Miracle-dz/UniFAR-FTUs huggingface dataset:
Lack of Pharmacokinetic Interaction between Gemifloxacin and Digoxin in Healthy Elderly Volunteers

Gemifloxacin is a novel fluoroquinolone with a broad spectrum of antibacterial activity. The objective of this double-blind, randomized, placebo-controlled, 2-way crossover study was to demonstrate the lack of a pharmacokinetic interaction between gemifloxacin and digoxin. During two 14-day treatment periods, healthy elderly volunteers received digoxin (0.25 mg, once daily) co-administered on days 8–14 with either gemifloxacin (320 mg, p.o., once daily) or placebo. On day 14 of each period, blood samples and urine were collected for 24 h post dose and analysed for digoxin levels by radioimmunoassay. Steady-state digoxin pharmacokinetics were not affected by multiple dosing with gemifloxacin. There was no significant difference in digoxin values for the area under the plasma concentration-time curve over the dosing interval 0–24 h (AUC(0–24)) or the trough plasma concentration (C24) after co-administration with either gemifloxacin or placebo. Geometric means for AUC(0–24) and C24 were 18.1 and 17.8 ng·h/ml and 0.597 and 0.566 ng/ml, respectively. The point estimates (90% confidence intervals) for AUC(0–24) and C24 (digoxin + gemifloxacin):(digoxin + placebo) were 1.01 (0.93, 1.10) and 1.05 (0.95, 1.16), respectively, entirely within the equivalence range (0.80, 1.25). There were no marked differences between co-administration regimens for maximum observed plasma concentration (Cmax) or renal clearance values. Gemifloxacin was well tolerated during co-administration with digoxin, and the incidence of adverse events was similar to that seen with placebo. There were no clinically relevant changes in vital signs, electrocardiogram readings or laboratory parameters. In conclusion, this study demonstrates that gemifloxacin may be co-administered with digoxin without the need for digoxin dose adjustment.
Management of the labyrinthine fistula in cholesteatoma surgery.

The presence of a labyrinthine fistula has remained one of the major problems in cholesteatoma surgery. Confronted with this problem, the surgeon may ultimately base his choice of procedure on four basic conditions: the size of the fistula, its location in the ear, the condition of the other ear, and the cochlear function. Our attitude has been changing, and currently we prefer to perform a staged closed tympanoplasty. When a closed technique is performed, we either remove the cholesteatoma matrix and then cover the fistula immediately or we leave the matrix in situ and re-explore the mastoid process 5 or 6 months later. The series consists of 88 cases out of a total of 701 patients with cholesteatoma operated on between January 1971 and June 1982. In 20 patients the matrix was left over the fistula at the first stage. The results suggest that a staged operation, i.e. closed tympanoplasty, is to be preferred even in cases with an extensive labyrinthine fistula.
Measurement of Health-Related and Oral Health–Related Quality of Life among Individuals with Nonsyndromic Orofacial Clefts: A Systematic Review and Meta-Analysis

Objective To compare health-related quality of life and oral health–related quality of life between nonsyndromic individuals with and without cleft lip and/or cleft palate and to identify the most affected quality of life dimensions in individuals with cleft lip and/or palate. Design Systematic review and meta-analysis were conducted. Of the 314 identified citations, 23 articles were submitted to quality assessment. Data from nine studies on health-related quality of life and six on oral health–related quality of life were extracted for meta-analysis. Main Outcome Measures Pooled mean differences of health-related quality of life between adults with and without cleft lip and/or palate, pooled means of health-related quality of life dimensions of children and adults with cleft lip and/or palate and oral health–related quality of life dimensions of children and adolescents with cleft lip and/or palate with a 95% confidence interval were calculated. Results Quality assessment revealed methodological differences between studies. Lack of subgroup stratification and absence of control for confounders were the main limitations. Heterogeneity was detected on the comparison of oral health–related quality of life and health-related quality of life between children with and without cleft lip and/or palate, and oral health–related quality of life between adolescents with and without cleft lip and/or palate. A random-effect model showed a significant difference on health-related quality of life between adults with and without cleft lip and/or palate (mean difference = 0.10; 95% confidence interval, 0.16 to 0.05). Psychological health (mean, 78.9; 95% confidence interval, 70.1 to 87.7) and vitality (mean, 68.1; 95% confidence interval, 48.0 to 88.1) were the most affected health-related quality of life dimensions in children and adults with cleft lip and/or palate, respectively. Means of health-related quality of life dimensions in children and adults with cleft lip and/or palate and oral health–related quality of life in children and adolescents with cleft lip and/or palate varied yet did not differ in indirect comparisons. Conclusion The presence of cleft lip and/or palate negatively affected the health-related quality of life of adults, mainly on psychosocial dimensions.
Identification of Gene Transcripts Implicated in Peritoneal Membrane Alterations

♦ Background: Permanent stimulation of the peritoneum during peritoneal dialysis (PD) is likely to result in increased expression of genes encoding proteins involved in inflammation and tissue remodeling. Peritoneal fibrosis and neoangiogenesis may develop. ♦ Objective: To assess highly expressed genes potentially in volved in peritoneal alterations during PD treatment using an animal model. ♦ Methods: A PD catheter was implanted in 36 male Wistar rats after 70% nephrectomy. The rats were divided into 3 groups, exposed to dialysis solution for 8 weeks, and sacrificed 2 weeks later. Group B was exposed to a buffer, group D was exposed to a 3.86% glucose-based dialysis solution, and in group D+H, a second hit of intraperitoneal blood on top of the dialysis solution was given to induce the development of peritoneal sclerosis. Before sacrifice, peritoneal function was assessed. Omental tissue was obtained for analysis of gene expression using RT-qPCR. ♦ Results: Fibrosis scores, vessel counts, and peritoneal function parameters were not different between the groups. Genes involved in the transforming growth factor beta signaling pathway, cell proliferation, angiogenesis, and inflammation were more expressed (p < 0.05) in the D+H group. Almost no differences were found between the control groups. We identified 4 genes that were related to peritoneal transport. ♦ Conclusion: Already a mid-term peritoneal exposure, when no microscopical and functional alterations are present, provokes activation of gene pathways of cell proliferation, fibrosis, neoangiogenesis, and inflammation.
Changes in the Meibomian Gland After Exposure to Intense Pulsed Light in Meibomian Gland Dysfunction (MGD) Patients

ABSTRACT Purpose: To observe (1) changes in meibomian gland (MG) after exposure to intense pulsed light (IPL) and (2) to understand the mechanism by which IPL treats meibomian gland dysfunction (MGD) in patients. Methods: A cohort study, including 35 MGD patients, was conducted. IPL treatment was administered in one group (IPL group; n = 18), and eyelid hygiene in another (control group; n = 17) for 3 months. All patients were given artificial tears during the treatment period. Associated ocular-surface indexes (ocular surface disease index, OSDI; tear breakup time, TBUT, Schirmer 1Test, corneal staining, and conjunctival staining), MG function, MG macro-morphology, and MG micro-morphology were examined before and after treatment. The relationships between the change in symptom score and the change in the other indexes (related ocular-surface indexes, MG functional indexes, and MG morphological indexes) were evaluated. Results: There was no statistical difference in pretreatment between the IPL and the control groups in terms of age, gender, related medical history, MGD stage, and all examined indexes, with the exception of conjunctival staining. OSDI, TBUT, meibum quality, MG expressibility, and MG dropout improved after treatment in both of the two groups (all P < 0.05). The MG microstructure indexes, including the MG acinar longest diameter (ALD), MG acinar unit density (AUD), and the positive rate of inflammatory cells (ICs) around glandular structures were significantly improved in the IPL group. No improvements of microstructure were found in the control group. Conclusion: IPL treatment improves the symptom score of patients, associated ocular-surface indexes, MG function, and MG macrostructure as well as eyelid hygiene. And IPL treatment particularly improves MG microstructure and decreases MG inflammation in MGD patients.
Effects of Budesonide on Cabazitaxel Pharmacokinetics and Cabazitaxel-Induced Diarrhea: A Randomized, Open-Label Multicenter Phase II Study

Purpose: Forty-seven percent of patients in the pivotal trial of cabazitaxel reported diarrhea of any grade. Aiming to reduce the incidence of diarrhea, we studied the effects of budesonide on the grade of cabazitaxel-induced diarrhea during the first two treatment cycles. Experimental Design: Between December 2011 and October 2015, 246 metastatic castration-resistant prostate cancer patients were randomized to receive standard-of-care cabazitaxel 25 mg/m2 every 3 weeks plus prednisone 10 mg/day (group CABA) or same dose/schedule of cabazitaxel with concomitant budesonide 9 mg daily during the first two treatment cycles (group BUD). The occurrence of diarrhea was reported by physicians and by patients in a diary. χ2 tests were used to compare incidence numbers. An intention-to-treat principle was used. Results: In the phase II trial, 227 patients were evaluable. Grade 2–3 diarrhea occurred in 35 patients (15%) and grade 4 diarrhea was not reported. The incidence of grade 2–3 diarrhea was comparable in both treatment groups: 14 of 113 patients in group CABA (12%) versus 21 of 114 patients in group BUD (18%; P = 0.21). Seven patients were admitted to the hospital with diarrhea (n = 5 group CABA vs. n = 2 group BUD). PSA response was seen in 30% of patients and was not affected by budesonide coadministration (P = 0.29). Also, other toxicities were not affected by budesonide coadministration. Conclusions: The incidence of cabazitaxel-induced diarrhea was notably lower than reported in the TROPIC trial and appears manageable in routine clinical practice. Budesonide coadministration did not reduce the incidence or severity of cabazitaxel-induced diarrhea. Clin Cancer Res; 23(7); 1679–83. ©2016 AACR.
Regulation of Synapse Development by Vgat Deletion from ErbB4-Positive Interneurons

GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter (Vgat) in ErbB4+ interneurons. We show that inhibitory axo–somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. Conversely, parvalbumin-positive (PV+)/ErbB4+ interneurons and PV-only interneurons receive a higher number of inhibitory synapses from PV+ErbB4+ interneurons compared with ErbB4-only interneurons. Vgat deletion from ErbB4+ interneurons reduced axo–somatic or axo–axonic synapses from PV+ErbB4+ interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the Vgat mutation seemed to have little effect on inhibitory synapses onto PV+ and/or ErbB4+ interneurons. Interestingly, perineuronal nets, extracellular matrix structures implicated in maturation, survival, protection, and plasticity of PV+ interneurons, were increased in the cortex of ErbB4-Vgat−/− mice. No apparent difference was observed between males and females. These results demonstrate that Vgat of ErbB4+ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly. SIGNIFICANCE STATEMENT GABA has been implicated in neural development, but in vivo genetic evidence is missing because mutant mice lacking GABA die prematurely. Here, we ablated Vgat in ErbB4+ interneurons in an inducible manner. We provide evidence that the formation of inhibitory and excitatory synapses onto excitatory neurons requires Vgat in interneurons. In particular, inhibitory axo–somatic and axo–axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly.
The Sda and Cad glycan antigens and their glycosyltransferase, β1,4GalNAcT‐II, in xenotransplantation

Antibody‐mediated rejection is a barrier to the clinical application of xenotransplantation, and xenoantigens play an important role in this process. Early research suggested that N‐acetyl‐D‐galactosamine (GalNAc) could serve as a potential xenoantigen. GalNAc is the immunodominant glycan of the Sda antigen. Recently, knockout of β1,4‐N‐acetylgalactosaminyltransferase 2 (β1,4GalNAcT‐II) from the pig results in a decrease in binding of human serum antibodies to pig cells. It is believed that this is the result of the elimination of the GalNAc on the Sda antigen, which is catalyzed by the enzyme, β1,4GalNAcT‐II. However, research into human blood group antigens suggests that only a small percentage (1%‐2%) of people express anti‐Sda antibodies directed to Sda antigen, and yet a majority appear to have antibodies directed to the products of pig B4GALNT2. Questions can therefore be asked as to (i) whether the comprehensive structure of the Sda antigen in humans, that is, the underlying sugar structure, is identical to the Sda antigen in pigs, (ii) whether the human anti‐Sda antibody binds ubiquitously to pig cells, but not to human cells, and (iii) what role the Sda++ (also called Cad) antigen is playing in this discrepancy. We review what is known about these antigens and discuss the discrepancies that have been noted above.
Ability of a Urine Assay of Type II Collagen Cleavage by Collagenases to Detect Early Onset and Progression of Articular Cartilage Degeneration: Results from a Population-based Cohort Study

Objective. To evaluate the association of a sandwich assay for cartilage collagenase-mediated degradation, the C2C human urine sandwich assay (IB-C2C-HUSA), with early and late knee cartilage pathology and with progression of cartilage damage. Methods. A population-based cohort with knee pain, age 40–79 years, was evaluated at baseline (n = 253) and after mean 3.3 years (n = 161). We evaluated the IB-C2C-HUSA and a related competitive inhibition assay (C2C). The C2C assay was applied to serum (sC2C) and urine (uC2C). Based on knee radiographs and magnetic resonance imaging (MRI), 3 subgroups [no cartilage pathology, preradiographic cartilage pathology, and radiographic osteoarthritis (ROA)] were evaluated cross-sectionally for association with biomarker levels. Longitudinally, we evaluated whether baseline assays predict subsequent progression of cartilage degeneration, defined by MRI cartilage loss. Results. Cross-sectionally, statistically significant differences were seen in the 3 subgroups for IB-C2C-HUSA (p < 0.001), with the highest levels seen in ROA, and for sC2C (p = 0.023), while no differences were seen for uC2C (p = 0.501). Baseline IB-C2C-HUSA levels were higher in progressors vs nonprogressors (p = 0.003). In logistic regression analysis, only baseline IB-C2C-HUSA was associated with an increased risk of progression of cartilage damage (OR 1.78, 95% CI 1.03–3.09). Conclusion. The IB-C2C-HUSA degradation assay detects the generation of a pathology-related cartilage collagen peptide(s) that increase(s) with onset of degeneration of knee articular cartilage. The baseline values are associated with progression of cartilage degeneration over 3 subsequent years. This assay may have value in clinical OA trials. Further, it points to collagenase activity as a therapeutic target for controlling degeneration of articular cartilage.
Development of decellularized conjunctiva as a substrate for the ex vivo expansion of conjunctival epithelium

This study was performed to develop a method to decellularize human conjunctiva and to characterize the tissue in terms of its deoxyribose nucleic acid (DNA) content, tensile strength, collagen denaturation, basement membrane, extracellular matrix components and its potential to support conjunctival epithelial growth. Human conjunctival tissues were subjected to a decellularization process involving hypotonic detergent and nuclease buffers. Variations in sodium dodecyl sulfate concentration (0.05–0.5%, w/v) were tested to determine the appropriate concentration of detergent buffer. DNA quantification, collagen denaturation, cytotoxicity and tensile strength were investigated. Human conjunctival cell growth by explant culture on the decellularized tissue substrate was assessed after 28 days in culture. Samples were fixed and paraffin embedded for immunohistochemistry including conjunctival epithelial cell markers and extracellular matrix proteins. Conjunctival tissue from 20 eyes of 10 donors (age range 65–92 years) was used. Decellularization of human conjunctiva was achieved to 99% or greater DNA removal (p < 0.001) with absence of nuclear staining. This was reproducible at the lowest concentration of sodium dodecyl sulfate (0.05% w/v). No collagen denaturation (p = 0.74) and no difference in tensile strength parameters was demonstrated following decellularization. No significant difference was noted in the immunolocalization of collagen IV, laminin and fibronectin, or in the appearance of periodic acid–Schiff‐stained basement membranes following decellularization. The decellularized tissue did not exhibit any cytotoxicity and explant culture resulted in the growth of stratified conjunctival epithelium. Allogeneic decellularized human conjunctiva can be successfully decellularized using the described protocol. It represents a novel substrate to support the expansion of conjunctival epithelium for ocular surface cellular replacement therapies. Copyright © 2017 John Wiley & Sons, Ltd.
Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation

Accumulating evidences showed metformin and berberine, well‐known glucose‐lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP‐activated protein kinase (AMPK) α1/2 were exploited to inactivate AMPK pathway. Cellular NAD+/NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD+/NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output in vitro, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis via non‐AMPK pathway, which may relate to the suppression of the cellular NAD+/NADH ratio.
Hepatitis E virus infection of slaughtered healthy pigs in Brazil

Hepatitis E virus (HEV) is an emerging pathogen that can be transmitted through contaminated raw or undercooked meat derived from domestic pigs. HEV infections have been documented among pig herds, pig products and environmental samples raising concern about the spread of the virus. HEV genotypes 3 and 4 are considered zoonotic and have been linked to human cases. HEV was detected in 51 of 335 bile samples (15.2%) from healthy pigs in Minas Gerais, Brazil. Phylogenetic analysis of partial sequences from ORF1 and ORF2 regions yielded discordant results, assigning isolates to subtypes 3c and 3i, respectively, suggesting intragenotypic HEV recombination.
Clinicopathologic significance of ROCK2 expression in oral squamous cell carcinomas

BACKGROUND Rho-associated coiled-coil kinase 2 (ROCK2) is an oncoprotein that controls cytoskeleton organization and acts as prognostic marker in different types of solid tumors. ROCK2 overexpression is also observed in cancer-associated fibroblasts (CAF), which suggests its relevance within the tumor microenvironment. This study aimed to access the prognostic value of ROCK2 in oral squamous cell carcinomas (OSCCs) and its association with CAF density. METHODS Rho-associated coiled-coil kinase 2 immunohistochemical analysis was applied in 93 OSCC samples from 2 centers in Brazil and Finland. The samples were also stained for isoform α of smooth muscle actin (α-SMA) to characterize the presence of CAF in the tumor stroma. Clinicopathological associations were analyzed using Chi-squared test, survival curves were constructed according to the Kaplan-Meier method, and Cox proportional hazard model was applied for multivariate survival analysis. RESULTS Advanced clinical stage (P = .002) and increased density of CAF (P = .002) were significantly associated with high ROCK2 expression. The high expression of ROCK2 was also associated with shortened disease-specific survival (HR: 2.22, 95% CI: 1.15-4.38, P = .04), but the association did not withstand the Cox multivariate survival analysis. CONCLUSIONS The findings suggest that high ROCK2 expression in OSCC is associated with advanced disease and follows the increase in CAF density, which may be important for tumor progression.