Miracle-dz/UniFAR-FTUs huggingface dataset:
PRECLINICAL STUDY: Stimulation of 5‐HT1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

Paradoxically, stimulation of 5‐HT1B receptors (5‐HT1BRs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5‐HT1BR agonist, CP94253, on cocaine reinforcement and cocaine‐primed reinstatement, predicting that CP94253 would enhance cocaine‐seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self‐administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine‐seeking behavior (operant responses without cocaine reinforcement). Next, they were pre‐treated with CP94253 (3–10 mg/kg, s.c.) and either tested for cocaine‐primed (10 or 2.5 mg/kg, i.p.) or cue‐elicited reinstatement of extinguished cocaine‐seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self‐administered cocaine doses (0–1.5 mg/kg, i.v.) were examined. Cocaine dose‐dependently reinstated cocaine‐seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue‐elicited reinstatement. In contrast, CP94253 shifted the self‐administration dose‐effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine‐seeking behavior). In subsequent control experiments, CP94253 decreased open‐arm exploration in an elevated plus‐maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5‐HT1BRs produces opposite effects on cocaine reinforcement and cocaine‐seeking behavior, and further suggest that 5‐HT1BRs may be a novel target for developing medications for cocaine dependence.
Portopulmonary Hypertension in Liver Disease Presenting in Childhood

Objective: Portopulmonary hypertension (POPH) is a known complication of cirrhosis in adults, but there is little information on its incidence and outcome in children with liver disease. We report 14 patients with POPH and present a synthesis of the medical literature. Methods: Diagnosis of POPH in the 14 patients was based on right-sided heart catheterization displaying mean pulmonary artery pressure (mPAP) >25 mmHg, indexed pulmonary vascular resistances >3 Wood units · m2, and pulmonary wedge pressure <15 mmHg. A literature review added 84 patients. Results: In our unit, POPH was found in 0.5% of the children with portal hypertension, 0.9% of the children with end-stage liver disease awaiting transplantation, and 3 children with congenital portosystemic shunts (CPSSs). Analysis of 98 reported patients, including the 14 presented here, showed the cause of liver disease to be chronic liver disease or portal cavernoma in 76 instances (34 with a history of surgical portosystemic shunt) and CPSS in 22 instances. There was a precession with proven hypoxemia caused by hepatopulmonary syndrome in 6 patients. Median survival was 3 months in 56 untreated patients. An 80% 5-year probability of survival in 42 patients was treated by CPSS closure, pulmonary vasodilators, and/or liver transplantation. Mean pretransplant mPAP was 34 and 49 mmHg in transplant survivors and nonsurvivors, respectively. Conclusions: POPH is a rare but extremely severe complication of childhood liver disease. Portosystemic shunts, whether congenital or acquired, likely play an important causative role. Early diagnosis is crucial and requires systematic screening by echocardiography in children at risk.
PTEN-deficient cancers depend on PIK3CB

Deregulation of the PI3K signaling pathway is observed in many human cancers and occurs most frequently through loss of PTEN phosphatase tumor suppressor function or through somatic activating mutations in the Class IA PI3K, PIK3CA. Tumors harboring activated p110α, the protein product of PIK3CA, require p110α activity for growth and survival and hence are expected to be responsive to inhibitors of its lipid kinase activity. Whether PTEN-deficient cancers similarly depend on p110α activity to sustain activation of the PI3K pathway has been unclear. In this study, we used a single-vector lentiviral inducible shRNA system to selectively inactivate the three Class IA PI3Ks, PIK3CA, PIK3CB, and PIK3CD, to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of PIK3CA in colorectal cancer cells harboring mutations in PIK3CA inhibited downstream PI3K signaling and cell growth. Surprisingly, PIK3CA depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the PIK3CB isoform, which encodes p110β, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and in vivo settings. This essential function of PIK3CB in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110α activation is required to sustain the proliferation of established PIK3CA-mutant tumors, PTEN-deficient tumors are dependent instead on p110β signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response.
Intracellular immunoglobulins

Formalin fixation followed by routine paraffin embedding allows the demonstration of intracellular immunoglobulin by a sandwich technique using either peroxidase or fluorescein isothyocyanate labelled antibody conjugates. The results compared favourably with those obtained using either the fresh frozen or the Sainte-Marie method for preserving tissue immunoglobulins. The formalin-paraffin method with peroxidase-labelled antibody has advantages for routine use. Morphology is excellent, preparations are permanent, and retrospective studies of stored paraffin-embedded tissue are possible. Some of the problems of labelled antibody studies are discussed.
Incidence of post‐stroke depression during the first year in a large unselected stroke population determined using a valid standardized rating scale

This study describes the development of post‐stroke depression (PSD) prospectively during the first year post‐stroke in 285 unselected stroke patients. An appropriate unselected population‐based control group without cerebral pathology is included for comparison. Psychiatric assessment with the Hamilton Depression Rating Scale (HDRS) was undertaken unmodified. PSD was defined as HDRS ≥ 13. The one‐year incidence of PSD among the 209 survivors able to communicate reliably at 1 month was 41%. Most cases develop within the first months following stroke (79%), the frequency of new cases of PSD at one year being 5%, a level comparable to that in the control group. Depressed and nondepressed stroke patients consistently scored 4 points greater on total HDRS than in the corresponding controls.
Absence of respiratory effects with ivabradine in patients with asthma.

AIM beta-Blockers are commonly prescribed for stable angina and are recommended as initial therapy. However, beta-blockers are contraindicated in patients with obstructive airway disease because of a risk of bronchoconstriction. Ivabradine is a specific heart rate-lowering agent that acts via I(f) pacemaker channels in the sinoatrial node with no beta-adrenoreceptor activity. Ivabradine has been recently approved for the treatment of stable angina. This study assessed the effects of repeated administration of ivabradine on lung function in patients with asthma. METHODS In this double-blind, placebo-controlled, crossover study, 20 subjects with asthma received either oral ivabradine 10 mg b.i. d. or placebo for 4.5 days. Forced expiratory volume in 1 s (FEV(1)) and peak expiratory flow rate (PEFR) were designated as the main outcome variable. Diary cards were used to monitor asthma symptoms on a five-point scale, rescue medication usage, and adverse events. RESULTS There were no significant differences in mean variation of FEV(1) (ivabradine P = 0.664; placebo P = 0.652) or PEFR (ivabradine P = 0.153; placebo P = 0.356) from baseline following administration of ivabradine. There was also no significant difference in maximum percent variation in FEV(1) or PEF between treatment groups (P = 0.994; FEV(1) and P = 0.704; PEF). On a similar note, there was no significant difference in asthma symptoms or rescue medication usage reported between the two groups. Adverse events were generally mild-to-moderate in intensity and no cardiovascular or serious adverse events were recorded. CONCLUSIONS This study confirms that ivabradine does not affect respiratory function or symptoms in patients with asthma and therefore represents a valuable therapeutic alternative to beta-blockers for treating patients with stable angina and asthma.
Trends in the management of registered sexual offenders across England and Wales: a geographical approach to the study of sexual offending

Abstract Social scientists, and geographers in particular, have long been interested in examining spatial patterns of offending in order to generate a “geography” of crime and criminality. This paper examines what value, if any, a geographical approach to the study of sexual offending might offer. Utilising published official data from England and Wales it presents for the first time geographical analyses of the registration, risk assessment and management of Registered Sexual Offenders (RSOs) across 42 Multi-Agency Public Protection Arrangement (MAPPA) areas. In doing so it considers and evaluates the methodological issues pertaining to the use of such data and such a geographical approach. We conclude that geographical interpretations of both the incidence of RSOs and the rates of risk allocations between MAPPA areas provide valuable insights and raise new questions about the way in which RSOs are managed nationally and are thus worthy of further exploration.
Acclimation to different thermal conditions in a northerly wintering shorebird is driven by body mass-related changes in organ size

SUMMARY Seasonal acclimatization and experimental acclimation to cold in birds typically results from increased shivering endurance and elevated thermogenic capacity leading to improved resistance to cold. A wide array of physiological adjustments, ranging from biochemical transformations to organ mass variations, are involved in this process. Several studies have shown that improved cold endurance is accompanied by increases in summit metabolic rate (Msum), a measure of maximal heat production and an indicator of the level of sustainable thermogenic capacity. However, improved endurance to cold can also be achieved without significant changes in Msum. The same is true for basal metabolic rate (BMR), which is known to increase in association with cold acclimatization or acclimation in some species but not in others. We investigated cold acclimation in a migrant shorebird known for extreme physiological flexibility, the red knot (Calidris canutus, the northerly wintering subspecies islandica). We measured BMR and Msum over two months in birds caught in the wild and transferred to experimentally controlled conditions representative of aspects of their seasonal thermal environment (two groups at constant 25°C, one group at constant 4°C and two groups experiencing variable outdoor temperatures). Birds maintained in both cold and variable ambient temperatures showed a 14-15% higher body mass, 33-45% higher food intake, and 26% and 13% elevations in BMR and Msum, respectively, compared with birds kept at thermoneutrality. These results, together with data on alimentary tract size and pectoral muscle thickness measured by ultrasonography, suggest that red knots acclimate to cold primarily through modulation of (lean) body mass components. Heavier individuals have larger muscles, which allow higher maximal heat production and better thermal compensation. Cold acclimation effects on BMR are most probably due to changes in the size of visceral organs, although not the alimentary tract in this specific case. The liver, known for its thermogenic capacity, is a probable candidate. Overall, our results indicate that relatively small changes in body mass and muscle size allow enough reserve capacity in terms of heat production to cope with typical wintering ambient temperature variations as measured on the red knot's wintering grounds.
Association of angiotensinogen gene M235T and angiotensin-converting enzyme gene I/D polymorphisms with essential hypertension in Han Chinese population: a meta-analysis

Background The polymorphisms of angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes have been linked to increased risk of essential hypertension in multiple populations, but the results were inconsistent. Objectives and methods To evaluate the associations of these polymorphisms with essential hypertension, we carried out a meta-analysis of the association studies within Han Chinese population. In this study, we reviewed two most commonly investigated polymorphisms, AGT M235T and ACE I/D, and provided summary estimates regarding their associations with essential hypertension. PubMed and China Biological Medicine Database were searched, and a total of 71 studies (31 studies for AGT M235T and 40 studies for ACE I/D) comprising 10 547 essential hypertension patients and 9217 controls from 23 provinces and special districts in China were finally included in this study. Results Statistically significant associations with essential hypertension were identified for TT genotype of AGT M235T polymorphism (odds ratio 1.54, 95% confidence interval 1.16–2.03, P = 0.002) and DD genotype of ACE I/D polymorphism (odds ratio 1.61, 95% confidence interval 1.32–1.98, P < 0.0001). Under dominant, recessive, and additive genetic models, positive associations were also found. The heterogeneity existed among the studies (P < 0.05), whereas the publication bias did not exist in both AGT analysis (P = 0.052) and ACE analysis (P = 0.103). Conclusion The present meta-analysis suggests that AGT M235T and ACE I/D modulate the risk of essential hypertension in Han Chinese population.
Occipital Alpha and Gamma Oscillations Support Complementary Mechanisms for Processing Stimulus Value Associations

Selective attention is reflected neurally in changes in the power of posterior neural oscillations in the alpha (8–12 Hz) and gamma (40–100 Hz) bands. Although a neural mechanism that allows relevant information to be selectively processed has its advantages, it may lead to lucrative or dangerous information going unnoticed. Neural systems are also in place for processing rewarding and punishing information. Here, we examine the interaction between selective attention (left vs. right) and stimulus's learned value associations (neutral, punished, or rewarded) and how they compete for control of posterior neural oscillations. We found that both attention and stimulus–value associations influenced neural oscillations. Whereas selective attention had comparable effects on alpha and gamma oscillations, value associations had dissociable effects on these neural markers of attention. Salient targets (associated with positive and negative outcomes) hijacked changes in alpha power—increasing hemispheric alpha lateralization when salient targets were attended, decreasing it when they were being ignored. In contrast, hemispheric gamma-band lateralization was specifically abolished by negative distractors. Source analysis indicated occipital generators of both attentional and value effects. Thus, posterior cortical oscillations support both the ability to selectively attend while at the same time retaining the ability to remain sensitive to valuable features in the environment. Moreover, the versatility of our attentional system to respond separately to salient from merely positively valued stimuli appears to be carried out by separate neural processes reflected in different frequency bands.
Limited proteolysis of herpes simplex virus glycoproteins that occurs during their extraction from vero cells

Herpes simplex virus glycoproteins extracted from infected Vero cells can be smaller in apparent size than the same viral products extracted from infected HEp-2 cells. Here we show that the differences in size result primarily from limited proteolysis, during or after their extraction, of the viral glycoproteins made in Vero cells. In the absence of appropriate protease inhibitors, both mature and immature forms of four different glycoproteins specified by herpes simplex virus type 2 were significantly smaller (based on electrophoretic mobilities in acrylamide gels) when extracted from Vero cells than when extracted from HEp-2 cells. Inclusion of certain protease inhibitors in the extraction buffer, however, permitted isolation of immature forms from Vero cells that were indistinguishable in size from the immature forms extracted from HEp-2 cells. Under these conditions, the mature forms of glycoproteins B and E were also indistinguishable by electrophoretic sizing from those made in HEp-2 cells, whereas the mature forms of glycoproteins D and F were smaller, indicating the possibility of differences between Vero and HEp-2 cells in the post-translational processing of glycoproteins D and F.
Probing the cosmic-ray content of galaxy clusters by stacking Fermi-LAT count maps

Aims. Observation in radio have shown that galaxy clusters are giant reservoirs of cosmic rays (CR). Although a gammaray signal from the cluster volume is expected to arise through interactions of CR protons with the ambient plasma, a confirming observation is still missing. Methods. We search for a cumulative gamma-ray emission in direction of galaxy clusters by analysing a collection of stacked Fermi-LAT count maps. Additionally, we investigate possible systematic differences in the emission between cool-core and non-cool core cluster populations. Results. Making use of a sample of 53 clusters selected from the HIFLUGCS catalog, we do not detect a significant signal from the stacked sample. The upper limit on the average flux per cluster derived for the total stacked sample is at the level of a few 10 11 phcm 2 s 1 at 95% confidence level in the 1-300 GeV band, assuming power-law spectra with photon indices 2.0, 2.4, 2.8 and 3.2. Separate stacking of the cool core and non-cool core clusters in the sample lead to similar values of around 5 × 10 11 phcm 2 s 1 and 2 × 10 11 phcm 2 s 1 , respectively. Conclusions. Under the assumption that decaying π 0 , produced in collisions between CRs and the ambient thermal gas, are responsible for the gamma-ray emission, we set upper limits on the average CR content in galaxy clusters. For the entire cluster population, our upper limit on the gamma-ray flux translates into an upper limit on the average CR-to-thermal energy ratio of 4.6% for a photon index of 2.4, although it is possible for individual systems to exceed this limit. Our 95% upper limits are at the level expected from numerical simulations, which likely suggests that the injection of CR at cosmological shocks is less efficient than previously assumed.
Scleral Buckling and Pars Plana Vitrectomy for Rhegmatogenous Retinal Detachment: An Analysis of 542 Eyes

Abstract Purpose: To investigate the anatomical success rates of scleral buckling (SB) and pars plana vitrectomy (PPV) performed for rhegmatogenous retinal detachment (RRD) in a large case series and to identify prognostic factors for the primary anatomical success rates of surgical techniques. Methods: We reviewed 542 consecutive eyes for primary RRD in this retrospective study. Follow-ups were performed for at least six months. In each of the two groups, 271 eyes were examined. The main outcome measure was the primary anatomical success rate. Multivariate analysis was also performed to determine whether independent risk factors of the preoperative parameters for redetachment exist. Results: The primary anatomical success rates were 93.7% and 96.3% in the SB and PPV groups; and the final anatomical success rates were 100% in both groups (each with 271 eyes). In the SB group, eyes with macula-off had significantly lower primary anatomical success rates than those with macula-on (p = 0.002). Preoperative break location or lens status had no significant effect on primary anatomical success rates in either group. Multivariate logistic regression analysis using four variables, namely, sex, posterior vitreous detachment, macular status and preoperative visual acuity, showed that the macular status was an independent risk factor for redetachment in the SB group (p = 0.039, odds ratio 3.7). The six-month follow-up visual acuity was significantly better than the preoperative visual acuity in both groups (p ≤ 0.001). Conclusions: Both SB and PPV gave excellent primary and final anatomical success rates. The macula-off status was associated with a lower success rate in the SB group, although break location and lens status had no significant effect on success rates in either group.
Long-term outcome after intestinal resection for Crohn's disease

Objective. To assess the need for intestinal repeat resection for recurrence of Crohn's disease in patients observed for more than 20 years after the first resection. Material and methods. Data were gathered retrospectively from the medical records of 53 (28 F) consecutive patients with Crohn's disease from May 1954 to December 2002. Median age at first intestinal resection was 24.5 (range 13–65) years, and median observation time thereafter was 26.5 (20.1–48.6) years. Disease location and behaviour were defined according to the Vienna classification. Results. The 53 patients had an average 2.7 and a median 2 intestinal resections. Out of 144 intestinal resections (77.1%) 111 were performed during the first three operations; no alterations in distribution of ileal, ileocolic and colic resections were found. From the first to the third operation there was an increase in penetrating disease from 15% to 39% (p=0.046) concomitant with a decrease in stricturing disease from 72% to 44% (p=0.048) of the patients. There was also a corresponding decrease in ileocolic disease from 45% to 5% (p=0.003) and a tendency towards an increase in ileal disease from 38% to 67%. One patient died (1.8%) from rectosigmoid perforation after the third resectional operation. Six patients needed reoperation (11.3%) for ileus, anastomotic bleeding, rectosigmoidal perforation and abdominal pain. Thirty-four patients (64.2%) needed intestinal repeat resection (median 8.3 years) during 25.3 years after the first repeat resection. Conclusions. This study indicates a diminution of Crohn's disease activity with time, as demonstrated by no need for intestinal repeat resection more than 25 years after the first resection.
Simplified Protocol for Carba NP Test for Enhanced Detection of Carbapenemase Producers Directly from Bacterial Cultures

ABSTRACT We compared carbapenemase detection among 266 Gram-negative bacilli (161 carbapenemase producers) using the Carba NP tests issued by the CLSI (CNPt-CLSI) and a novel protocol (CNPt-direct) designed for carbapenemase detection direct from bacterial cultures (instead of bacterial extracts required by the CLSI tests). The specificities were comparable (100%), but the CNPt-direct was more sensitive (98% versus 84%). The CNPt-direct was easier to perform due to the direct use of colonies and offered a more robust detection of carbapenemase producers.