Miracle-dz/UniFAR-FTUs huggingface dataset:
The In Vitro Effects of Pentamidine Isethionate on Coagulation and Fibrinolysis

Pentamidine is bis-oxybenzamidine-based antiprotozoal drug. The parenteral use of pentamidine appears to affect the processes of blood coagulation and/or fibrinolysis resulting in rare but potentially life-threatening blood clot formation. Pentamidine was also found to cause disseminated intravascular coagulation syndrome. To investigate the potential underlying molecular mechanism(s) of pentamidine’s effects on coagulation and fibrinolysis, we studied its effects on clotting times in normal and deficient human plasmas. Using normal plasma, pentamidine isethionate doubled the activated partial thromboplastin time at 27.5 µM, doubled the prothrombin time at 45.7 µM, and weakly doubled the thrombin time at 158.17 µM. Using plasmas deficient of factors VIIa, IXa, XIa, or XIIa, the concentrations to double the activated partial thromboplastin time were similar to that obtained using normal plasma. Pentamidine also inhibited plasmin-mediated clot lysis with half-maximal inhibitory concentration (IC50) value of ~3.6 μM. Chromogenic substrate hydrolysis assays indicated that pentamidine inhibits factor Xa and plasmin with IC50 values of 10.4 µM and 8.4 µM, respectively. Interestingly, it did not significantly inhibit thrombin, factor XIa, factor XIIIa, neutrophil elastase, or chymotrypsin at the highest concentrations tested. Michaelis-Menten kinetics and molecular modeling studies revealed that pentamidine inhibits factor Xa and plasmin in a competitive fashion. Overall, this study provides quantitative mechanistic insights into the in vitro effects of pentamidine isethionate on coagulation and fibrinolysis via the disruption of the proteolytic activity of factor Xa and plasmin.
Intraventricular placement of a spring expander does not attenuate cardiac atrophy of the healthy heart induced by unloading via heterotopic heart transplantation.

An important complication of the prolonged left ventricle assist device support in patients with heart failure is unloading-induced cardiac atrophy which proved resistant to various treatments. Heterotopic heart transplantation (HT(x)) is the usual experimental model to study this process. We showed previously that implantation of the newly designed intraventricular spring expander can attenuate the atrophy when examined after HT(x) in the failing heart (derived from animals with established heart failure). The present study aimed to examine if enhanced isovolumic loading achieved by implantation of the expander would attenuate cardiac post-HT(x) atrophy also in the healthy heart. Cardiac atrophy was assessed as the ratio of the transplanted-to-native heart weight (HW) and its degree was determined on days 7, 14, 21 and 28 after HT(x). The transplantation resulted in 32±3, 46±2, 48±3 and 46±3 % HW loss when measured at the four time points; implantation of the expander had no significant effect on these decreases. We conclude that enhanced isovolumic loading achieved by intraventricular implantation of the expander does not attenuate the development of cardiac atrophy after HT(x) in the healthy heart. This indicates that such an approach does not represent a useful therapeutic measure to attenuate the development of unloading-induced cardiac atrophy.
Lycopene Inhibits Smoke-Induced Chronic Obstructive Pulmonary Disease and Lung Carcinogenesis by Modulating Reverse Cholesterol Transport in Ferrets

Chronic obstructive pulmonary disease (COPD) and lung cancer share the same etiologic factor, cigarette smoking. Higher consumption of dietary lycopene has been associated with lower risks of COPD and lung cancer in smokers. We investigated whether lycopene feeding protects against COPD and lung cancer in ferrets, a nonrodent model that closely mimics cigarette smoke (CS)-induced chronic bronchitis, emphysema, and lung tumorigenesis in human. We also explored whether the protective effect of lycopene is associated with restoring reverse cholesterol transport (RCT), a key driver in persistent inflammation with CS exposure. Ferrets (4 groups, n = 12–16/group) were exposed to a combination of tobacco carcinogen (NNK) and CS with or without consuming lycopene at low and high doses (equivalent to ∼30 and ∼90 mg lycopene/day in human, respectively) for 22 weeks. Results showed that dietary lycopene at a high dose significantly inhibited NNK/CS-induced chronic bronchitis, emphysema, and preneoplastic lesions, including squamous metaplasia and atypical adenomatous hyperplasia, as compared with the NNK/CS alone (P < 0.05). Lycopene feeding also tended to decrease the lung neoplastic lesions. Furthermore, lycopene feeding significantly inhibited NNK/CS-induced accumulation of total cholesterol, and increased mRNA expression of critical genes related to the RCT (PPARα, LXRα, and ATP-binding cassette transporters ABCA1 and ABCG1) in the lungs, which were downregulated by the NNK/CS exposure. The present study has provided the first evidence linking a protective role of dietary lycopene against COPD and preneoplastic lesions to RCT-mediated cholesterol accumulation in lungs.
Caregiver-Delivered Stroke Rehabilitation in Rural China.

Background and Purpose- Stroke disability is a major health burden in rural China where rehabilitation services are inadequate. We aimed to determine the effectiveness of a novel nurse-led, caregiver-delivered model of stroke rehabilitation in rural China. Methods- A multicenter prospective, randomized open, blinded outcome assessed, controlled trial was conducted in 3 rural county hospitals in China: Zhangwu, Liaoning Province (Northeast); Qingtongxia, Ningxia Hui Autonomous Region (Northwest); and Dianjiang, Chongqing Municipality (Southwest). Adult patients (age 18-79 years) with residual disability (Barthel Index score ≤80/100) after a recent acute stroke were randomized to a new service model or usual care. The new intervention was multifaceted and was based on a task-shifting / training-the-trainers model, supported by a custom-designed smartphone application, where patients and caregivers received evidence-based in-hospital education and stroke rehabilitation training (focus on mobility, self-care, and toileting), delivered by trained nurses before hospital discharge, and 3 postdischarge support telephone calls. Outcome assessments were undertaken before hospital discharge and at 3 and 6 months. Primary outcome was physical functioning (Barthel Index scores) at 6 months, assessed by research staff blind to treatment allocation, adjusted for baseline covariates in an intention-to-treat analysis. Secondary outcomes included measures of mobility, health-related quality of life, mood, and caregiver burden. The study included a process evaluation that assessed intervention fidelity. Results- From November 2014 to December 2016, 246 stroke patients were randomized to intervention (n=118) or control (n=128) groups. There was no statistically significant difference in adjusted 6-month Barthel Index scores between groups (70.1 versus 74.1, mean difference, -4.0 [95% CI, -10.0 to 2.9]), nor any differences across the other outcome measures. Process evaluation interviews revealed that the intervention was desirable and positively accepted by nurses, caregivers, and patients but was considered too complex despite efforts to simplify materials for the rural context. Key strategies identified for future studies included the use of community health workers, smartphone application enhancement, and simpler and more frequent training for nurses, caregivers, and patients. Conclusions- A novel nurse-led, digital supported, caregiver-delivered stroke rehabilitation program did not improve patient physical functioning after stroke in rural China. Further stroke rehabilitation research suitable for resource-poor settings is required, with several components being suggested through stakeholder interviews in our study. Clinical Trial Registration- URL: https://www.clinicaltrials. gov . Unique identifier: NCT02247921.
Systematic review of ultrasound visual biofeedback in intervention for speech sound disorders.

BACKGROUND As cost and access barriers to ultrasound technology have decreased, interest in using ultrasound visual biofeedback (U-VBF) as a tool for remediating speech sound disorders (SSD) has increased. A growing body of research has investigated U-VBF in intervention for developmental SSD; however, diversity in study design, participant characteristics, clinical methods and outcomes complicate the interpretation of this literature. Thus, there is a need for a synthesis and review of the evidence base for using U-VBF in intervention for SSD. AIMS To synthesise and evaluate the research evidence for U-VBF in intervention for developmental SSD. METHODS A systematic review was conducted. Eight electronic databases were searched for peer-reviewed articles published before 2018. Details about study design, participants, intervention procedures, service delivery, intervention intensity and outcomes were extracted from each study that met the inclusion criteria. The included studies were rated using both a critical appraisal tool and for their reporting of intervention detail. MAIN CONTRIBUTIONS Twenty-eight papers, comprising 29 studies, met the inclusion criteria. The most common research design was single-case experimental design (44.8% of studies). The studies included between one and 13 participants (mean = 4.1) who had a mean age of approximately 11 years (range = 4;0-27 years). Within the research evidence, U-VBF intervention was typically provided as part of, or as an adjunct to, other articulatory-based therapy approaches. A range of lingual sounds were targeted in intervention, with 80.6% of participants across all reviewed studies receiving intervention targeting rhotics. Outcomes following therapy were generally positive with the majority of studies reporting that U-VBF facilitated acquisition of targets, with effect sizes ranging from no effect to a large effect. Difficulties with generalisation were observed for some participants. Most studies (79.3%) were categorised as efficacy rather than effectiveness studies and represented lower levels of evidence. Overall, the reviewed studies scored more highly on measures of external validity than internal validity. CONCLUSIONS The evidence base for U-VBF is developing; however, most studies used small sample sizes and lower strength designs. Current evidence indicates that U-VBF may be an effective adjunct to intervention for some individuals whose speech errors persist despite previous intervention. The results of this systematic review underscore the need for more high-quality and large-scale research exploring the use of this intervention in both controlled and community contexts.
Modulating Fermentative, Varietal and Aging Aromas of Wine Using non-Saccharomyces Yeasts in a Sequential Inoculation Approach

The goal of this study is to assess to what extent non-Saccharomyces yeasts can introduce aromatic changes of industrial interest in fermentative, varietal and aged aromas of wine. Aroma precursors from Riesling and Garnacha grapes were extracted and used in two independent sequential experiments. Synthetic musts were inoculated, either with Saccharomyces cerevisiae (Sc) or with Pichia kluyveri (Pk), Torulaspora delbrueckii (Td) or Lachancea thermotolerans (Lt), followed by Sc. The fermented samples were subjected to anoxic aging at 50 °C for 0, 1, 2 or 5 weeks before an aroma analysis. The fermentative aroma profiles were consistently changed by non-Saccharomyces: all strains induced smaller levels of isoamyl alcohol; Pk produced huge levels of aromatic acetates and can induce high levels of fatty acids (FA) and their ethyl esters (EE); Td produced large levels of branched acids and of their EE after aging, and induced smaller levels of FA and their EE; Lt produced reduced levels of FA and their EE. The varietal aroma was also deeply affected: TDN (1,1,6-trimethyl-1,2- dihydronaphthalene) levels in aged wines were reduced by Pk and enhanced by Lt in Garnacha; the levels of vinylphenols can be much reduced, particularly by Lt and Pk. TD and Lt can increase linalool and geraniol in young, but not in aged wines.
Interparental conflict and gender moderate the prospective link between parents' perceptions of adolescents' weight and weight concerns.

OBJECTIVE Parents' comments about their adolescents' weight have been linked with adolescents' disordered eating, but we know little about the personal and contextual conditions that promote or mitigate the effects of parents' perceptions on adolescents' weight concerns. This study examined whether the prospective association between parents' perceptions of adolescents' weight and adolescents' weight concerns differed as a function of exposure to interparental conflict or adolescent gender. METHOD Participants were 386 adolescents (52% female; ages 11-18 years; predominately Caucasian/European American) from 197 families (i.e., up to two adolescents per family) and their parents. Two-parent families with a firstborn child in 8th, 9th, or 10th grade and a secondborn child 1-4 years younger were recruited to participate in a short-term longitudinal study of adolescent development and family relationships. Annual home interviews were conducted with adolescents and parents. Multilevel models tested whether parents' perceptions of adolescents' weight predicted adolescents' weight concerns one year later and whether interparental conflict and youth gender moderated this prospective association. RESULTS A significant three-way interaction revealed that when interparental conflict was low, increases in fathers' but not mothers' perceptions of daughters' overweight predicted increases in daughters' weight concerns the following year. In contrast, females exposed to high interparental conflict reported elevated weight concerns the following year regardless of parents' perceptions. Results for males were not significant. DISCUSSION Findings highlight the role of personal and family context characteristics in the development of weight concerns and the value of addressing family processes within preventive interventions for adolescent females' weight concerns.
Strength and Function Across Maturational Levels in Young Athletes at the Time of Return to Sport After ACL Reconstruction

Background: The impact of maturation on lower extremity strength and function after anterior cruciate ligament reconstruction (ACLR) may help guide future studies of age-specific rehabilitation. Hypothesis Pediatric ACLR patients would demonstrate higher thigh strength symmetry and knee-related function at return to sport (RTS) compared with adolescent and young adult participants who underwent traditional ACLR. Study Design: Prospective cohort study. Level of Evidence: Level 2. Methods: A total of 144 young athletes at the time of RTS clearance post-ACLR were classified into 3 maturational groups (pediatric, n = 16 with physeal-sparing ACLR [mean age = 12.3 years; range = 9.2-14.6 years]; adolescent, n = 113 [mean age = 16.5 years; range = 14.1-19.8 years]; young adult, n = 15 [mean age = 22.0 years; range = 20.5-24.9 years]). Quadriceps and hamstring strength were measured using an electromechanical dynamometer. Knee-related function was measured using the International Knee Documentation Committee (IKDC) subjective form and single-leg hop tests. The Limb symmetry Index (LSI) was used in calculations for hop and strength tests. Group differences were compared with Kruskal-Wallis tests and Mann-Whitney U post hoc tests. Proportions of participants meeting literature-recommended RTS criterion cutoffs were compared among the groups using chi-square tests. Results: The pediatric group demonstrated higher quadriceps LSI (P = 0.01), IKDC scores (P < 0.01), single-hop LSI (P < 0.01), and crossover-hop LSI (P = 0.02) compared with the young adult group. In addition, the pediatric group demonstrated higher IKDC scores (P < 0.01) and single-hop LSI (P = 0.02) compared with the adolescent group. The adolescent group demonstrated higher IKDC scores (P < 0.01), single-hop LSI (P = 0.02), and crossover-hop LSI (P = 0.03) compared with the young adult group. The proportions of participants meeting all RTS criterion cutoffs were highest in the pediatric group and lowest in the young adult group (P = 0.03). Conclusion: Young athletes at RTS clearance after pediatric ACLR demonstrated higher quadriceps strength symmetry and knee-related function than adolescents and young adults after traditional ACLR. Clinical Relevance: These findings demonstrate the need for further study regarding the impact of these group differences on longitudinal outcomes after ACLR, including successful RTS and risk of second ACL injury.
Association Between Urinary Catecholamine Excretion and Urine Volume

Abstract Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients’ age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p<0.0001). Epinephrine (p=0.0026), dopamine (p<0.0001), and metanephrine (p=0.0106) excretion decreased with age. BMI was associated with urinary excretion of dopamine (p<0.0001), norepinephrine (p=0.0026), normetanephrine (p<0.0001), and homovanillylmandelic acid (HVMA; p=0.0251). Urine volume correlated with urinary dopamine (p=0.0127), metanephrine (p<0.0001), normetanephrine (p=0.0070), and HVMA (p<0.0028) excretion. In addition to the established associations between urinary catecholamine excretion and age, gender, and BMI in the present study, urinary catecholamine excretion correlated also with urine volume.
Health-Related Quality of Life Impact from Adding Bevacizumab to Cisplatin-Pemetrexed in Malignant Pleural Mesothelioma in the MAPS IFCT-GFPC-0701 Phase III Trial

Purpose: The IFCT-GFPC-0701 MAPS phase III trial highlighted significant improvement in overall survival from adding bevacizumab to the standard first-line chemotherapy regimen [cisplatin plus pemetrexed (PC)] in advanced malignant pleural mesothelioma (MPM). We present the results of health-related quality of life (HRQoL), a secondary endpoint of MAPS. Patients and Methods: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and the lung cancer–specific module QLQ-LC13 at randomization and then every 9 weeks until disease progression. HRQoL deterioration–free survival (QFS), used to analyze longitudinal HRQoL data, was defined as the interval between randomization and the occurrence of the first clinically relevant definitive deterioration compared with the HRQoL score at baseline, or death. Results: A total of 448 patients were included in the MAPS trial between 2008 and 2014. At baseline, 425 patients (94.8%) completed the HRQoL questionnaire. We report that adding bevacizumab to cisplatin and pemetrexed (PCB) significantly improved QFS for the peripheral neuropathy dimension, with a median QFS of 12.09 months [95% confidence interval (CI), 9.59–13.67] in the PCB arm versus 7.59 months (95% CI, 6.57–8.61) in the PC arm [HR (PCB vs. PC) = 0.74; 95% CI, 0.61–0.91; P = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69–1.02; P = 0.08). Conclusions: This study demonstrated that adding bevacizumab to standard chemotherapy in patients with advanced MPM had no negative impact on HRQoL. A significant improvement in the peripheral neuropathy and pain HRQoL dimensions was even observed.
Heteromeric Neuronal Nicotinic Acetylcholine Receptors with Mutant β Subunits Acquire Sensitivity to α7-Selective Positive Allosteric Modulators

Homomeric α7 nicotinic acetylcholine receptors (nAChR) have an intrinsically low probability of opening that can be overcome by α7-selective positive allosteric modulators (PAMs), which bind at a site involving the second transmembrane domain (TM2). Mutation of a methionine that is unique to α7 at the 15′ position of TM2 to leucine, the residue in most other nAChR subunits, largely eliminates the activity of such PAMs. We tested the effect of the reverse mutation (L15′M) in heteromeric nAChR receptors containing α4 and β2, which are the nAChR subunits that are most abundant in the brain. Receptors containing these mutations were found to be strongly potentiated by the α7 PAM 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS) but insensitive to the alternative PAM 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea. The presence of the mutation in the β2 subunit was necessary and sufficient for TQS sensitivity. The primary effect of the mutation in the α4 subunit was to reduce responses to acetylcholine applied alone. Sensitivity to TQS required only a single mutant β subunit, regardless of the position of the mutant β subunit within the pentameric complex. Similar results were obtained when β2L15′M was coexpressed with α2 or α3 and when the L15′M mutation was placed in β4 and coexpressed with α2, α3, or α4. Functional receptors were not observed when β1L15′M subunits were coexpressed with other muscle nAChR subunits. The unique structure-activity relationship of PAMs and the α4β2L15′M receptor compared with α7 and the availability of high-resolution α4β2 structures may provide new insights into the fundamental mechanisms of nAChR allosteric potentiation. SIGNIFICANCE STATEMENT Heteromeric neuronal nAChRs have a relatively high initial probability of channel activation compared to receptors that are homomers of α7 subunits but are insensitive to PAMs, which greatly increase the open probability of α7 receptors. These features of heteromeric nAChR can be reversed by mutation of a single residue present in all neuronal heteromeric nAChR subunits to the sequence found in α7. Specifically, the mutation of the TM2 15′ leucine to methionine in α subunits reduces heteromeric receptor channel activation, while the same mutation in neuronal β subunits allows heteromeric receptors to respond to select α7 PAMs. The results indicate a key role for this residue in the functional differences in the two main classes of neuronal nAChRs.