Miracle-dz/UniFAR-FTUs huggingface dataset:
Macrophage MicroRNA-155 Promotes Cardiac Hypertrophy and Failure

Background— Cardiac hypertrophy and subsequent heart failure triggered by chronic hypertension represent major challenges for cardiovascular research. Beyond neurohormonal and myocyte signaling pathways, growing evidence suggests inflammatory signaling pathways as therapeutically targetable contributors to this process. We recently reported that microRNA-155 is a key mediator of cardiac inflammation and injury in infectious myocarditis. Here, we investigated the impact of microRNA-155 manipulation in hypertensive heart disease. Methods and Results— Genetic loss or pharmacological inhibition of the leukocyte-expressed microRNA-155 in mice markedly reduced cardiac inflammation, hypertrophy, and dysfunction on pressure overload. These alterations were macrophage dependent because in vivo cardiomyocyte-specific microRNA-155 manipulation did not affect cardiac hypertrophy or dysfunction, whereas bone marrow transplantation from wild-type mice into microRNA-155 knockout animals rescued the hypertrophic response of the cardiomyocytes and vice versa. In vitro, media from microRNA-155 knockout macrophages blocked the hypertrophic growth of stimulated cardiomyocytes, confirming that macrophages influence myocyte growth in a microRNA-155-dependent paracrine manner. These effects were at least partly mediated by the direct microRNA-155 target suppressor of cytokine signaling 1 (Socs1) because Socs1 knockdown in microRNA-155 knockout macrophages largely restored their hypertrophy-stimulating potency. Conclusions— Our findings reveal that microRNA-155 expression in macrophages promotes cardiac inflammation, hypertrophy, and failure in response to pressure overload. These data support the causative significance of inflammatory signaling in hypertrophic heart disease and demonstrate the feasibility of therapeutic microRNA targeting of inflammation in heart failure.
TEAL as an innovative teaching model Insights from “Educational Avant-Garde” Movement in Italy

This paper presents a project carried out by INDIRE (National Institute for Documentation, Innovation and Educational Research of the Italian Ministry of Education, University and Research), called “Educational Avant-Garde” (“Avanguardie Educative”) and aiming at changing the lecture-based teaching and learning routines into student-centered, hands-on and collaborative practices. Changes in teaching and learning practices are especially relevant due to the high dropout rates in secondary education and the recent PISA low-test results. Since 2013, INDIRE has been carrying out research activities with the goal of identifying practices that could represent a disruptive and radical change in the traditional classroom pedagogy. Among all the innovative teaching models, (twelve identified at present), INDIRE selected the practice adopted by a network of Italian schools and imported by the Massachusetts of Technology (MIT), in Cambridge, MA. This practice, whose acronym is TEAL (Technology Enabled Active Learning), proved to be effective in changing the classroom routines and in improving students’ learning achievements. In particular, similar to the US studies on the impact of TEAL, Italian schools have pointed out that by using TEAL, students improve their learning experience and outcomes, feel more engaged, satisfied, aware of ICT pros and cons, and take more responsibility over their learning. Teachers remark that a TEAL-style pedagogy helps them work closely with their colleagues because the problem-solving approach forces them to rethink their subject curriculum. Moreover, by using TEAL, the education setting is rearranged, the uses of technologies require making conscious pedagogical choices and flipping the classroom becomes more natural. This paper analyses the original TEAL model at MIT and the derivative practices observed in the Italian schools with reference to the three main strands of INDIRE research, implementing a radical reappraisal of the concepts of time, space and teaching/learning processes in the Italian school system. Even if other publications describe the TEAL Model, this paper reflects on the positive results of its impact on the Italian school system, underlying strengths and weakness of the process of innovation in schools.
Triggering Avoidance: Dissociable Influences of Aversive Pavlovian Conditioned Stimuli on Human Instrumental Behavior

The present study investigates human aversive Pavlovian-to-Instrumental Transfer (PIT) and possible influences of outcome devaluation and instrumental overtraining on this effect. PIT measures the extent to which a Pavlovian conditioned stimulus (CS) can increase instrumental responses independently paired with the same (outcome-specific transfer) or a different (general transfer) reinforcer. Two measures of PIT were obtained: the percentage of instrumental responses and the vigor of such responses. Thirty-eight volunteers performed a standard PIT task sequence. Results showed a double dissociation between outcome-specific and general transfer: the first selectively expressed in the amount of responses, the second in the vigor measure solely. Furthermore, outcome-specific transfer was enhanced by overtraining, but not affected by devaluation. General transfer, on the other hand, was affected by neither overtraining, nor devaluation. A positive correlation between general transfer and sensitivity to punishments was found. Findings are discussed in terms of hypothetically different underlying neurobehavioral mechanisms and their relations to habits and goal-directed behavior.
Novel incentive-based approaches to adherence

Background Adherence to medications for chronic conditions is often very low, limiting the benefit to patients, even when the medications are effective and have favorable side effect profiles. Purpose This article reviews some of the prior work on treatment adherence, introduces novel concepts from behavioral economics that can be used to design interventions to improve adherence, and proposes new approaches for clinical trials. Methods Relevant experience of the authors and insights from the literature were combined to identify key issues and propose methodological improvements. Specific examples regarding adherence to warfarin are provided. Results Several new approaches to trial design can be effectively applied in the context of medication adherence. These include tailored intervention strategies and sequential multiple assignment randomized trial (SMART) designs. Limitations While we have proposed to use these new approaches for ongoing studies of adherence in behavioral health, practical experience with their application is still somewhat limited. Conclusions Behavioral economics offer a variety of concepts that, when used in the design of interventions to improve adherence, may be more successful than traditional approaches. New clinical trial designs can also be adopted to improve the efficiency of studies that assess these approaches.
Host Immune Responses Differ between M. africanum- and M. tuberculosis-Infected Patients following Standard Anti-tuberculosis Treatment

Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility.
Association of the metabolic syndrome with both vigorous and moderate physical activity.

BACKGROUND Cross-sectional relationships between moderate and vigorous physical activity and the metabolic syndrome (MS) were examined in the Whitehall II study of civil servants (age 45-68 years). We assessed cardiovascular fitness and body mass index (BMI) as possible mediators of the observed association. METHODS Measures of 2-hour glucose, systolic blood pressure, fasting triglycerides, waist-hip ratio, and high density lipoprotein (HDL) cholesterol were obtained in 5153 white European participants. Participants in the most adverse sex-specific quintile for three or more of these risk factors were classified as having MS. Self-reported leisure-time physical activity was categorized into separate moderate and vigorous activity classes. BMI and resting heart rate (HR) were used to estimate body fatness and cardiovascular fitness respectively. RESULTS The odds ratios (95% CI) for having the metabolic syndrome in the top categories of vigorous and moderate activity were 0.52 (95% CI: 0.40, 0.67) and 0.78 (95% CI: 0.63, 0.96) respectively, adjusted for age, sex, smoking, alcohol intake, socioeconomic status, and other activity. Adjustment for BMI and resting HR substantially attenuated both of the above associations. CONCLUSIONS Moderate and vigorous physical leisure-time activity are each associated with reduced risk of being classified with MS independently of age, smoking, and high alcohol intake. Both vigorous and moderate activities may be beneficial to the MS cluster of risk factors among middle-aged populations. Reduced BMI and increased cardiovascular fitness may be important mediators of this association for both intensities of activity.
The role of nitric oxide in the induction of caudal-type homeobox 2 through epidermal growth factor receptor in the development of Barrett's esophagus

Abstract Objective. The high concentration of nitric oxide (NO) around the gastro-esophageal junction (GEJ) might play an important role in the development of Barrett's esophagus (BE), a precursor of Barrett's adenocarcimona. Although previous studies revealed that the expression of caudal-type homeobox 2 (CDX2), an important marker of BE, might be induced through Epidermal Growth Factor Receptor (EGFR), the roles of NO in this signal transduction remain unclear. Material and methods. First, we investigated the expressions of EGFR, CDX2 and nitrotyrosine by immunohistochemical study for BE and squamous epithelium of human specimens. Second, we studied the effect of peroxynitrite, peroxynitrite stimulator, SIN-1, or NO donor, NOC7, on the expression of phosphorylated EGFR and CDX2 in KYSE30, an EGFR-rich human esophageal squamous cell carcinoma cell-line. Specific inhibitors for EGFR, AG1478 and small interfering RNA for EGFR (EGFR-siRNA) were employed to elucidate the role of EGFR in the induction of CDX2. Results. The immunohistochemical study revealed that the expressions of EGFR, CDX2 and nitrotyrosine in BE were stronger than those in squamous epithelium with positive correlations. Exposure to peroxynitrite, SIN-1 or NOC7 induced EGFR phosphorylation and CDX2 expression in dose- and time-dependent manners. Both EGFR phosphorylation and CDX2 induction were significantly diminished by AG 1478 and EGFR-siRNA. Conclusions. We revealed for the first time that extrinsic NO might directly induce CDX2 expression through EGFR phosphorylation. We suggested that NO had an important role in the development of BE from squamous epithelium around GEJ.
Contribution of sensory afferents and sympathetic efferents to joint injury in experimental arthritis

We used pharmacological and surgical methods to determine the contribution of several neural components to joint injury in rats with adjuvant-induced arthritis. Both neonatal administration of capsaicin, which eliminates small-diameter afferents, and peripheral sympathectomy, which depletes catecholamines, attenuated joint injury. In contrast, the arthritis was more severe in spontaneously hypertensive rats, which have increased sympathetic tone. To address the contribution of the central vs peripheral afferent terminal selectively, a group of rats underwent unilateral dorsal rhizotomy. These rats developed a more severe arthritis in the deafferented limb. The increase in arthritis severity produced by dorsal rhizotomy could be reduced by prior sympathectomy or, less effectively, by prior treatment with capsaicin. The latter observation suggests that large- diameter afferents that are cut during dorsal rhizotomy also influence inflammation. Finally, intracerebroventricular injection of morphine attenuated the severity of arthritis, possibly through activation of bulbospinal sympathoinhibitory circuits. Taken together, these data indicate that no one class of nerve fiber is wholly responsible for the neurogenic component of inflammation in experimental arthritis but that large- and small-diameter afferents, sympathetic efferents, and CNS circuits that modulate those fiber systems all influence the severity of joint injury in arthritic rats.
Algorithms for the Capture and Adjudication of Prevalent and Incident Diabetes in UK Biobank

Objectives UK Biobank is a UK-wide cohort of 502,655 people aged 40–69, recruited from National Health Service registrants between 2006–10, with healthcare data linkage. Type 2 diabetes is a key exposure and outcome. We developed algorithms to define prevalent and incident diabetes for UK Biobank. The algorithms will be implemented by UK Biobank and their results made available to researchers on request. Methods We used UK Biobank self-reported medical history and medication to assign prevalent diabetes and type, and tested this against linked primary and secondary care data in Welsh UK Biobank participants. Additionally, we derived and tested algorithms for incident diabetes using linked primary and secondary care data in the English Clinical Practice Research Datalink, and ran these on secondary care data in UK Biobank. Results and Significance For prevalent diabetes, 0.001% and 0.002% of people classified as “diabetes unlikely” in UK Biobank had evidence of diabetes in their primary or secondary care record respectively. Of those classified as “probable” type 2 diabetes, 75% and 96% had specific type 2 diabetes codes in their primary and secondary care records. For incidence, 95% of people with the type 2 diabetes-specific C10F Read code in primary care had corroborative evidence of diabetes from medications, blood testing or diabetes specific process of care codes. Only 41% of people identified with type 2 diabetes in primary care had secondary care evidence of type 2 diabetes. In contrast, of incident cases using ICD-10 type 2 diabetes specific codes in secondary care, 77% had corroborative evidence of diabetes in primary care. We suggest our definition of prevalent diabetes from UK Biobank baseline data has external validity, and recommend that specific primary care Read codes should be used for incident diabetes to ensure precision. Secondary care data should be used for incident diabetes with caution, as around half of all cases are missed, and a quarter have no corroborative evidence of diabetes in primary care.
A Multimodal Approach to Control Postoperative Pathophysiology and Rehabilitation in Patients Undergoing Abdominothoracic Esophagectomy

This two-armed study was designed to determine whether recovery after esophageal resection may be improved by introducing a new multimodal approach. For 8 mo after the new approach was introduced, all patients undergoing abdominothoracic esophageal resection were studied (Group 2; n = 42). For comparison, a retrospective analysis was also conducted using the data of all patients who had undergone this operation in the 8 mo before the introduction of the new regimen, when the traditional therapy was still in use (Group 1; n = 49). All patients received an epidural catheter at the level of T6-9 before the induction of general analgesia. Afterward, Group 1 patients were operated under general anesthesia. For postoperative pain relief, a mixture of bupivacaine 1.25 mg/mL and sufentanil 1 micro g/mL was administered during 5 days without titration of the quality of analgesia. Patients in Group 2 received a preoperative bolus of 10-15 mL bupivacaine 2.5 mg/mL and 20-30 micro g sufentanil. After sensory block up to T4 was confirmed, general anesthesia was introduced and intraoperatively combined with a continuous infusion of 5 mL/h of a solution containing bupivacaine 1.75 mg/mL and sufentanil 1 micro g/mL. Postoperatively, the epidural infusion rate was adjusted to the need of the individual patients, who were able to administer themselves additional bolus doses of 2 mL with a lockout time of 20 min. Early tracheal extubation and forced mobilization were pursued to improve recovery. Demographic data of both groups were comparable. The pain relief of Group 2 patients was superior to that of patients in Group 1. The nitrogen balance of a subgroup of nine matched pairs of patients with comparable nutritional status was less negative in Group 2 patients on Postoperative Days 1 and 2. Patients in Group 2 were tracheally extubated earlier (mean 6.7 vs 25.1 h after admission to the intensive care unit [ICU]), mobilized earlier (mean 1.2 vs 2.0 days after surgery), discharged from the ICU earlier (mean 1.7 vs 4.0 days), and fulfilled criteria for discharge from the ICU (mean 1.8 vs 4.1 days) and from the intermediate care unit earlier (4.9 vs 6.4 days). We conclude that the multimodal approach may improve recovery and thus reduce costs after abdominothoracic esophageal resection. Implications: Analgesia and blockade of the perioperative stress response, combined with other aspects of postoperative therapy, may improve recovery after surgery. The intensive care unit stay after esophageal resection was reduced by a new regimen (thoracic epidural analgesia, early tracheal extubation, forced mobilization). This approach may influence the cost of major surgery. (Anesth Analg 1998;86:228-34)
PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells.

Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150 000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long-term prognosis. Thus, there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down-regulation of E-cadherin expression concomitant with a suppression of cell:cell junctions, and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell:cell junctions and the level of PAK5 expression. Interestingly, exogenous PAK5 has recently been described to be associated with cell:cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that, in both our own patient samples and a commercially available dataset, PAK5mRNA levels are reduced in human bladder cancer compared with normal controls. Taken together, the present study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression.
Timing matters: open‐loop stimulation does not improve overnight consolidation of word pairs in humans

The application of auditory clicks during non‐rapid eye movement (NREM) sleep phase‐locked to the up state of the slow oscillation (closed‐loop stimulation) has previously been shown to enhance the consolidation of declarative memories. We designed and applied sequences of three clicks during deep NREM sleep to achieve a quasi‐phase‐dependent open‐loop stimulation. This stimulation was successful in eliciting slow oscillation power in the stimulation period. Although fast and slow spindle power were markedly decreased during the stimulation period, memory consolidation did not differ from control. During putative up states fast spindle power remained, however, at control levels. We conclude that concurrence of slow oscillations and fast spindles suffices to maintain memory consolidation at control levels despite an overall decreased spindle activity.
Why is Mini-Mental state examination performance correlated with estimated premorbid cognitive ability?

Background Tests requiring the pronunciation of irregular words are used to estimate premorbid cognitive ability in patients with clinical diagnoses, and prior cognitive ability in normal ageing. However, scores on these word-reading tests correlate with scores on the Mini-Mental State Examination (MMSE), a widely used screening test for possible cognitive pathology. This study aimed to test whether the word-reading tests’ correlations with MMSE scores in healthy older people are explained by childhood IQ or education. Method Wechsler Test of Adult Reading (WTAR), National Adult Reading Test (NART), MMSE scores and information about education were obtained from 1024 70-year-olds, for whom childhood intelligence test scores were available. Results WTAR and NART were positively correlated with the MMSE (r ≈ 0.40, p < 0.001). The shared variance of WTAR and NART with MMSE was significantly attenuated by ~70% after controlling for childhood intelligence test scores. Education explained little additional variance in the association between the reading tests and the MMSE. Conclusions MMSE, which is often used to index cognitive impairment, is associated with prior cognitive ability. MMSE score is related to scores on WTAR and NART largely due to their shared association with prior ability. Obtained MMSE scores should be interpreted in the context of prior ability (or WTAR/NART score as its proxy).