Miracle-dz/UniFAR-FTUs huggingface dataset:
Analysis of safety and efficacy of pegylated-interferon alpha-2a in hepatitis C virus positive hemodialysis patients: results from a large, multicenter audit.

BACKGROUND Hepatitis C virus (HCV) infection rates are still high in hemodialysis (HD) centers in developing countries. Standard interferon (IFN) monotherapy is associated with good results in HCV-positive patients (more than 30% rate of sustained virological response) but with poor tolerance. Pegylated interferon (PEG-IFN) is better tolerated and has a more sustained antiviral effect in the general population. There have been no large trials to date with PEG-IFN in hemodialysis populations. METHODS We report the largest series to date of HCV+ HD patients (n=78) treated with PEG-IFN alfa -2a 135 microg s.c. weekly monotherapy. The primary outcomes were (a) efficacy - assessed by the viral response at 12, 48 weeks and 6 months after completion of therapy, and (b) rate of serious adverse events. RESULTS In 48/78 (61.5%) patients an early (12 weeks) viral response was obtained. Viral end-of-treatment response (ETR) was evaluated in the 21 patients (26.9%) who reached week 48 on therapy: only 15 subjects (19.2% of the initial population) had undetectable HCV-RNA levels. In these 15 patients, a sustained viral response (SVR) was recorded in 11 - i.e. 14.1% of the initial intention-to-treat (ITT) population. A high prevalence of noncompliance (32%) and of adverse events (83%) was recorded; minor adverse effects (flu-like syndrome, mild-to-moderate thrombocytopenia, leukopenia and anemia) responded to symptomatic therapy or dose reduction, but often caused lack of compliance. The incidence rate of serious adverse events was 0.19/patient-year (median time to event 20.5 weeks), and incidence of deaths was 0.11/patient-year. CONCLUSIONS In dialysis patients, PEG-IFN alfa -2a is poorly tolerated and associated with a high number of serious adverse events, causing a significant lack of compliance/discontinuation of therapy. In this largest HCV-positive hemodialysis population survey, we report a low sustained viral response in an ITT analysis, compared with previously published historical data using non-PEG-IFN, a low compliance rate and an unsatisfactory overall safety profile, not supporting the superiority of PEG-IFN monotherapy.
No Pharmacokinetic Interaction Between Lacosamide and Carbamazepine in Healthy Volunteers

Lacosamide is a new antiepileptic drug for adjunctive treatment of adult partial‐onset seizures. Two open‐label, multiple‐dose clinical trials were conducted to evaluate the potential for pharmacokinetic interaction between lacosamide and carbamazepine. The influence of carbamazepine on lacosamide pharmacokinetics (trial A) and lacosamide on carbamazepine pharmacokinetics (trial B) was investigated in 19 (trial A) and 18 (trial B) healthy male participants. Trial A participants received lacosamide 200 mg bid alone and with carbamazepine 200 mg bid. Trial B participants received carbamazepine 200 mg bid alone and with lacosamide 200 mg bid. Pharmacokinetic parameters, area under the concentration‐time curve during a dosage interval at steady state (AUCτ,ss), and maximum steady‐state plasma drug concentration during a dosage interval (Cmax,ss) of lacosamide, carbamazepine, and carbamazepine‐10,11‐epoxide were measured and compared for each drug alone and together. The AUCτ,ss and Cmax,ss point estimates (combined vs sole treatment) showed relative bioavailability of approximately 100% for both drugs. All 90% confidence intervals of AUCτ,ss and Cmax,ss were within the generally accepted bioequivalence ranges of 80% to 125%. No changes in rate or extent of absorption or terminal half‐life were observed. These results suggest that lacosamide and carbamazepine have a low potential for pharmacokinetic drug‐drug interaction in clinical use.
Premenstrual Symptoms in Women with Premenstrual Asthma

Study Objectives. To characterize and compare premenstrual symptoms (mood, physical) throughout two menstrual cycles with and without estradiol administration, in women with premenstrual asthma (PMA), and to examine relationships between asthma symptoms versus premenstrual symptoms and pulmonary function versus premenstrual symptoms in these women.
LTV vs. DTI Constraints: When Did They Bind, and How Do They Interact?

I document that the elasticity of mortgage loan origination with respect to house prices is highly dependent on the change in personal incomes and vice versa, using U.S. county-level panel data. I rationalize this in a model with two occasionally binding borrowing constraints: a loan-to-value (LTV) constraint and a debt-service-to-income (DTI) constraint. A Bayesian estimation of the model infers when the LTV and DTI constraints have been binding during 1975-2017, and which shocks that caused them to bind. A macroprudential experiment shows that countercyclical LTV limits cannot dampen mortgage debt growth in expansions, but DTI limits can.
New trends in medium-voltage power converters and motor drives

This paper describes a five-level diode-clamped PWM inverter intended for a medium-voltage motor drive without regenerative braking. It is equipped with a specially-designed circuit that plays an important role in achieving voltage balancing of the four split dc capacitors connected in series at the dc input terminals of the inverter. The voltage-balancing circuit frees the inverter to concentrate on the motor control. Then, this paper has an intensive discussion on the modular multilevel cascade converter (MMCC) family that are characterized by the modular structure of either bridge cell or chopper cell. The four family members are compared from various points of view, along with applications of two promising members to a medium-voltage battery energy storage system and a medium-voltage motor drives for energy savings.
Study of sociodemographic variables linked to lifestyle and their possible influence on cognitive reserve

Cognitive reserve is an active mechanism based on the application of resources learned thanks to a good education, profession, or premorbid intelligence. The aim of this research is to study whether the inclusion of sociodemographic variables linked to lifestyle can discriminate individuals more effectively regarding their level of cognitive reserve. Results show the importance of educational, intellectual, and professional type variables, which can contribute to a deeper knowledge of this construct. In our view, a broad number of variables should be used to assess cognitive reserve effectively.
The carboxy-terminal transcription enhancement region of the human spumaretrovirus transactivator contains discrete determinants of the activator function

The bel1 gene of human spumaretrovirus (HSRV) encodes a 300-amino-acid nuclear protein termed Bel1 that is a potent activator of transcription from the cognate long terminal repeat (LTR). Bel1 can also efficiently activate the human immunodeficiency virus type 1 (HIV-1) LTR. We have previously shown that the amino-terminal 227-residue region (minimal activator region) of Bel1 can activate the HSRV LTR at low levels and that two distinct domains within the carboxy-terminal 73 residues, from residues 255 to 266 and 272 to 300, that bear little sequence homology can independently enhance the activity of the minimal activator domain (L. K. Venkatesh, C. Yang, P. A. Theodorakis, and G. Chinnadurai, J. Virol. 67:161-169, 1993). We now report on the further characterization of these two transcriptional enhancement regions. Mutational analysis of the region comprising residues 255 to 266 indicates that a cluster of leucine residues is critical to the function of this region. Also, residues 273 to 287, which are identical in sequence to a 15-amino-acid segment near the carboxy terminus of the simian foamy virus transcriptional activator Taf, can independently enhance the activity of the minimal activator region. To delineate the region(s) of Bel1 that could function autonomously as an activator domain, we tested the activity of chimeric proteins comprising either wild-type or functionally defective forms of Bel1 fused to the DNA binding domain, Gal4(1-147), of the yeast transcriptional activator Gal4 on a synthetic promoter comprising Gal4 DNA binding sites linked to the adenovirus E1B TATA box (minimal promoter). Gal4-Bel1 was found to activate basal transcription from the E1B TATA box at least 35-fold, and the region responsible for this activation function was localized to the carboxy-terminal 73 amino acids. When the transcriptional enhancement regions were tested for autonomous activator function as Gal4(1-147) chimeras, residues 272 to 300, but not 255 to 266, were found to activate transcription efficiently when targeted to the E1B TATA motif and also to HSRV and HIV-1 LTRs. The highly conserved region between amino acids 273 and 287 alone was found to activate transcription efficiently when targeted to the HSRV LTR but not to the E1B TATA box or the HIV-1 LTR. Thus, our results demonstrate that the carboxy-terminal 29-amino-acid region (residues 272 to 300) contributes to Bel1 transactivation by functioning as an autonomous activator of TATA motif-directed transcription in a manner similar to that of other modular transcriptional activators. (ABSTRACT TRUNCATED AT 400 WORDS)
Oxygen Radical Generation and Acute Pancreatitis: Effects of Dibutyltin Dichloride/Ethanol and Ethanol on Rat Pancreas

Recent studies suggest that enhanced release of free oxygen radicals plays an important role in the pathogenesis of acute pancreatitis. Therefore, we studied the activity of the oxygen radical generating xanthine ox-idase (XOD) in pancreatic tissue from rats treated with either dibutyltin dichloride/ethanol (DBTCiEtOH: 6 mg kg−1/13.7 mg kg−I, i.v.), ethanol alone (EtOH: 13.7 mmol kg−1, i.v.), or isotonic saline (NaCl) as control. We also investigated activities of the oxygen radical scavengers superoxide dismutase (SOD) and glutathione peroxidase (GPX). In addition, levels of the lipid peroxidation marker malondialdehyde (MDA) were determined. Enhanced activity of XOD was not detected. While SOD activity 1 and 6 h after treatment was significantly more reduced by DBTC/EtOH than by EtOH alone, no difference was found thereafter. Correspondingly, both regimens diminished GPX activity. Moreover, DBTC/EtOH and EtOH rapidly increased MDA levels within 1 h, in dicating release of oxygen radicals early on after administration. After 16 h the MDA concentration was still elevated only in the DBTCiEtOH group. Although similar metabolic alterations were observed in both groups, only DBTCiEtOH induced acute interstitial pancreatitis within 24 h. We conclude that (a) a tissue imbalance between oxidants and antioxidants might be of importance in the pathogenesis of DBTCiEtOH-induced acute interstitial pancreatitis; (b) although EtOH increases oxygen radical levels, additional damage is required for development of acute pancreatitis; (c) XOD does not seem to be responsible for significant oxygen radical generation; and (d) the DBTC/EtOH model is a useful tool to study acute interstitial pancreatitis in rats.
Tourism intermediaries and innovation in the hotel industry

ABSTRACT This paper examines the influence of tourism intermediaries on innovation in SMEs in the hotel industry from the perspective of the global value chain approach. The paper contributes towards characterizing the changing patterns of governance in the tourism global value chains. In addition, it provides useful information about SMEs’ innovation for tourism destination managers. The dataset for this study comes from a survey of hotel SMEs in Spain. The results indicate that dependence on tour operators leads to lower levels of marketing innovation, while dependence on on-line travel agencies stimulates it. Dependence on traditional travel agencies is observed to be associated with less product innovation. Overall, dependence on tourism intermediaries implies lower autonomy in a hotel's determination of rates and margins, but can favour innovation by means of stimulating the introduction of information and communication technologies and quality standards.
Different Influences of Extracellular and Intracellular Superoxide on Relaxation Through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Abstract: Superoxide production is increased in diseased blood vessels, which is considered to lead to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. To investigate the respective influence of extracellular and intracellular superoxide on vascular function through the NO/sGC/cGMP pathway, mechanical responses of rat external iliac arteries without endothelium were studied under exposure to a superoxide-generating agent, pyrogallol, or menadione. Exposure to pyrogallol impaired the relaxation induced by acidified NaNO2 (exogenous NO) but not that by nitroglycerin (organic nitrate), BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), or 8-Br-cGMP (cGMP analog). Superoxide dismutase (SOD) and tempol restored the impaired relaxation by acidified NaNO2. Superoxide production in the bathing solution, but not in artery segments, was significantly increased by exposure to pyrogallol, which was abolished in the presence of SOD or tempol. However, exposure to menadione impaired the relaxant response to acidified NaNO2, nitroglycerin, or BAY 41-2272, whereas it augmented that to BAY 60-2770. Also, this exposure had no effect on the 8-Br-cGMP-induced vasorelxation. Superoxide production in artery segments was dramatically enhanced by exposure to menadione, whereas that in the bathing solution was not affected. This increase in vascular superoxide production was normalized by tempol but not by SOD. These findings suggest that extracellular superoxide reacts with NO only outside the cell, whereas intracellular superoxide not only scavenges NO inside the cell but also shifts the sGC redox equilibrium.
Tumor-Infiltrating Regulatory T Cells Inhibit Endogenous Cytotoxic T Cell Responses to Lung Adenocarcinoma

Immune cells comprise a substantial proportion of the tumor mass in human nonsmall cell lung cancers (NSCLC), but the precise composition and significance of this infiltration are unclear. In this study, we examined immune complexity of human NSCLC as well as NSCLC developing in CC10-TAg transgenic mice, and revealed that CD4+ T lymphocytes represent the dominant population of CD45+ immune cells, and, relative to normal lung tissue, CD4+Foxp3+ regulatory T cells (Tregs) were significantly increased as a proportion of total CD4+ cells. To assess the functional significance of increased Tregs, we evaluated CD8+ T cell–deficient/CC10-TAg mice and revealed that CD8+ T cells significantly controlled tumor growth with antitumor activity that was partially repressed by Tregs. However, whereas treatment with anti-CD25–depleting mAb as monotherapy preferentially depleted Tregs and improved CD8+ T cell–mediated control of tumor progression during early tumor development, similar monotherapy was ineffective at later stages. Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8+ T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.
Adverse drug reactions in Singaporean children.

INTRODUCTION Allergic reactions to drugs are considered rare in the paediatric population. Host genetic and environmental factors influence the reported incidence and characteristics of adverse drug reactions (ADRs), and cause significant variation according to the population described and case definition used. We aimed to define the prevalence and characteristics of reported drug allergies in hospitalised children in Singapore. METHODS A retrospective case control study was performed through the hospital's inpatient electronic medical record (EMR) for the period of August 2002 to December 2002. The EMR was used to identify children with a previously reported ADR. The control group was randomly selected from patients hospitalised during the same period. RESULTS Of the 8437 patients hospitalised during the study period, reports of previous ADRs were found in the records of 222 patients. The mean age of the patients was 7.4 years, range 2 months to 17 years (95 percent confidence interval [CI] 6.3 - 8.4). There were 146 males and 160 Chinese. The most commonly-involved medications were betalactam antibiotics (45 percent) and non steroidal anti-inflammatory drug (18.5 percent). Compared to the control group, children with a reported ADR were more likely to be older, with a mean age of 7.4 years versus 4.6 years (p-value less than 0.001), male (odds ratio [OR] 1.7, 95 percent CI 1.2-2.4), of Chinese descent (OR 1.8, 95 percent CI 1.5-5), have an associated chronic illness (OR 3.5, 95 percent CI 2.5-5), and a diagnosis of asthma (OR 2.7, 95 percent CI 1.7-4.5). CONCLUSION In our paediatric inpatient population, the risk of reported ADRs increases with age, male gender, Chinese descent and the presence of chronic disease. The major drugs involved are betalactam antibiotics and non-steroidal anti inflammatory drugs.
Effects of alpha 4/beta 2- and alpha 7-nicotine acetylcholine receptor agonists on prepulse inhibition of the acoustic startle response in rats and mice.

RATIONALE Nicotine and agonists at subtypes of the nicotine acetylcholine receptor (nAChR) affect auditory gating, but the magnitude and direction of such effects appear highly variable. This variability may be due to differences in the tested dose range, selectivity of the test compound, species and strain, and suggests that nAChR subtypes are differentially involved in the control of auditory gating. OBJECTIVES AND METHODS This study aimed to characterise the effects of nicotine and agonists with preferential activity at alpha4/beta2- and alpha7-nAChRs on auditory sensorimotor gating using a prepulse inhibition (PPI) paradigm. Similar experimental conditions were employed in rats and two strains of mice. The paradigm used startle stimuli of 120 dB and prepulse intensities of 3, 6 and 12 dB above a background of 70 dB. RESULTS In Sprague-Dawley rats, nicotine disrupted PPI [minimal effective dose (MED): 1 mg/kg, SC] and this effect was mimicked by the potent nAChR agonist, epibatidine, (MED: < or = 0.001 mg/kg, IP) and the potent, and relatively selective, alpha4/beta2-nAChR agonist A-85380 (MED: < or = 0.1 mg/kg, IP). The effects of epibatidine, A-85380 and, to a lesser extent, nicotine were blocked by the non-selective nAChR antagonist mecamylamine. The relatively selective alpha7-nAChR agonists, GTS-21 and AR-R-17779, did not affect PPI in a consistent manner, both in rats and in DBA/2 mice, a strain expressing a disrupted gating phenotype, presumably due to altered activity of hippocampal alpha7-nAChRs. In BALB/c mice, a strain expressing a normal gating phenotype, nicotine (MED: 10 mg/kg, SC), epibatidine (MED: 0.03 mg/kg, IP) and A-85380 (MED: 0.3 mg/kg, IP) predominantly augmented PPI and mecamylamine attenuated these effects. CONCLUSIONS The present results confirm that the effects of nAChR agonists on PPI are species dependent and suggest that stimulation of heteromeric nAChRs containing both alpha and beta subunits, and possibly of the alpha4/beta2 type, affect sensorimotor gating. Evidence supporting a role for alpha7-nAChRs in the control of PPI of the acoustic startle response was not obtained.
Does an Acute Surgical Model increase the rate of negative appendicectomy or perforated appendicitis?

The clinical outcomes from suspected appendicitis depend on balancing the rate of negative appendicectomy (NA) with perforated appendicitis (PA). An Acute Surgical Model (ASM) was introduced at Geelong Hospital (GH) in 2011 involving a dedicated emergency general surgery theatre list every business day giving greater access to theatre for general surgeons. The aim of this study was to evaluate the effect of the ASM at GH on the management of appendicitis, in particular the NA and PA rates.
Prescrition Drug Therapies

OBJECTIVE To characterize the changes in bone mass with age in women and men, explain the physiology and pathophysiology of the bone remodeling process, identify the targets for prescription osteoporosis drugs in this process, and provide details about the uses, efficacy, safety, and economics of prescription drug therapies for osteoporosis prevention and treatment. BACKGROUND Preventing accelerated bone loss and decreasing age-related decreases in bone density are the primary goals of prescription drug therapy for osteoporosis. Bisphosphonates are the drugs of choice for preventing and treating postmenopausal osteoporosis. Alternatives for patients who cannot take bisphosphonates include raloxifene and calcitonin salmon. SUMMARY Menopause is accompanied by a rapid loss in bone mass that is followed by annual losses due to aging in women, which are similar to age-related bone mass decreases in men. Most prescription drug therapies for osteoporosis prevention or treatment reduce bone resorption by inhibiting osteoclast activation and activity, with only one medication class able to increase bone formation by stimulating osteoblasts. Denosumab, an investigational monoclonal antibody that inhibits nuclear factor kB ligand, would be a new class of anti-resorptive medications. Bisphosphonates currently are the drugs of choice for preventing and treating osteoporosis, with 7- and 10-year safety data available for risedronate and alendronate, respectively. Weekly and monthly regimens of bisphosphonates improve patient acceptance. Recently, an injectable form of ibandronate received U.S. Food and Drug Administration approval for once every 3 months administration. Raloxifene and calcitonin salmon are alternatives for patients who cannot take bisphosphonates because of contraindications or adverse effects. Teriparatide, a recombinant parathyroid hormone fragment, not only increases bone mineral density but also increases bone connectivity. CONCLUSIONS Osteoporosis medications are usually safe, especially if used correctly with proper patient education. Treating osteopenia has not been found to be cost effective in women. However, obtaining a dual-energy X-ray absorptiometry scan and treating osteoporosis has resulted in cost savings in senior women living in community and nursing home residences. Pharmacists have multiple opportunities for preventing and treating osteoporosis.