Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of long‐acting β2 agonists on exacerbation rates of asthma in children

The purpose of this analysis was to examine the effect of long‐acting β2‐adrenoceptor agonists (LABAs) on the asthma exacerbation rate in pediatric patients. Randomized controlled trials (RCT) that included the use of LABAs to treat symptoms of pediatric asthma in children on inhaled corticosteroids, that reported asthma exacerbation rates, and that were published as full papers in peer‐reviewed journals were retrieved from a search of the medical literature. Eight studies were identified that fulfilled these criteria. An exacerbation was defined as deterioration in a patient's asthma requiring a change in prescribed medication or not defined but reported as an asthma exacerbation or an asthma‐related hospitalization. Analysis of data from the eight studies revealed no apparent protection from an asthma exacerbation among children on a LABA compared to patients on comparator treatment. The relative risk of an asthma exacerbation for LABA compared to placebo or short‐acting β2‐adrenoceptor agonist (SABA) ranged from 0.95–1.86. The relative risk of hospitalization for asthma in patients treated with LABAs with regular maintenance with ICS ranged from 3.3–21.6 in the three studies that reported asthma‐related hospitalizations. The lack of evidence for the control of asthma exacerbations in children regularly using a LABA should bring into question its general use as add‐on therapy. Studies should be designed to directly explore the implications of these observations in pediatric patients. Pediatr Pulmonol. 2003; 36:391–398. © 2003 Wiley‐Liss, Inc.
Dynamics of telomere shortening in neutrophils and T lymphocytes during ageing and the relationship to skewed X chromosome inactivation patterns

Human haemopoiesis undergoes profound changes throughout life, resulting in compromised regenerative capacity of haemopoietic stem cells. It has been suggested that telomere shortening results in senescence of haemopoietic stem cell subsets and may influence the balance between stem cell renewal and proliferation. Telomere length and telomerase activity was measured in whole blood leucocytes, neutrophils and T cells from cord blood and individuals aged from 1 year to 96 years. Rapid telomere shortening [700 base pairs (bp)] was demonstrated in the first year of life, followed by a gradual decline of 31 bp/year. T cells were shown to have longer telomeres than neutrophils (mean difference 372 bp, P = < 0·001) but demonstrated similar rates of shortening (20 ± 0·3 bp/year vs. 22 ± 0·3 bp/year). Telomerase was detectable in T cells but not in neutrophils, suggesting that telomerase is not the rate‐limiting step for regulation of telomere length in haemopoietic cells. Stem cell utilization as measured by X chromosome inactivation patterns was found to be independent of telomere length. This supports the concept that age‐dependent skewed haemopoiesis is the result of random stem cell loss or X‐allelic exclusion rather than telomeric senescence. These studies provide insight into the ageing process and a reference point for evaluating replicative stress in individuals of different age groups.
Effect of Instructions on Selected Jump Squat Variables

Abstract Talpey, SW, Young, WB, and Beseler, B. Effect of instructions on selected jump squat variables. J Strength Cond Res 30(9): 2508–2513, 2016—The purpose of this study was to compare 2 instructions on the performance of selected variables in a jump squat (JS) exercise. The second purpose was to determine the relationships between JS variables and sprint performance. Eighteen male subjects with resistance training experience performed 2 sets of 4 JS with no extra load with the instructions to concentrate on (a) jumping for maximum height and (b) extending the legs as fast as possible to maximize explosive force. Sprint performance was assessed at 0- to 10-m and 10- to 20-m distances. From the JS jump height, peak power, relative peak power, peak force, peak velocity, and countermovement distance were measured from a force platform and position transducer system. The JS variables under the 2 instructions were compared with paired t-tests, and the relationships between these variables and sprint performance were determined with Pearson’s correlations. The jump height instruction produced greater mean jump height and peak velocity (p < 0.05), but the fast leg extension instruction produced greater (p < 0.05) peak force (3.7%). There was a trivial difference between the instructions for peak power output (p > 0.05). Jump height was the variable that correlated most strongly with 10-m time and 10- to 20-m time under both instructions. The height instruction produced a stronger correlation with 10-m time (r = −0.455), but the fast leg extension JS produced a greater correlation with 10–20 time (r = −0.545). The results indicate that instructions have a meaningful influence on JS variables and therefore need to be taken into consideration when assessing or training athletes.
Innovations to Achieve Excellence in COPD Diagnosis and Treatment in Primary Care

Abstract Recognition of chronic obstructive pulmonary disease (COPD) is often missed or delayed in primary care. Once recognized, COPD is often undertreated or episodically treated, focusing on acute exacerbations without establishing maintenance treatment to control ongoing disease. Diagnostic and therapeutic pessimism result in missed opportunities to reduce exacerbations, maintain physical functioning, and reduce emergent health care requirements. Proactive diagnosis and evidence-based management can alleviate the impact of COPD on patients' lives. Smoking cessation has been proven to slow the rate of lung function decline. Maintenance pharmacotherapy and immunizations reduce exacerbations. Pulmonary rehabilitation improves respiratory symptoms and physical functioning and reduces rehospitalizations after exacerbations. Self-management education improves health-related quality of life and reduces inpatient and emergency care usage. Maintenance treatment with long-acting inhaled bronchodilators is appropriate beginning in moderate COPD to maintain airway patency and reduce exacerbations. Tiotropium is US Food and Drug Administration (FDA) approved to treat bronchospasm and reduce exacerbations in patients with COPD; salmeterol/fluticasone is FDA approved to treat airflow obstruction in COPD and reduce exacerbations in patients with a history of exacerbations. Other maintenance long-acting bronchodilators—salmeterol, formoterol, and budesonide/formoterol—are FDA approved to treat airway obstruction in COPD but lack an approved indication against exacerbations. FDA warnings on the use of long-acting beta-adrenergic agents (LABAs) in asthma specifically exempt COPD and do not apply to LABA/inhaled corticosteroid combinations used in COPD. The actual effectiveness achieved in practice with any COPD therapies depends on patients' inhaler technique, adherence, and persistence. Medication usage rates and inhaler proficiency may be improved by concordance, in which the health care provider and patient collaborate to make treatment plans sustainable in the patient's daily life. Practice redesign for whole-patient primary care provides additional tools for comprehensive COPD management. Innovations such as group visits and the patient-centered medical home provide newer ways to interact with COPD patients and their families. Patient-focused and evidence-based options enable primary care practices to manage COPD longitudinally and improve patient outcomes through the course of the disease.
Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies.

RATIONALE Critical limb ischemia is a life-threatening complication of peripheral arterial disease. In patients who are ineligible for revascularization procedures, there are few therapeutic alternatives, leading to amputations and death. OBJECTIVE To provide a systematic review of the literature and a meta-analysis of studies evaluating safety and efficacy of autologous cell therapy for intractable peripheral arterial disease/critical limb ischemia. METHODS AND RESULTS We retrieved 19 randomized controlled trials (837 patients), 7 nonrandomized trials (338 patients), and 41 noncontrolled studies (1177 patients). The primary outcome was major amputation. Heterogeneity was high, and publication bias could not be excluded. Despite these limitations, the primary analysis (all randomized controlled trials) showed that cell therapy reduced the risk of amputation by 37%, improved amputation-free survival by 18%, and improved wound healing by 59%, without affecting mortality. Cell therapy significantly increased ankle brachial index, increased transcutaneous oxygen tension, and reduced rest pain. The secondary analysis (all controlled trials; n=1175 patients) shows that there may be potential to avoid ≈1 amputation/year for every 2 patients successfully treated. The tertiary analysis (all studies; n=2332 patients) precisely estimated the changes in ankle brachial index, transcutaneous oxygen tension, rest pain, and walking capacity after cell therapy. Intramuscular implantation appeared more effective than intra-arterial infusion, and mobilized peripheral blood mononuclear cells may outperform bone marrow-mononuclear cells and mesenchymal stem cells. Amputation rate was improved more in trials wherein the prevalence of diabetes mellitus was high. Cell therapy was not associated with severe adverse events. Remarkably, efficacy of cell therapy on all end points was no longer significant in placebo-controlled randomized controlled trials and disappeared in randomized controlled trials with a low risk of bias. CONCLUSIONS Although this meta-analysis highlights the need for more high-quality placebo-controlled trials, equipoise may no longer be guaranteed because autologous cell therapy has the potential to modify the natural history of intractable critical limb ischemia.
Reconsidering the effects of respiratory constraints on the optimal running speed.

INTRODUCTION Although both humans and quadrupeds frequently coordinate breathing and limb movement during running, early studies in humans focused on how increased breathing flexibility in humans allowed for relaxed or even transient coordination during locomotion. This difference was used to explain why quadrupeds had an optimal running speed whereas humans did not. Recent research, however, has clearly demonstrated that humans, like quadrupeds, have an optimal running speed. Because these findings are new, it remains unclear why this is true: whether because entrainment in humans was more important than initially predicted or because another restraint is acting. Here, we try to explain the observed minimum cost of transport (CoT) by analyzing metabolic cost with respect to entrainment and a standard set of anthropometrics. METHODS We measured the energetic cost of human running at five different speeds and calculated individual CoT curves for each participant (N = 9). Simultaneously, entrainment was determined by the degree to which a poststimulus histogram (breaths per 0.05-s bin after a footfall) differed from a uniform plot. RESULTS We compared the degree of entrainment to each participant's optimal running speed and found that although all of our subjects clearly entrained at some speeds, entrainment was not a function of CoT (P = 0.897). Because entrainment was also not correlated with speed (P = 0.304), it seems that bipedalism removed the respiratory constraints associated with quadrupedalism as originally suggested. CONCLUSIONS Unlike quadrupeds, for whom respiratory constraints remain implicated in the speed dependence of CoT, constraints that lead to a minimum CoT for people must involve other mechanisms of efficiency such as the storage and release of energy in the lower limbs.
ENERGETICS OF CONTRACTILE ACTIVITY IN ISOLATED RADULA PROTRACTOR MUSCLES OF THE WHELK BUSYCON CONTRARIUM: ANAEROBIC END PRODUCT ACCUMULATION AND RELEASE.

Anaerobic energy metabolism during contractile activity was investigated in the isolated radula protractor muscle of the whelk Busycon contrarium. Spectrophotometric assay of enzyme activities in crude tissue extracts revealed particularly high pyruvate reductase activities with octopine dehydrogenase displaying the highest activity. During electrically induced isotonic contractions of the radula protractor muscles, the following end products, listed in order of increasing level, accumulated in the tissue: strombine, octopine and alanopine (the "opines"), and D-lactate. Pyruvate levels increased three-fold during muscle contraction, suggesting that pyruvate plays a key role in the regulation of the pyruvate reductases. The muscle released lactate, but none of the opines, into the incubation medium, with rates exceeding 3 µmoles · min-1 · g wet wt-1 · During the later phases of contraction, more D-lactate was released into the medium than accumulated in the muscle. We conclude that transport of D-lactate permits sustained flux through lactate dehydrogenase because of a reduction in product inhibition. Furthermore, we hypothesize that D-lactate transport may be coupled to H+ export or OH- import, which would then serve to regulate the extent of accumulation of glycolytically produced protons.
Use of everted sacs of mouse small intestine as enzyme sources for the study of drug oxidation activities in vitro

1. The use of everted sacs of the small intestine as an enzyme source for the study of the first-pass metabolism of xenobiotics by cytochrome P450s (P450, CYP) is described. Several drug oxidation activities for testosterone, chlorzoxazone, tolbutamide, bufuralol and warfarin were observed when everted sacs (1-cm segment) from different parts of mouse small intestine were incubated with an NADPH-generating system and each substrate. 2. Most of the drug hydroxylase activities resided in the upper part of mouse small intestine and these activities were much higher than those of intestinal microsomes. Drug oxidation activities decreased along the distance from the upper part of the small intestine except for warfarin hydroxylation. 3. Testosterone 6β-hydroxylation in the everted sacs exhibited the highest catalytic activities among the drug oxidations tested here. In the upper part of the small intestine, the testosterone 6β-hydroxylase activities of everted sacs subjected once to freezing and thawing were substantially decreased compared with the untreated everted sacs. 4. Testosterone 6β-hydroxylase activities in the everted sacs of the small intestine were significantly inhibited by ketoconazole. Immunoreactive proteins using anti-CYP3A antibodies were detected in the upper and middle parts of the small intestine. 5. The results demonstrated that the upper part of the mouse small intestine serves as the major site for intestinal P450 mediated first-pass metabolism. Everted sacs of the small intestine are therefore useful for the study of drug metabolism as well as of transport and absorption.
Neuroticism Predicts Depression and Disability in Age‐Related Macular Degeneration

OBJECTIVES Age-related macular degeneration (AMD) is a common, disabling disorder of older age that is associated with depression. We investigated the incidence rate of depression and its risk factors and consequences in this 6-month longitudinal study. DESIGN A prospective cohort study in which subjects were interviewed 6 weeks after the onset of bilateral vision loss and 6 months later. SETTING The sample was recruited from the retinovascular clinic of a specialty eye hospital. PARTICIPANTS Subjects were 51 patients with new onset bilateral AMD. MEASUREMENTS We assessed depressive symptoms, personality traits, visual acuity, and vision and physical functioning. Additionally, we interviewed informants to obtain independent assessments of subjects' personality traits. RESULTS The baseline prevalence rate of syndromal depression was 23.5% and high levels of depressive symptoms persisted over time. The 6-month incidence rate of depression was 27.8%. The strongest risk factors for incident depression were self-rated and informant-rated neuroticism. Patients who developed syndromal depression were 8.3 times (95% confidence interval = 1.1-63.4) more likely than nondepressed patients to become disabled in vision function, independent of change in visual acuity. CONCLUSION AMD is associated with high rates of depression and visual disability independent of severity of vision loss. The personality trait of neuroticism is highly predictive of incident depression and identifies patients at high risk for excess disability. Psychotherapeutic treatments targeted to this group may prevent depression and reduce disability.
Stretch‐induced phosphorylation of ERK1/2 depends on differentiation stage of osteoblasts

The goal of this study was to investigate the effect of mechanical loading on osteoblasts and extracellular signal‐regulated kinase (ERK1/2) signaling in relation to osteoblast differentiation and mineralization. A human osteoblast cell line (SV‐HFO) was triggered to differentiate to the advanced state of mineralization by addition of the osteogenic factors dexamethasone and β‐glycerophosphate. Osteoblasts were subjected to cyclic, equibiaxial stretch for 5, 15, or 60 min at different stages of differentiation (days 7, 14, and 21). Baseline (static) phosphorylated ERK1/2 and total ERK1/2 levels gradually increased during osteoblast differentiation. Cyclic stretch induced a rapid increase in ERK1/2 phosphorylation with a maximum between 5 and 15 min. Prolonged stretching for 60 min resulted in a decrease of phosphorylated ERK1/2 towards baseline level, suggesting a desensitization mechanism. The effect of stretch on ERK1/2 phosphorylation was strongest at later stages of differentiation (days 14 and 21). At day 21, the increase of ERK1/2 phosphorylation in response to stretch was significantly lower in non‐differentiating than in differentiating osteoblasts. This could not be explained by differences in cell density, but did correlate with the formation of extracellular matrix, collagen fibrils. Mineralization of the extracellular matrix did not lead to a further increase of ERK1/2 phosphorylation. In conclusion, the current study demonstrates that the extent of activation of the ERK1/2 pathway is dependent on the differentiation or functional stage of the osteoblast. The presence of an extracellular matrix, but not per se mineralization, seems to be the predominant determinant of osteoblastic response to strain. © 2004 Wiley‐Liss, Inc.
Selective targeting of Toll‐like receptors and OX40 inhibit regulatory T–cell function in follicular lymphoma

Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin‐containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression‐free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD‐1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll‐like receptors (TLR) with TLR ligands Pam3CSK4 (TLR 1/2), flagellin (TLR 5), and CpG‐B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor‐specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients.
Anti‐diabetic activity of Zingiber officinale in streptozotocin‐induced type I diabetic rats

The fresh and dried rhizome of Zingiber officinale Roscoe (commonly known as ginger) is widely used in traditional medicine. We have studied the effect of the juice of Z. officinale (4 mL kg−1, p.o. daily) for 6 weeks on streptozotocin (STZ)‐induced type I diabetic rats with particular reference to the involvement of serotonin (5‐hydroxytryptamine; 5‐HT) receptors in glycaemic control. In normoglycaemic rats, 5‐HT (1 mg kg−1, i.p.) produced hyperglycaemia and hypoinsulinaemia, which was significantly prevented by the juice of Z. officinale. STZ‐diabetes produced a significant increase in fasting glucose levels that was associated with a significant decrease in serum insulin levels. Treatment with Z. officinale produced a significant increase in insulin levels and a decrease in fasting glucose levels in diabetic rats. In an oral glucose tolerance test, treatment with Z. officinale was found to decrease significantly the area under the curve of glucose and to increase the area under the curve of insulin in STZ‐diabetic rats. Treatment with Z. officinale also caused a decrease in serum cholesterol, serum triglyceride and blood pressure in diabetic rats. Our data suggest a potential antidiabetic activity of the juice of Z. officinale in type I diabetic rats, possibly involving 5‐HT receptors.
Cellular and molecular mechanisms involved in placental separation in the bovine: A review

Retention of fetal membranes (RFM), where the fetal placenta is not expelled within 8–12 hr after calving, lowers bovine productivity and fertility, resulting in significant economic loss to the dairy industry. Several risk factors that predispose an individual to RFM are known, but a unifying pathogenesis remains elusive due to its multifactorial etiology. Fetal membrane separation and expulsion after parturition involves structural and immunological changes of the bovine placentome that are governed predominantly by steroid hormones and the prostaglandin milieu of late pregnancy and parturition. Maturation of the placentome, a gradual and concerted event of late gestation, is likely initiated by the up‐regulation of fetal major histocompatibility complex class I in the interplacentomal region—which increases the apoptosis of binucleate and other trophoblastic cells, the degradation of collagen in the extracellular matrix by matrix metalloproteinases, and an influx of phagocytic leukocytes. Shear force further distorts the crypt architecture of the mature placentomes when they are forced against the fetus during the second stage of labor. Cotyledon dehiscence from the caruncular crypts is completed following fetal expulsion as a result of acute shrinkage of the cotelydonary villi as well as reduced perfusion to the caruncle; the secundinae is expelled by uterine contractions. A better understanding of placentomal maturation, intra‐partum, and immediate postpartum changes of the placentome should help develop strategies for the treatment and prevention of RFM. The present review proposes a model of placentome maturation and separation of fetal membranes in the dairy cow. Mol. Reprod. Dev. 83: 287–297, 2016. © 2016 Wiley Periodicals, Inc.