing capabilities. Furthermore, although our experimental recordings were conducted in the visual cortex, our model and simulation results can apply more generally to any brain region with analogous neuron types in which heterogeneity in the strength of rhythmic inhibition can arise during gamma oscillations.
Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

CONTEXT Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown. OBJECTIVE To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke. DATA SOURCES Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions. STUDY SELECTION Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events. DATA EXTRACTION The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I(2) statistic. DATA SYNTHESIS After a detailed screening of 103 articles, 17 trials enrolling 13,645 [corrected] patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 134 of 6984 [corrected] patients (1.9%) [corrected] receiving inhaled anticholinergics and 83 of 6661 [corrected] patients (1.2%) receiving control therapy (RR, 1.60 [corrected] [95% confidence interval {CI}, 1.22-2.10]; [corrected] P < .001, I(2) = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.52 [95% CI 1.04-2.22]; [corrected] P = .03, I(2) = 0%) and cardiovascular death (RR, 1.92 [95% CI, 1.23-3.00]; P = .004, [corrected] I(2) = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I(2) = 0%). All-cause mortality was reported in 146 [corrected] of the patients treated with inhaled anticholinergics (2.1%) and 108 [corrected] of the control patients (1.6%) (RR, 1.29 [95% CI, 1.00-1.65]; P = .05, I(2) = 0%) [corrected] A sensitivity analysis restricted to 6 [corrected] long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95% CI, 1.27-2.35]; [corrected] P < .001, I(2) = 0%). CONCLUSION Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.
Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

BACKGROUND Hereditary transthyretin amyloidosis is caused by pathogenic single‐nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2′‐O‐methoxyethyl–modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS We conducted an international, randomized, double‐blind, placebo‐controlled, 15‐month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, ‐22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient‐reported Norfolk Quality of Life–Diabetic Neuropathy (QOL‐DN) questionnaire (range, ‐4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least‐squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was ‐19.7 points (95% confidence interval [CI], ‐26.4 to ‐13.0; P<0.001) for the mNIS+7 and ‐11.7 points (95% CI, ‐18.3 to ‐5.1; P<0.001) for the Norfolk QOL‐DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO‐TTR ClinicalTrials.gov number, NCT01737398.)
Role of Ultrasonography (“Honeycomb Sign”) in Early Detection of Dengue Hemorrhagic Fever -

Aim: This study was conducted to evaluate the early, specific ultrasonographic (USG) findings in clinically suspected dengue hemorrhagic fever (DHF) along with its prognostic value. Methods: From May 2009 to June 2012, 20 patients were referred with high-grade fever and abdominal pain. All the patients underwent immediate abdominal USG. A specific change – “Honeycomb” pattern in the thickened gallbladder (GB) wall (mostly in the fundal area) – on USG suggested the diagnosis of DHF, which was subsequently confirmed by serology in all patients. Treatment was stated on the bases of USG findings before the positive serology report. After starting treatment the USG on the 3rd day showed reduction in GB wall thickening, which was almost cleared by the 7th day in clinically improving patients. Results: All 20 patients had type-2 dengue fever, i.e., DHF Grades I and II, as confirmed after USG by platelet count and serologic tests. USG features included a much-thickened GB wall in all the patients, but showing a “Honeycomb” pattern (proposed as Sachar and Sunder’s sign) in 19 patients (95%), multilayered (laminated/onion peel) in 1 patient (5%), ascites in 15 patients (75%), splenomegaly in 8 patients (40%), and pleural effusion in 14 patients (70%). (Pleural effusion was either right-sided or bilateral, but never alone on the left side.) Conclusions: Abdominal emergency USG can be used as a first-line imaging modality in patients with suspected DHF to detect early signs that are suggestive of the disease prior to obtaining serologic confirmation test results, especially in a dengue fever epidemic area. Also, reducing GB wall thickness can be used as a prognostic sign in cases of DHF.
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma

BACKGROUND Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double‐blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression‐free survival and the objective response rate. RESULTS At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression‐free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high‐grade events were palmar–plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). CONCLUSIONS Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression‐free survival than placebo. The rate of high‐grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426.)
Long‐term depression of synaptic transmission in the adult mouse insular cortex in vitro

The insular cortex (IC) is known to play important roles in higher brain functions such as memory and pain. Activity‐dependent long‐term depression (LTD) is a major form of synaptic plasticity related to memory and chronic pain. Previous studies of LTD have mainly focused on the hippocampus, and no study in the IC has been reported. In this study, using a 64‐channel recording system, we show for the first time that repetitive low‐frequency stimulation (LFS) can elicit frequency‐dependent LTD of glutamate receptor‐mediated excitatory synaptic transmission in both superficial and deep layers of the IC of adult mice. The induction of LTD in the IC required activation of the N‐methyl‐d‐aspartate (NMDA) receptor, metabotropic glutamate receptor (mGluR)5, and L‐type voltage‐gated calcium channel. Protein phosphatase 1/2A and endocannabinoid signaling are also critical for the induction of LTD. In contrast, inhibiting protein kinase C, protein kinase A, protein kinase Mζ or calcium/calmodulin‐dependent protein kinase II did not affect LFS‐evoked LTD in the IC. Bath application of the group I mGluR agonist (RS)‐3,5‐dihydroxyphenylglycine produced another form of LTD in the IC, which was NMDA receptor‐independent and could not be occluded by LFS‐induced LTD. Our studies have characterised the basic mechanisms of LTD in the IC at the network level, and suggest that two different forms of LTD may co‐exist in the same population of IC synapses.
Functional integrity of the habenula is necessary for social play behaviour in rats

During post‐weaning development, a marked increase in peer–peer interactions is observed in mammals, including humans, which is signified by the abundance of social play behaviour. Social play is highly rewarding, and known to be modulated through monoaminergic neurotransmission. Recently, the habenula has received widespread attention because of its role in the regulation of monoaminergic neurotransmission as well as in a variety of emotional and cognitive functions. Therefore, in the present study, we investigated the involvement of the habenula in social play behaviour. Using the neuronal activity maker c‐fos, we showed that the habenula was activated after 24 h of social isolation in adolescent rats, and that a subsequent social play interaction reduced c‐fos activity in the medial part of the lateral habenula. This suggested that habenula activity modulated the aversive properties of social isolation, which was alleviated by the positive effects of social play. Furthermore, after functional inactivation of the habenula, using a mixture of the GABA receptor agonists baclofen and muscimol, social play behaviour was markedly reduced, whereby responsiveness to play solicitation was more sensitive to habenula inactivation than play solicitation itself. Together, our data indicate an important role for the habenula in the processing of positive (i.e. social play behaviour) and negative (i.e. social isolation) social information in adolescent rats. Altered habenula function might therefore be related to the social impairments in childhood and adolescent psychiatric disorders such as autism, attention deficit/hyperactivity disorder and early‐onset schizophrenia.
Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy

&NA; JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo–expanded, partially HLA‐matched, third‐party–produced, cryopreserved BK virus–specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord‐blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T‐cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor‐derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698.)
Procalcitonin‐Guided Use of Antibiotics for Lower Respiratory Tract Infection

BACKGROUND The effect of procalcitonin‐guided use of antibiotics on treatment for suspected lower respiratory tract infection is unclear. METHODS In 14 U.S. hospitals with high adherence to quality measures for the treatment of pneumonia, we provided guidance for clinicians about national clinical practice recommendations for the treatment of lower respiratory tract infections and the interpretation of procalcitonin assays. We then randomly assigned patients who presented to the emergency department with a suspected lower respiratory tract infection and for whom the treating physician was uncertain whether antibiotic therapy was indicated to one of two groups: the procalcitonin group, in which the treating clinicians were provided with real‐time initial (and serial, if the patient was hospitalized) procalcitonin assay results and an antibiotic use guideline with graded recommendations based on four tiers of procalcitonin levels, or the usual‐care group. We hypothesized that within 30 days after enrollment the total antibiotic‐days would be lower — and the percentage of patients with adverse outcomes would not be more than 4.5 percentage points higher — in the procalcitonin group than in the usual‐care group. RESULTS A total of 1656 patients were included in the final analysis cohort (826 randomly assigned to the procalcitonin group and 830 to the usual‐care group), of whom 782 (47.2%) were hospitalized and 984 (59.4%) received antibiotics within 30 days. The treating clinician received procalcitonin assay results for 792 of 826 patients (95.9%) in the procalcitonin group (median time from sample collection to assay result, 77 minutes) and for 18 of 830 patients (2.2%) in the usual‐care group. In both groups, the procalcitonin‐level tier was associated with the decision to prescribe antibiotics in the emergency department. There was no significant difference between the procalcitonin group and the usual‐care group in antibiotic‐days (mean, 4.2 and 4.3 days, respectively; difference, ‐0.05 day; 95% confidence interval [CI], ‐0.6 to 0.5; P=0.87) or the proportion of patients with adverse outcomes (11.7% [96 patients] and 13.1% [109 patients]; difference, ‐1.5 percentage points; 95% CI, ‐4.6 to 1.7; P<0.001 for noninferiority) within 30 days. CONCLUSIONS The provision of procalcitonin assay results, along with instructions on their interpretation, to emergency department and hospital‐based clinicians did not result in less use of antibiotics than did usual care among patients with suspected lower respiratory tract infection. (Funded by the National Institute of General Medical Sciences; ProACT ClinicalTrials.gov number, NCT02130986.)