Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Rho/MRTF/SRF Inhibitors Block Matrix-stiffness and TGF-&bgr;–Induced Fibrogenesis in Human Colonic Myofibroblasts

Background:Ras homolog gene family, member A (RhoA)/Rho-associated coiled-coil forming protein kinase signaling is a key pathway in multiple types of solid organ fibrosis, including intestinal fibrosis. However, the pleiotropic effects of RhoA/Rho-associated coiled-coil forming protein kinase signaling have frustrated targeted drug discovery efforts. Recent recognition of the role of Rho-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) suggest a novel locus for pharmacological intervention. Methods:Because RhoA signaling is mediated by both physical and biochemical stimuli, we examined whether pharmacological inhibition of RhoA or the downstream transcription pathway of MRTF-A/SRF could block intestinal fibrogenesis in 2 in vitro models. Results:In this study, we demonstrate that inhibition of RhoA signaling blocks both matrix-stiffness and transforming growth factor beta–induced fibrogenesis in human colonic myofibroblasts. Repression of alpha-smooth muscle actin and collagen expression was associated with the inhibition of MRTF-A nuclear localization. CCG-1423, a first-generation Rho/MRTF/SRF pathway inhibitor, repressed fibrogenesis in both models, yet has unacceptable cytotoxicity. Novel second-generation inhibitors (CCG-100602 and CCG-203971) repressed both matrix-stiffness and transforming growth factor beta–mediated fibrogenesis as determined by protein and gene expression in a dose-dependent manner. Conclusions:Targeting the Rho/MRTF/SRF mechanism with second-generation Rho/MRTF/SRF inhibitors may represent a novel approach to antifibrotic therapeutics.
The C3-V4 Region Is a Major Target of Autologous Neutralizing Antibodies in Human Immunodeficiency Virus Type 1 Subtype C Infection

ABSTRACT The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection.
Feasibility of Computerized Screening for Intimate Partner Violence in a Pediatric Emergency Department

Objectives: This study aimed to evaluate the feasibility of caregiver-initiated computerized screening in a pediatric emergency department (ED) to identify home safety risks, with a specific emphasis on intimate partner violence (IPV). Methods: Home safety screening kiosks were developed using information technology as the first step in a plan to decrease family violence. Caregivers self-initiated a standard-of-care screening process that included both non-IPV and IPV items. An ED social worker received an automated text page and printed summary of the findings when a caregiver endorsed IPV. System activity was tracked by comparing frequency of completed screens to the daily ED census and by determining the percentage of completed screens that were positive for IPV. The reliability of the technology was evaluated as percentage of days of system downtime. Meetings with ED personnel and direct observations of families were conducted to identify potential barriers and successes to the technology utilization. Results: During a 15-month period, 13,057 computerized screens occurred, with a 4-fold increase in the computerized screening rate after ED triage nurses became champions of these efforts. Fourteen percent of the computerized screens were positive for IPV. The reliability of the technology was considered quite high, with rare system downtime (4.2% of days) reported during the 15 months. There were several themes identified by caregivers and providers regarding barriers to successful use of the safety screening. Conclusions: A reliable, caregiver-initiated system is possible to offer consistent opportunity to conduct unobtrusive, private screening for IPV and other home safety concerns.
Risk factors for psychological distress following injury.

OBJECTIVES To identify predictors of psychological morbidity among injured patients admitted to an Emergency Department (ED). DESIGN A prospective cohort study. PARTICIPANTS Participants were consecutive male ED attenders. 210 (97.7%) patients consented to participate. At one month, 128 (61.0%) responded, at six months, 114 (54.3%), at eighteen months 96 (45.7%). MAIN OUTCOME MEASURES Measures immediately following injury were the Hospital Anxiety and Depression Scale, the Eysenck Personality Questionnaire and the McGill pain questionnaire. Recovery at one month was recorded using the SF-36 Health Survey, COPE scale, Perceived Stress Scale and Revised Impact of Events Scale. At six and eighteen months outcome was measured using the General Health Questionnaire (28 items) and Revised Impact of Events Scale. Multivariate analysis identified pre-morbid, accident-related and recovery factors influencing outcome at six and eighteen months. RESULTS The strongest predictors of outcome were initial levels of anxiety and depression, prior history of mental health problems, early PTSD symptoms and involvement in litigation. These factors predicted between 40-60% of the variance at six months (p<0.001), and 50-60% of the variance in psychological distress at eighteen months (p<0.001). CONCLUSION Factors identifying individuals at-risk from psychological distress following injury include those related to the immediate response and the recovery phases of injury. Further development is needed to convert identified predictors into a comprehensive screening tool for clinical use.
Circulating angiotensin converting enzyme activity is correlated with muscle strength.

PURPOSE The D-variant of the angiotensin-1 converting enzyme (ACE) gene is associated with higher circulating and tissue ACE activity. Some studies have suggested a similar association of genotype with muscle strength or the gain in strength in response to training. This study has assessed the relationship between circulating ACE activity, strength, and the response to training. METHODS Eighty-one untrained men were tested for quadriceps muscle strength, and 44 of these performed an 8-wk program of dynamic strength training of the quadriceps muscle group. Venous blood was obtained for assessment of circulating ACE activity before and after the training program. ACE genotype was also determined. RESULTS At baseline, circulating ACE activity was significantly correlated with isometric (r = 0.25-0.29, P < 0.02) and isokinetic (r = 0.38, P < 0.0005) quadriceps muscle strength. ACE genotype also seemed to be related to pretraining muscle strength. However, circulating ACE activity showed no significant association with the 9-14% mean increases of muscle strength in response to the training intervention. ACE genotype also showed no association with the training-induced change in muscle strength. Circulating ACE activity did not change significantly after the training program. CONCLUSIONS The data support a role for ACE in the regulation of human skeletal muscle strength, but do not confirm a role in altering the response to short-term training.
Attention Deficit/Hyperactivity Disorder and pediatric burn injury: important considerations regarding premorbid risk

Purpose of review The purpose of this review is to provide an overview of the literature on the effects of Attention Deficit/Hyperactivity Disorder on pediatric burn injury, to identify specific considerations and trends relevant to this topic, and to call attention to areas for future research. Recent findings There is growing evidence for increased risk of burn injury in children with Attention Deficit/Hyperactivity Disorder and externalizing behavioral disorders. Research indicates increased risk of burn morbidity and poorer adjustment following burn injury in these patients. Evidence suggests that stimulant treatment may be useful for reducing risk of burn injury and questions the use of ‘drug holidays’. Research suggests prevention measures specific to this population, including increased supervision. Primary care providers can further educate patients and families regarding increased risk for injury due to Attention Deficit/Hyperactivity Disorder or symptoms of impulsivity and inattention that accompany other behavioral disorders, neurological conditions, and disabilities. Summary Information regarding the risk of burn injury in children with symptoms of Attention Deficit/Hyperactivity Disorder is gradually gaining more attention. There is continued need for further investigation in this area, as well as critical assessment of intervention programs for this subgroup of individuals.
Comparing Viability of Periodontal Ligament Stem Cells Isolated From Erupted and Impacted Tooth Root

Purpose:The aim of the study was to compare the viability of periodontal ligament-derived stem/progenitor cells (PDLSCs) from 2 different sources. Materials and Methods:Periodontal ligament (PDL) tissue was obtained from 20 surgically extracted human third molars and 20 healthy premolars extracted for orthodontic reasons. Periodontal ligament-derived stem/progenitor cells were isolated from 2 different PDL tissue sources and characterized by colony forming unit assay, cell surface marker characterizations, and their osteogenic differentiation potential. To determine cell viability within 2 groups, the colorimetric 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) metabolic activity assay was used. Data were statistically analyzed using independent t-test by SPSS 16 software (SPSS Inc, Chicago, IL). Results:According to the MTT assay, the mean viability rate ± standard deviation of PDLSCs in the impacted third molar sample cells was 0.355 ± 0.411 and for erupted premolar sample cells was 0.331 ± 0.556. Based on One-Sample Kolmogorov-Smirnov test, P value for impacted and erupted teeth was 0.954 and 0.863, respectively. No statistical difference was seen between 2 groups. (P value > 0.05) Conclusions:Our results demonstrated that if surgical aseptic technique is a method employed to maintain asepsis, PDLSCs obtained from impacted and erupted tooth root would have the same viability rate.
Born to be Anxious: Neuroendocrine and Genetic Correlates of Trait Anxiety in HAB Rats

This review summarises behavioural, neuroendocrine, and genetic characteristics of Wistar rats bred for either high (HAB) or low (LAB) anxiety-related behaviour. Compared to LABs, HAB animals show signs of extreme trait anxiety in a variety of behavioural tests; they further prefer passive coping strategies, indicative of a genetically linked depression-like behaviour, and show signs of increased stress vulnerability. All behavioural parameters associated with trait anxiety are robust and consistent. Resembling psychiatric patients, HAB rats respond to exposure to ethologically relevant stressors with a hyper-reactivity of the hypothalamic-pituitary-adrenal axis and show a pathological outcome of the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) challenge test. Experimental evidence indicates that over-expression and -release of vasopressin in the hypothalamic paraventricular nucleus is responsible for these behavioural and neuroendocrine phenomena, making the neuropeptide gene a candidate gene of trait anxiety/depression. Indeed, preliminary molecular genetic approaches succeeded in identifying polymorphisms in the promoter structure of the vasopressin gene. This may have implications for understanding the molecular basis for individual variations in trait anxiety and for psychopathology.
Effects of Synchronous Whole Body Vibration Training on a Soft, Unstable Surface in Athletes with Chronic Ankle Instability

Abstract The aim of this study was to evaluate the effects of a 6-week WBV training program, performed on a soft, unstable surface, on peak torque, reaction time and the electrical activity of ankle muscles in recreational athletes with chronic ankle instability (CAI). 50 recreational athletes with self-reported unilateral CAI were randomly assigned to a vibration group (VIB), non-vibration group (N-VIB) or control group. The VIB and N-VIB groups performed unilateral balance training on the unstable ankle on a BOSU® Balance Trainer 3 times weekly for 6 weeks. The VIB group trained on a vibration platform, and the N-VIB group trained on the floor. Muscle reaction times and electrical activity of the peroneus brevis (PB), peroneus longus (PL) and tibialis anterior (TA) muscles were assessed in response to sudden inversion, isokinetic peak torque and isokinetic strength ratios of the ankle evertor muscles. After 6 weeks of training, a significant improvement was shown in reaction times of the PB (Pre=60.99±9.17 ms, Post1=54.90±6.99 ms, p=0.003), PL (Pre=61.20±10.72 ms, Post1=55.21±9.04 ms, p=0.007) and TA (Pre=65.31±11.78 ms, Post1=59.07±9.99 ms, p=0.007) muscles in the VIB group, whereas no significant changes were found in the N-VIB group or the control group. There were no significant changes in electrical activity, peak torque and eccentric-concentric ratio for any of the groups after training. In conclusion, a 6-week WBV training program on a soft, unstable surface improves the reaction times of the PB, PL and TA muscles in recreational athletes with CAI. Trial registration: ClinicalTrials.gov NCT02794194
Body fat excess and stimulated growth hormone levels in adult patients with Prader–Willi syndrome

It has been suggested that reduced GH secretion in Prader–Willi syndrome (PWS) may simply reflect their excessive fat body mass. However, the GH response to standard provocative tests is significantly lower in PWS adults than obese controls with similar body mass index (BMI). Nevertheless, BMI is an inadequate measure of body composition, because PWS harbor a higher percentage of fat body mass (FM%) than simple obesity, under the same degree of weight excess. This study evaluated either the GH response to combined GHRH + arginine administration and the FM%, by DEXA, in 11 PWS adults (8 females, aged 20.1–41.1 years, BMI 43.6 ± 1.8, FM% 53.0 ± 1.5), in comparison to those obtained in 10 patients with essential obesity (8 females, aged 23.5–45.8 years), matched for BMI and FM% (42.9 ± 0.4 and 51.5 ± 1.0, respectively). Moreover, IGF‐I levels were measured in both groups. The GH response to GHRH + arginine was significantly lower in PWS patients (GH peak 5.4 ± 1.3 µg/L; area under the curve (AUC) 311.2 ± 72.5 µg/L/hr) than obese controls (GH peak 21.0 ± 4.1 µg/L, P < 0.005; AUC 1241.1 ± 272.8 µg/L/hr; P < 0.01), as well as IGF‐I values (110.5 ± 16.7 µg/L vs. 242.1 ± 31 µg/L, P < 0.005). The GHRH + arginine induced GH rise in patients with del15q11‐q13 was significantly higher than subjects with UPD15 (GH peak 7.7 ± 1.7 µg/L vs. 2.7 ± 1.0 µg/L, P < 0.05; AUC 458.5 ± 91.0 µg/L/hr vs. 134.4 ± 46.0 µg/L/hr, P < 0.02). These findings suggested that stimulated GH levels are significantly lower in PWS adults when compared to obese controls and that GH response to GHRH + arginine is different in PWS individuals having separate genetic subtypes. © 2009 Wiley‐Liss, Inc.
Decorin: a possible marker for fetal growth restriction

Abstract The aim of this study was to compare decorin (DCN) levels between pregnancies complicated by idiopathic fetal growth restriction (FGR) and uncomplicated pregnancies and to determine the relationship between DCN levels and clinical parameters. The study population consisted of two groups: control group consisted of 13 women with uncomplicated singleton pregnancies in the third trimester. Study group consisted of 14 singleton pregnancies complicated by idiopathic FGR who were admitted to the hospital for delivery in the third trimester of pregnancy. Maternal and fetal DCN levels were measured. Color Doppler flow assessments were performed. Relationship between DCN levels and clinical parameters was determined. Maternal DCN serum levels were significantly higher in complicated pregnancies by idiopathic FGR (p = 0.01). A statistically significant negative correlation was observed between maternal DCN serum levels and neonatal birth weight (r = −0.0506; p = 0.007). There was a significant correlation between umbilical artery (UA) DCN levels and UA S/D ratio (r = 0.512; p = 0.006) and UA RI (r = 0.405; p = 0.036). The risk of high DCN maternal serum levels (>7986.6 pg/mL) in pregnancy complicated by FGR was 8.25 times higher (RR = 8.25; 95% CI, 1.4–46.8). The results of our study showed that the presence of increased DCN levels in women with FGR could contribute to pathogenesis of the disease.
Optical Coherence Tomography-based Diagnosis of Polypoidal Choroidal Vasculopathy in Korean Patients

Purpose To evaluate the efficacy of an optical coherence tomography (OCT)-based diagnosis of polypoidal choroidal vasculopathy (PCV) in Korean patients. Methods This retrospective, observational case series included 263 eyes of 263 patients (147 eyes with PCV and 116 eyes with typical exudative, age-related macular degeneration [AMD]) who had been diagnosed with treatment naïve exudative AMD. Eyes with three or more of the following OCT findings were diagnosed with PCV: multiple retinal pigment epithelial detachment (RPED), a sharp RPED peak, an RPED notch, a hyporeflective lumen representing polyps, and hyperreflective intraretinal hard exudates. The OCT-based diagnosis was compared with the gold-standard indocyanine green angiography-based method. The sensitivity and specificity of the OCT-based diagnosis was also estimated. An additional analysis was performed using a choroidal thickness criterion. Eyes with a subfoveal choroidal thickness greater than 300 µm were also diagnosed with PCV despite having only two OCT features. Results In eyes with PCV, three or more OCT features were observed in 126 of 147 eyes (85.7%), and the incidence of typical exudative AMD was 16 of 116 eyes (13.8%). The sensitivity and specificity of an OCT-based diagnosis were 85.7% and 86.2%, respectively. After applying the choroidal thickness criterion, the sensitivity increased from 85.7% to 89.8%, and the specificity decreased from 86.2% to 84.5%. Conclusions The OCT-based diagnosis of PCV showed a high sensitivity and specificity in Korean patients. The addition of a choroidal thickness criterion improved the sensitivity of the method with a minimal decrease in its specificity.
Network Meta-Analysis of Pharmacological Agents for Osteoporosis Treatment and Fracture Prevention

Background and Objective: Osteoporosis afflicts a large number of populations in the world and is featured by systemic impairment of bone mass and strength which may further trigger an increase in the risk of fragile fractures. This network meta-analysis (NMA) is designed to distinguish therapies more preferable than others with respect to efficacy and safety. Methods: We searched the medical literature for relevant studies systematically. Both direct and indirect evidence were synthesized to compare the efficacy, described by odds ratios (OR) and 95% credible intervals (CrI). Moreover, the surface under cumulative ranking curve was calculated to rank probabilities with respect to clinical outcomes. The new non-vertebral fractures, hip and wrist fractures, and adverse events were evaluated in this NMA. Results: Patients treated by alendronate, denosumab, teriparatide were associated with a reduced risk of new non-vertebral fractures compared to those treated by placebo. Alendronate, denosumab and zoledronic acid had better efficacy in preventing hip fractures. With respect to wrist fractures prevention, no significant difference was observed. Zoledronic acid exhibited significantly increased risk of adverse events than placebo, alendronate, denosumab, and raloxifene. According to SUCRA, teriparatide ranked highest in new non-vertebral fractures prevention, etidronate and denosumab balanced safety and efficacy well. Conclusion: In summary, teriparatide appeared to be the most efficacious drug for preventing new non-vertebral fractures, while etidronate and denosumab were preferable for balancing safety and efficacy well.
Preparation and characterization of beta-glucan particles containing a payload of nanoembedded rifabutin for enhanced targeted delivery to macrophages

β-glucan particles (GP) are polymeric carbohydrates, mainly found as components of cell wall fungi, yeast, bacteria and also in cereals such as barley and oat, and have been recently shown to have application in macrophage-targeted drug delivery. The aim of this study was to prepare and characterize GP containing a large payload of Rifabutin (RB), an anti-tuberculosis drug effective against MDR-TB at lower MIC than Rifampicin. GP were prepared from yeast cells by acidic and alkaline extraction were either spray dried or lyophilized, prior to RB loading and alginate sealing. The FTIR and 13C-NMR spectra of the GP confirmed a β-(1→3) linked glucan structure, with a triple-helical conformation. The spray dried GP exhibited better characteristics in terms of uniformity, size range (2.9 to 6.1 µm) and more than 75 % particles were below 3.5 μm. The RP-HPLC analysis of spray dried GP revealed drug entrapment and drug loading up to 81.46 ± 4.9 % and ~40.5 ± 1.9 %, respectively, as compared to those dried by lyophilization. Electron microscopy showed nearly spherical and porous nature of GP, and the presence of drug 'nanoprecipitates' filling the pore spaces. The formulation showed adequate thermal stability for pharmaceutical application. The particles were readily phagocytosed by macrophage(s) within 5 min of exposure. Drug release occurred in a sustained manner via diffusion, as the release kinetics best fit for drug release was obtained using Higuchi's equation. Thus, the spray dried GP-based-formulation technology holds promise for enhanced targeted delivery of anti-TB drug(s) to macrophage within a therapeutic window for the clearance of intracellular bacteria.