Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis

Background and aims Extrahepatic manifestations of HCV are responsible for morbidity and mortality in many chronically infected patients. New, interferon-free antiviral treatment regimens, which present the opportunity to treat all HCV-infected patients, call for a better understanding of the benefits of treating non-cirrhotic chronically infected individuals. Methods A systematic review was conducted. Identified studies from targeted database searches on Embase and Medline were screened. The methodological quality of the included publications was evaluated. Random-effect model meta-analyses were performed. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Results Data were extracted from a total of 48 identified studies. Achieving sustained virological response (SVR) was associated with reduced extrahepatic mortality (vs no SVR, OR 0.44 (95% CI 0.28 to 0.67)). SVR was associated with higher complete remissions in patients with cryoglobulinemia vasculitis (OR 20.76 (6.73 to 64.05)) and a higher objective response in those with malignant B-cell lymphoproliferative diseases (OR 6.49 (2.02 to 20.85)). Achieving SVR was also associated with reduced insulin resistance at follow-up (OR 0.42 (0.33 to 0.53)) and a significant protective effect on the incidence of diabetes (OR 0.34 (0.21 to 0.56)). Lack of randomised data comparing SVR versus non-SVR patients for the relevant extrahepatic indications attenuated these analyses. Conclusion Antiviral therapy can reduce extrahepatic manifestations related to HCV when SVR is achieved. Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies.
A quantitative description of membrane currents in rabbit myelinated nerve.

1. Voltage‐clamp studies were carried out on single rabbit myelinated nerve fibres at 14 degrees C with the method of Dodge & Frankenhaeuser (1958). 2. A method was developed to allow the ionic currents through the modal membrane to be calibrated exactly under voltage‐clamp conditions by measuring the resistance of the internode through which the current was injected. 3. The ionic currents in a rabbit node of Ranvier can be resolved into two components, a sodium current and a leak current. Potassium current is almost entirely absent. 4. The sodium currents in rabbit nodes were fitted by the Hodgkin‐Huxley model using m2h kinetics. The kinetics of sodium currents in a rabbit node differ from that in a frog node under similar experimental conditions in two respects: (a) inactivation is faster, tau h for rabbit being 2‐3 times smaller around ‐50 mV; (b) the P(Na) (E) curve for mammal is shifted 10‐15 mV in the hyperpolarizing direction. 5. From the kinetics of sodium current, the non‐propagating rabbit action potential was reconstructed at 14 degrees C. The transient inward sodium current is responsible for the fast initial depolarization phase of the action potential, while the repolarizing phase is accounted for by leak alone. The computed shape of the action potential was in good agreement with the experimentally obtained action potential. 6. At 14 degrees C, frog and rabbit nodes with similar diameters have similar measured gNa values.
Persistence of Chicken Herpesvirus and Retroviral Chimeric Molecules upon In Vivo Passage

Abstract Marek's disease virus (MDV), a herpesvirus, and avian leucosis virus subgroup J (ALV-J), a retrovirus, were used for experimental coinfection of chickens. Chimeric molecules having sequences of both viruses were detected by the hotspot–combined polymerase chain reaction (HS-cPCR) system. The detection of chimeric molecules provided evidence for avian retroviral inserts in the herpesvirus genome. The persistence of chimeric molecules on in vivo passage served to indicate the infectivity of the recombinant virus. The evaluation of formation and persistence of the chimeric molecules was performed in two trials involving three in vivo passages. The chimeric molecules were identified according to the primer sets, their product length, and pattern. The persistence of chimeric molecules on in vivo passages served as an indication of their ability to replicate in and infect chickens. In the first experimental passage, MDV and ALV-J prototype strains, MD11 and HC-1, were intraperitoneally (IP) injected into 1-day-old chicks. The second trial included two passages. Passage II chicks were injected IP and passage III chickens were in contact with the chickens of passage II. For passage II, enriched white blood cells from blood samples of chickens from the first trial that had chimeric molecules were injected IP into 1-day-old chicks. For passage III, uninfected chicks were included together with the infected chicks. Synthesis evidence for the various species of chimeric molecules was assessed in the tissues of birds of the second trial. DNA was extracted from blood and feathers and analyzed by the hotspot–combined PCR and by pulsed field gel electrophoresis. To overcome the limits of detection, three amplification assays followed by hybridization of the products to specific viral probes were conducted. A variety of chimeric molecules were detected in low concentrations. Five species of chimeric molecules were characterized in blood, tumors, and feathers. Chimeric molecules were detected in 18 of 36 dually infected birds from the first trial and in 14 of 21 dually infected birds from the second trial. The findings show that, in four out of seven groups of the second trial, the chimeric molecule species persisted on passage.
The lymphocyte to monocyte ratio in peripheral blood represents a novel prognostic marker in patients with pancreatic cancer

Abstract Background: Intra-tumoral macrophages have been involved as important players in the pathogenesis and progression of cancer. Recently, inflammatory parameters of the systemic inflammatory response have also been proposed as usefully prognostic biomarkers. One of these, the lymphocyte to monocyte ratio (LMR) in peripheral blood has been shown as a prognostic factor in hematologic and some solid tumors. In this study we analyzed for the first time the prognostic value of LMR in a large middle European cohort of pancreatic cancer (PC) patients. Methods: Data from 474 consecutive patients with ductal adenocarcinoma of the pancreas were evaluated retrospectively. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method. To further evaluate the prognostic significance of the LMR, univariate and multivariate Cox regression models were calculated. Results: Increased LMR at diagnosis was significantly associated with well-established prognostic factors, including high tumor stage and tumor grade (p<0.05). In univariate analysis, we observed that an increased LMR was a significant factor for better CSS in PC patients (HR 0.70; 95% CI 0.57–0.85; p<0.001). In multivariate analysis including age, Karnofsky Index, tumor grade, tumor stage, administration of chemotherapy, LMR and surgical resection, we confirmed increased LMR as an independent prognostic factor for CSS (HR 0.81; 95% CI 0.66–0.99; p=0.04). Conclusions: In conclusion, we identified LMR as an independent prognostic factor in PC patients. Our results indicate that the LMR might represent a novel and useful marker for patient stratification in PC management.
Inhibition of Cathepsins B Induces Neuroprotection Against Secondary Degeneration in Ipsilateral Substantia Nigra After Focal Cortical Infarction in Adult Male Rats

Stroke is the leading cause of adult disability in the world. In general, recovery from stroke is incomplete. Accumulating evidences have shown that focal cerebral infarction leads to dynamic trans-neuronal degeneration in non-ischemic remote brain regions, with the disruption of connections to synapsed neurons sustaining ischemic insults. Previously, we had reported that the ipsilateral striatum, thalamus degenerated in succession after permanent distal branch of middle cerebral artery occlusion (dMCAO) in Sprague-Dawley (SD) rats and cathepsin (Cath) B was activated before these relay degeneration. Here, we investigate the role of CathB in the secondary degeneration of ipsilateral substantia nigra (SN) after focal cortical infarction. We further examined whether the inhibition of CathB with L-3-trans-(Propyl-carbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline methyl ester (CA-074Me) would attenuate secondary degeneration through enhancing the cortico-striatum-nigral connections and contribute to the neuroprotective effects. Our results demonstrated that secondary degeneration in the ipsilateral SN occurred and CathB was upregulated in the ipsilateral SN after focal cortical infarction. The inhibition of CathB with CA-074Me reduced the neuronal loss and gliosis in the ipsilateral SN. Using biotinylated dextran amine (BDA) or pseudorabies virus (PRV) 152 as anterograde or retrograde tracer to trace striatum-nigral and cortico-nigral projections pathway, CA-074Me can effectively enhance the cortico-striatum-nigral connections and exert neuroprotection against secondary degeneration in the ipsilateral SN after cortical ischemia. Our study suggests that the lysosomal protease CathB mediates the secondary damage in the ipsilateral SN after dMCAO, thus it can be a promising neuroprotective target for the rehabilitation of stroke patients.
A problem with empirical studies of party policy shifts: Alternative measures of party shifts are uncorrelated

Many recent cross‐national studies analyse the causes and electoral consequences of party policy shifts, using party position measures derived from election manifestos, expert surveys or voter surveys. However few studies validate their findings by analysing multiple measures of party policy shifts. In this article, data on European parties’ position shifts on both European integration and left‐right ideology is analysed, showing that this is problematic because, while alternative measures of party policy positions correlate strongly in cross‐sectional analyses, alternative measures of parties’ policy shifts are essentially uncorrelated in longitudinal analyses. Suggestions are offered on how to address this problem.
Association of n-3 and n-6 long-chain polyunsaturated fatty acids in plasma lipid classes with inflammatory bowel diseases

In order to establish the biochemical basis for dietary interventions, we investigated the fatty acid composition of plasma lipid classes in patients with inactive inflammatory bowel disease. In this cross-sectional study thirty patients with ulcerative colitis (UC), twenty-one with Crohn disease (CD) and twenty-four controls were investigated (mean age: UC, 40·8 (sd 12·1); CD, 37·6 (sd 11·0); control, 31·5 (sd 8·4) years). Fatty acid composition of plasma lipids was determined by high-resolution capillary GLC. In plasma phospholipids, significantly higher values of eicosapentaenoic (20 : 5n-3), docosapentaenoic (22 : 5n-3) and γ-linolenic (18 : 3n-6) acids were found in control patients and patients with UC as compared to patients with CD [median % (weight by weight), control v. UC v. CD : 20 : 5n-3, 0·09 (interquartile range (IQR) 0·05) v. 0·14 (IQR 0·10) v. 0·16 (IQR 0·10), P < 0·05; 22 : 5n-3, 0·14 (IQR 0·10) v. 0·27 (IQR 0·16) v. 0·31 (IQR 0·10), P < 0·001; 18 : 3n-6, 0·02 (IQR 0·02) v. 0·03 (IQR 0·02) v. 0·05 (IQR 0·03), P < 0·05]. When compared to the control, values of the principal n-3 and n-6 long-chain PUFA, arachidonic acid (20 : 4n-6) and DHA (22 : 6n-3) were significantly higher in patients with UC but not in patients with CD [median % (w/w), UC v. control: 20 : 4n-6, 8·43 (IQR 3·23) v. 6·92 (IQR 2·96), P < 0·05; 22 : 6n-3, 1·22 (IQR 0·56) v. 0·73 (IQR 0·39), P < 0·05]. As seen there are considerable differences between the long-chain PUFA status of patients suffering from UC or CD. The data obtained in the present study do not support the concept of eicosapentaenoic acid or DHA deficiency in patients with either UC or CD.
Hypermethylated in Cancer 1 (HIC1) Recruits Polycomb Repressive Complex 2 (PRC2) to a Subset of Its Target Genes through Interaction with Human Polycomb-like (hPCL) Proteins*

Background: HIC1 is a transcriptional repressor recruiting CtBP and NuRD complexes. Results: HIC1 interacts with human Polycomb-like proteins. Conclusion: HIC1 recruits the Polycomb PRC2 on a subset of its target genes through interactions with Polycomb-like proteins. Significance: Our results implicate hPCL proteins in the recruitment of PRC2 by transcription factors in mammals. HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene epigenetically silenced or deleted in many human cancers. HIC1 is involved in regulatory loops modulating p53- and E2F1-dependent cell survival, growth control, and stress responses. HIC1 is also essential for normal development because Hic1-deficient mice die perinatally and exhibit gross developmental defects throughout the second half of development. HIC1 encodes a transcriptional repressor with five C2H2 zinc fingers mediating sequence-specific DNA binding and two repression domains: an N-terminal BTB/POZ domain and a central region recruiting CtBP and NuRD complexes. By yeast two-hybrid screening, we identified the Polycomb-like protein hPCL3 as a novel co-repressor for HIC1. Using multiple biochemical strategies, we demonstrated that HIC1 interacts with hPCL3 and its paralog PHF1 to form a stable complex with the PRC2 members EZH2, EED, and Suz12. Confirming the implication of HIC1 in Polycomb recruitment, we showed that HIC1 shares some of its target genes with PRC2, including ATOH1. Depletion of HIC1 by siRNA interference leads to a partial displacement of EZH2 from the ATOH1 promoter. Furthermore, in vivo, ATOH1 repression by HIC1 is associated with Polycomb activity during mouse cerebellar development. Thus, our results identify HIC1 as the first transcription factor in mammals able to recruit PRC2 to some target promoters through its interaction with Polycomb-like proteins.
Labor Courts and Firing Costs: The Labor‐Market Effects of Trial Delays

Employment protection is the result of labour laws as well as of institutional factors which are not encompassed in official legislation. Courts' delays in settling labour disputes are among those factors. Using individual data from the Italian Labour Force Survey for the period 2008-2010 and exploiting the territorial heterogeneity in the duration of labour trials across Italian regions, we investigate the effect of dismissal costs on the composition of employment. We find that labour courts' delays reduce the employment rate and increase inactivity of specific categories of workers, i.e. women, young and low skilled individuals. Furthermore, lengthy trials reduce the likelihood of accessing a permanent occupation and increase the incidence of long term unemployment for the same groups of workers. These results also imply that trials length and, more generally, courts activity have an impact on labour market outcomes which goes in the same direction as explicitly written rules.
Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.
Influence of the perception of biological or non-biological motion on movement execution

Abstract The perception of a human actor performing movements may involve processes related to action execution. This resonance of the motor system may support observational learning and imitation, and could also explain the fact that observers'/actors' movements are disturbed by the observation of a human model making different movements (Kilner et al., 2003). In this study, we tried to specify what information available in the model's behaviour triggers this influence on an observer's behaviour. In two experiments, we had participants make horizontal or vertical arm movements while observing similar movements. In the first experiment, the observers' pattern of behaviour was affected by the observation of a human model making incongruent movements. In the second experiment, similar results were obtained with participants observing a moving dot depicting either biological or non-biological motion. Movement execution was affected differentially by biological and non-biological motion observation. These results show that an observer's behaviour is sensitive to information available in biological motion.
Cocaine-primed craving and its relationship to depressive symptomatology in individuals with cocaine dependence

Several lines of evidence suggest a link between cocaine-primed craving and depressive symptomatology. The purpose of this study was to directly relate these two clinical phenomena. Thirty-three cocainedependent subjects were rated on the Hamilton Rating Scale for Depression (HRSD) at baseline and then administered an i.v. bolus of cocaine (0.2 mg/kg). Multiple regression analysis revealed that only the HRSD score was an independent predictor of cocaine-primed craving (F= 4.09; d.f. = 10,22; r=0.81, p< 0.003) when baseline spontaneous craving during early withdrawal, age, gender, frequency of use, time since last use, monetary expenditure on cocaine and the Addiction Severity Index Drug Composite Scores were considered. These data support the hypothesis that depressive symptomatology affects cocaine-primed craving and that this relationship is relatively specific to symptoms defined by the HRSD and is not seen with a number of other clinical and demographic variables.
Pharmacokinetic characteristics of intravenous ceftriaxone in normal adults

The multiple-dose pharmacokinetics and tolerance of intravenous ceftriaxone were investigated in 44 adults with normal renal function. Doses of 0.5, 1.0, and 2.0 g every 12 h and 2 g every 24 h were administered intravenously at a constant rate over 30 min. Plasma and urine samples were collected after the first (day 1) and last (day 4) dose and assayed for ceftriaxone by high-pressure liquid chromatography. Considering all four doses, mean peak plasma concentrations ranged from 79 to 255 micrograms/ml on day 1 and from 101 to 280 micrograms/ml on day 4. Trough concentrations at 12 h on day 1 were 15 to 45 micrograms/ml and 20 to 59 micrograms/ml on day 4. After a dose regimen of 2 g every 24 h, trough levels were still in the clinically therapeutic range (13 to 15 microgram/ml). The mean beta-phase t1/2 was markedly long (6.3 to 6.9 h) and was independent of dose. The fraction of dose excreted unchanged in the urine (0.33 to 0.44) indicated a substantial nonrenal mechanism of elimination. The plasma clearance ranged between 1,002 and 1,449 ml/h, and renal clearance ranged from 353 to 529 ml/h. The apparent volume of distribution varied from 9.2 to 13.5 liters. The dose-related increases in calculated Vd and Clp could be attributed to concentration-dependent plasma protein binding because of a larger free fraction of drug at higher concentrations. The drug was well tolerated, and no significant clinical or laboratory abnormalities were noted.
Interrogating the Dilemma of Foreign Aid as a Tool for Economic Development in Latin America in the 20th Century

The paper examines the dilemma of foreign aid as an invaluable tool for the economic development of Latin American region up till the 1990s. The study employed the narrative and analytical historical methods of research and analysis. Data was generated through library search. It was critically analysed employing the qualitative technique of content analysis of historical documents. The study notes that some advanced countries like USA, Canada, and Australia pumped and has still been pumping vast amount of money as aid to the region since the 1930s. Some goals of the aid regime were to: stimulate improved standard of living of citizens of Latin American states; alleviate poverty; promote rural infrastructural development and; enhance economic growth and sustainable development. Ironically, however, the paper records that all the Latin American states had to show for the huge inflow of foreign aid have been unparalleled level of corruption; huge foreign debt profile, significant level of illiteracy; political instability; incessant regime change; endemic conflicts; low level of domestic savings and significant impoverishment of women population, among others, with the possible exception to Cuba. It concludes that leaders of Latin American states should institute economic policies that are domestic-savings dependent and shun corruption to ostensibly promote sustainable development in the nearest future.
PPAR&ggr; Agonists Attenuate Trigeminal Neuropathic Pain

Objectives: The aim of this study is to investigate the role of peroxisome proliferator-activated receptor-gamma isoform (PPAR&ggr;), in trigeminal neuropathic pain utilizing a novel mouse trigeminal inflammatory compression (TIC) injury model. Results: The study determined that the PPAR&ggr; nuclear receptor plays a significant role in trigeminal nociception transmission, evidenced by: 1) Intense PPAR&ggr; immunoreactivity is expressed 3 weeks after TIC nerve injury in the spinal trigeminal caudalis, the termination site of trigeminal nociceptive nerve fibers. 2) Systemic administration of a PPAR&ggr; agonist, pioglitazone (PIO), attenuates whisker pad mechanical allodynia at doses of 300 mg/kg i.p. and 600 mg/kg p.o. 3) Administration of a PPAR&ggr; antagonist, GW9662 (30 mg/kg i.p.), prior to providing the optimal dose of PIO (300 mg/kg i.p.) blocked the analgesic effect of PIO. Discussion: This is the first study localizing PPAR&ggr; immunoreactivity throughout the brainstem trigeminal sensory spinal nucleus (spV) and its increase three weeks after TIC nerve injury. This is also the first study to demonstrate that activation of PPAR&ggr; attenuates trigeminal hypersensitivity in the mouse TIC nerve injury model. The findings presented here suggest the possibility of utilizing the FDA approved diabetic treatment drug, PIO, as a new therapeutic that targets PPAR&ggr; for treatment of patients suffering from orofacial neuropathic pain.