Miracle-dz/UniFAR-FTUs huggingface dataset:
Intracellular Effects of the Hepatitis C Virus Nucleoside Polymerase Inhibitor RO5855 (Mericitabine Parent) and Ribavirin in Combination

ABSTRACT Mericitabine (RG7128) is the prodrug of a highly selective cytidine nucleoside analog inhibitor (RO5855) of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. This study evaluated the effects of combining RO5855 and ribavirin on HCV replication in the HCV subgenomic replicon by using two drug-drug interaction models. The effects of RO5855 and ribavirin on the intracellular metabolism of each compound, on interferon-stimulated gene (ISG) expression, and on the viability of hepatocyte-derived cells were also investigated. RO5855 and ribavirin had additive inhibitory activities against HCV subgenomic replicon replication in drug-drug interaction analyses. RO5855 did not affect the uptake or phosphorylation of ribavirin in primary human hepatocytes, human peripheral blood mononuclear cells, or genotype 1b (G1b) replicon cells. Similarly, ribavirin did not affect the concentrations of intracellular species derived from RO5855 in primary human hepatocytes or the formation of the triphosphorylated metabolites of RO5855. Ribavirin at concentrations of >40 μM significantly reduced the viability of primary hepatocytes but not of Huh7, the G1b replicon, or interferon-cured Huh7 cells. RO5855 alone or with ribavirin did not significantly alter the viability of Huh7 or G1b replicon cells, and it did not significantly affect the viability of primary hepatocytes when it was administered alone. The viability of primary hepatocytes was reduced when they were incubated with RO5855 and ribavirin, similar to the effects of ribavirin alone. RO5855 alone or with ribavirin had no effect on ISG mRNA levels in any of the cells tested. In conclusion, RO5855 did not show any unfavorable interactions with ribavirin in human hepatocytes or an HCV subgenomic replicon system.
Wide-Range Structural and Chemical Stability of the Magnetic Oxide NiFe2O4 Grown by O2-Assisted Pulsed Laser Deposition

We present a study of the structural and chemical properties of the magnetic insulator NiFe<sub>2</sub>O<sub>4</sub> on conductive Nb-doped SrTiO<sub>3</sub> (001) substrates. Special regard is given to the dependence of the thin film properties on the O<sub>2</sub>:Ar ratio during pulsed laser deposition. Using stoichiometric NiFe<sub>2</sub>O<sub>4</sub> target material and varying the O<sub>2</sub> partial pressure from 0% to 100%, we find a nonzero oxygen threshold for heteroepitaxial growth and a stoichiometric Fe:Ni cation distribution. Moreover, our study clearly demonstrates that NiFe<sub>2</sub>O<sub>4</sub> thin films grow with high quality over a wide range of oxygen partial pressures. These optimized NiFe<sub>2</sub>O<sub>4</sub>/SrTiO<sub>3</sub> heterostructures are envisioned as efficient spin filter tunnel contacts for room temperature application.
Low-dose aspirin and incidence of colorectal tumors in a randomized trial.

BACKGROUND Laboratory, clinical, and epidemiologic studies have recently suggested that regular use of aspirin can reduce colorectal cancer incidence or mortality. However, observational epidemiologic analyses have had limited opportunity to control for confounding bias or to specify aspirin doses used. PURPOSE Our purpose was to examine the relationship between regular use of low-dose aspirin and incidence of invasive and noninvasive colorectal tumors by utilizing data from the Physicians' Health Study, a randomized, double-blinded, placebo-controlled trial of aspirin and beta carotene. We also attempted to determine whether invasive cancers among aspirin users were associated with rectal bleeding and early stage at diagnosis. METHODS The Physicians' Health Study includes 22071 U.S. male physicians. The aspirin arm was terminated in 1988 after a mean follow-up of 5 years. Stage at diagnosis and signs and/or symptoms during presentation were abstracted from medical records. Cox proportional hazards models were used to estimate relative risk (RR), 95% confidence intervals (CIs), and the association between aspirin and bleeding. Differences between aspirin and placebo groups in tumor risk over time were visualized with Kaplan-Meier curves. We assessed the association between aspirin and stage at diagnosis with a Mann-Whitney rank sum statistic for non-parametric comparison of two ordinal distributions. RESULTS The RR of developing colorectal cancer for aspirin compared with placebo was 1.15 (95% CI = 0.80-1.65). For in situ cancers and polyps, the RR was 0.86 (95% CI = 0.68-1.10). There was no significant trend for decreasing RR by year of follow-up for invasive cancers (P = .09) or noninvasive tumors (P = .96). Aspirin and placebo groups did not differ in stage or prevalence of rectal bleeding at diagnosis. CONCLUSIONS Regular aspirin use, at a dose adequate for preventing myocardial infarction, was not associated with a substantial reduction in the incidence of colorectal cancer during 5 years of randomized treatment and follow-up. A small decrease in polyps in the aspirin group could not be reliably distinguished from a chance association. Our results suggest that among low-dose aspirin users, (a) colorectal cancer mortality is not likely to be reduced by earlier detection and (b) incidence is not likely to be increased due to aspirin-induced gastrointestinal bleeding. IMPLICATIONS The potential for a benefit from higher doses of aspirin or longer duration of use should be addressed by more detailed observational epidemiologic studies and prevention trials with longer follow-up of randomized participants.
The effects of Medicaid policy changes on adults' service use patterns in Kentucky and Idaho.

BACKGROUND In 2006, Idaho and Kentucky became two of the first states to implement changes to their Medicaid programs under authority granted by the 2005 Deficit Reduction Act (DRA). The DRA granted new flexibility in the design of state Medicaid programs, including a state plan amendment (SPA) option for changes that previously would have required a waiver. This paper uses state Medicaid administrative data to analyze the impact of Medicaid policy changes implemented in these states through a series of SPAs in 2006 and 2007. METHODS Changes in utilization are examined for multiple services, including physician, dental, and ER visits, inpatient stays, and prescriptions, among non-elderly adult Medicaid recipients following changes in cost sharing, reimbursement, service delivery, and covered services. Where possible, enrollees not affected by the changes served as a comparison group. RESULTS While relatively few adults in Idaho received a wellness exam after such coverage was added, the adoption of managed care for dental services was associated with increased receipt of dental care, including preventive care. The new limits on brand name prescriptions in Kentucky were associated with a reduction in the proportion of enrollees with two or more monthly name brand prescriptions while the small copayments introduced did not appear to have a dramatic impact. CONCLUSIONS We find that changes in financial incentives on both the supply-side (such as reimbursement increases) and the demand-side (i.e., benefit changes) alone may not be enough to generate the desired levels of preventive care, especially among those with chronic health conditions.
The influence of scale structure and sex on parental reports of children’s social (pragmatic) communication symptoms

ABSTRACT The addition of social (pragmatic) communication disorder [S(P)CD] to the DSM-5 taxonomy has left clinicians and researchers searching for appropriate diagnostic measures. Factor analysis procedures examined the extent to which S(P)CD symptoms presented within the Children’s Communication Checklist-Second Edition (CCC-2) represented a unique construct and whether these factors were influenced by children’s sex. Parents of 208 children (males = 125 and females = 83) from a community-based sample completed the CCC-2. Two pragmatic scores from the CCC-2 were analysed as follows: the social interaction difference index (SIDI) and a pragmatic composite from the original CCC (PC-5). Factor analysis failed to find a unique factor structure for either pragmatic composite. Analyses uncovered different factor structures for the CCC-2 SIDI and PC-5 composites and for boys and girls. S(P)CD represents a complex combination of symptoms that are poorly differentiated from other language and socioemotional behavioural difficulties.
Characterization of the Atypical MAPK ERK4 and Its Activation of the MAPK-activated Protein Kinase MK5*

The extracellular-regulated kinase (ERK) 4 (MAPK4) and ERK3 (MAPK6) are structurally related atypical MAPKs displaying major differences only in the C-terminal extension. ERK3 is known as an unstable mostly cytoplasmic protein that binds, translocates, and activates the MAPK-activated protein kinase (MK) 5. Here we have investigated the stability and expression of ERK4 and have analyzed its ability to bind, translocate, and activate MK5. We show that, in contrast to ERK3, ERK4 is a stable protein that binds to endogenous MK5. Interaction of ERK4 with MK5 leads to translocation of MK5 to the cytoplasm and to its activation by phosphorylation. In transfected HEK293 cells, where overexpressed catalytically dead ERK3 is able to activate MK5, catalytic activity of ERK4 is necessary for activation of MK5, indicating that ERK4 directly phosphorylates MK5. Interestingly, ERK4 dimerizes and/or oligomerizes with ERK3, suggesting that overexpressed inactive ERK3 recruits active endogenous ERK4 to MK5 for its activation. Hence, ERK3 and ERK4 cooperate in activation of MK5.
GALACTORRHEA ASSOCIATED WITH LYMPHOCYTIC ADENOHYPOPHYSITIS CASE REPORT

A young woman, 14 months post partum, committed suicide when she noticed milk discharging from her nipples and thought she was pregnant. At autopsy the uterus was found to be non‐gravid and the pituitary gland enlarged. Histological examination revealed lymphocytic adenohypophysitis, a rarely identified condition usually associated with hypopituitarism. Immunoperoxidase studies of the pituitary demonstrated prolactin cell hyperplasia. None of the other known causes of galactorrhea was present suggesting that this may be a new addition to the differential diagnosis of galactorrhea. To this date lymphocytic adenohypophysitis has been reported only in women, the majority within 14 months postpartum, and is usually identified only at autopsy.
Altered omega‐3 polyunsaturated fatty acid status in depressed post‐myocardial infarction patients

Objective: Lower levels of long‐chain omega‐3 polyunsaturated fatty acids (n‐3 LCPUFAs) and increased inflammation have been associated with both depressive disorder and myocardial infarction (MI). The present study investigated whether patients who develop depression post‐MI, have higher arachidonic acid/eicosapentanoic acid (AA/EPA) ratios than non‐depressed post‐MI patients and whether depressed post‐MI patients have signs of increased inflammation as measured by C‐reactive protein (CRP).
Caregiver Voices

Children with complex chronic conditions (CCC) receive care from multiple providers and agencies for a prolonged period of time. Coordination of care between providers is essential in the care of children with CCC. The purpose of this study was to determine which aspects of care coordination are important to caregivers and explore the challenges faced by caregivers in coordinating care. Using focus group methodology, the authors elicited experiences of caregivers relative to care coordination for children with CCC. Several themes emerged: (a) more information sharing and quality communication is needed among all those involved in providing care for children with CCC, (b) caregivers need help in navigating the system of care, and (c) caregivers develop strategies to cope with care coordination demands. Caregiver burden of coordinating care for children with CCC can be alleviated in part through improved communication and collaboration between agencies and providers and through developing easier ways to navigate a complex health system.
Factors Related to Delay in the Diagnosis of Basal Cell Carcinoma

Background: There is often a delay between the clinical emergence of a basal cell carcinoma (BCC) and the point in time at which the patient presents for definitive diagnosis and treatment. Previously published studies on delays regarding skin cancer have focused on melanoma rather than Bcc. We conducted a study aimed at identifying factors associated with the detection of Bcc and reasons for the delay in diagnosis. Method: A monocentric study was performed. Patients with a primary BCC diagnosed in 2010 were included in the study. They were asked about factors concerning BCC awareness and detection, tumor characteristics, previous history of nonmelanoma cutaneous cancer, family history of nonmelanoma cutaneous cancer, and the presence of comorbidities. Data were analyzed using SPSS software. Results: The mean diagnostic delay for BCC in our hospital setting was estimated at 19.79 ± 14.71 months. Delayed diagnosis was significantly associated with patients over 65 years, those without a previous history of BCC, those without a family history of BCC, those with BCC located elsewhere than the head or neck, and those with lesions not associated with itching or bleeding. Conclusion: This study revealed considerable delay in the diagnosis of BCC. The main reason for delay in the diagnosis seems to be the initial decision of the patient to seek medical advice. These data suggest a need for greater information for the general public on the symptoms and signs that should prompt suspicion of a BCC.
Handedness and Differences in Birthweight of Twins

The role of twins in analysing the generics of handedness is complicated by the phenomenon of mirror-imaging in monozygotic ( M Z ) twins (3 , 5 ) . If the twins split late in embryogenes~s after bilateral symmetry has been established, they may be discordant, or mirror-images, for handedness and many other physical and behavioural asymmetries ( 2 ) . Another consequence of late-splitting is the identical twin transfusion syndrome, occurring when twlns split more than 4 or 5 days after conception and hence are rnonochorionic. In 30% ( 4 ) or more ( 3 ) of these cases, arteriovenous anastomoses can occur, leading to gloss physical discrepancies between the donor and recipient twins. Nothing comparable occurs in dizygotic ( D Z ) twins. Large birrhweight differences can often be one indication of the transfusion syndrome and hence may provide a more convenient indication of late-splitting than detailed observations of asymmetries ( 2 ) . W e examined binhweight and handedness in 16 sets of MZ and 13 sets of D Z twins aged between 5 and 25 yr. , participating in a familial study of stuttering. Zygosity was determined by questionnaire, physical appearance and blood-typing, and handedness by performance on 11 different manual aaivities ( t ) . Subjects were classed as mixed-handed if one or more activities were performed w ~ t h the other hand.
A Longitudinal Study of the Readability of the Chairman’s Narratives in Corporate Reports: Malaysian Evidence

: This paper examines the readability of the chairman’s narratives, as determined by the Flesch score, of a Malaysian public listed company’s corporate reports from 1962 to 2009. It partially supports earlier studies which demonstrated that corporate reports were difficult to read, and had shown very negligible decrease in difficulty over time. Net profit to sales and readability was significantly positively correlated but number of financial statements was significantly negatively correlated with readability.
Pramipexole versus bromocriptine for levodopa-induced complications in Parkinson's disease.

OBJECTIVES To compare the efficacy and safety of adjuvant pramipexole versus bromocriptine therapy in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. SEARCH STRATEGY Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn and Boehringer Ingelheim. SELECTION CRITERIA Randomised controlled trials of pramipexole versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. DATA COLLECTION AND ANALYSIS Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of drop outs and adverse events. MAIN RESULTS One randomised controlled trial has compared pramipexole with bromocriptine using a double-blind, parallel group, multicentre design. It was not powered to examine differences between active treatment arms. There was a larger reduction in off time with pramipexole therapy compared with bromocriptine (weighted mean difference 1.4 hours; 0, 2.8, 95% CI). No differences occurred in dyskinesia rating scale, dyskinesia as an adverse event or UPDRS complication score. The UPDRS ADL and motor scores showed similar improvements compared to placebo with both agonists. Levodopa dose reduction was similar with both agonists. Subscales of the Functional Status Questionnaire showed significant improvements compared to placebo with both agonists. The finding that the EuroQol improved significantly compared with placebo with pramipexole but not bromocriptine should be treated with caution. Dopaminergic adverse events were similar with each agonist, as was the all cause withdrawal rate. REVIEWER'S CONCLUSIONS Although pramipexole and bromocriptine improved off time and reduced parkinsonian motor impairments and disability compared with placebo, no conclusions regarding their comparative effectiveness and safety can be drawn as this single trial did not have adequate power to assess such differences. Further larger trials are required to examine this issue in the future.
Role of the Visual and Auditory Systems in Postural Stability in Alzheimer's Disease.

BACKGROUND Postural stability requires the integration of multisensory input information and translation into appropriate motor responses. Surprisingly, few previous studies have addressed the role of auditory input on postural stability in healthy subjects, and none has investigated this in Alzheimer's disease (AD). OBJECTIVE To assess the influence of the visual and auditory systems on postural stability in patients with AD and healthy subjects. METHODS Twenty-four patients with AD and healthy age-matched subjects were examined by kinematic postural analysis (inertia measurement units placed at the center of mass of the body) under four different conditions: stance with eyes open and eyes closed, with and without suppression of background noise (using ear defenders). The effects of visual and auditory influences were analyzed independently and in conjunction. RESULTS In both groups, visual suppression had a negative impact on postural stability, while suppression of background noise, non-specifically and without spatial cues, significantly benefited postural stability. We also observed that in both groups, the positive effect of background noise suppression was insufficient to compensate for the negative effect of visual suppression, to which the patients were significantly more vulnerable. CONCLUSIONS Audition, albeit less significant than vision, also plays a role in the multi-sensorial dynamic control of postural stability by the central nervous system. In everyday life, audition is likely to be a relevant factor in postural stability. This is especially relevant in AD in which, even when the peripheral sensory system is intact, the central processing is impaired and sensory dependence is re-weighted.
Adenosine Deaminase and Malignant Cells

Several factors have suggested that there might be an interrelationship between the enzyme adenosine deaminase (ADA) and cancer. Numerous compounds that have antitumor activity interfere with purine intermediary metabolism, and adenosine deaminase plays a key role in purine recycling (FIGURE l). ’ In addition many investigators have proposed that cancer is an expression of a breakdown in natural immunologic defense mechanisms. ’ This has led to speculation about a possible relationship between failure of immunological surveillance and adenosine deaminase deficiency. Research aimed at exploring the possible biochemical validity of hypotheses linking cancer to aberrant function of adenosine deaminase has been concerned with levels of the enzyme, qualitative variations in the functional enzyme, and changes in the “conversion protein. ” Evidence has been accumulating that suggests there may be alterations in all three parameters. In our own laboratory we initiated studies on the possible differences between the ADA in the rapidly dividing cells of the intestinal crypts of the rat as compared to that found in the well differentiated cells of the villus tip. ’ Two variants were detected. They had slightly different isoelectric points (4.80 vs. 4.85) and they could be resolved on this basis (FIGURE 2). Furthermore the two forms had small but definitely different molecular weights (37,000 vs. 33,500) and they could be resolved on this basis (FIGURE 3). That these were not experimental artifacts was indicated by the reisolation of the two forms following admixture and by the different K,,, values of the two forms (0.07 mM for the form with the higher PI and 0.38 mM for the other). Not only did the nature of the enzyme change as the cells migrated up the villus, but so also did the amount of activity. The specific activity per cell increased about thirty times. Administration of the inhibitor of protein synthesis, cycloheximide, resulted in the prevention of the normal increase in specific activity and also in the production of the tip-specific form of the enzyme, thus the production of the variant found in the well differentiated cells required protein synthesis. This plus the higher molecular weight of the enzyme in the tip suggests that the new form might be derived from the other by the addition of a small (ca. 3,500 daltons) peptide. i n a similar study we found that the normal rat colon had only one form of ADA. However if the rat was treated with the carcinogen methylazoxymethanol the resultant colonic tumors contained at least two forms of adenosine deaminase, at least one of which is not the same as the ADA found in normal colonic mucosa (FIGURE 4)P These tumor variants appear to have the same molecular weight as the normal colon