40 research outputs found

    Population screening for liver fibrosis: towards early diagnosis and intervention for chronic liver diseases

    Get PDF
    Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy non-invasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using non-invasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate -18 to 27%- in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression

    Focal Distribution of Hepatitis C Virus RNA in Infected Livers

    Get PDF
    Background: Hepatitis C virus (HCV) is a plus-strand RNA virus that replicates by amplification of genomic RNA from minus strands leading to accumulation of almost one thousand copies per cell under in vitro cell culture conditions. In contrast, HCV RNA copy numbers in livers of infected patients appear to be much lower, estimated at a few copies per cell. Methodology/Principal Findings: To gain insights into mechanisms that control HCV replication in vivo, we analyzed HCV RNA levels as well as expression of interferon beta (IFNb) and several interferon stimulated genes (ISGs) from whole liver sections and micro-dissected subpopulations of hepatocytes in biopsy samples from 21 HCV-infected patients. The results showed that intrahepatic HCV RNA levels range form less than one copy per hepatocyte to a maximum of about eight. A correlation existed between viral RNA levels and IFNb expression, but not between viral RNA and ISG levels. Also, IFNb expression did not correlate with ISGs levels. Replication of HCV RNA occurred in focal areas in the liver in the presence of a general induction of ISGs. Conclusion/Significance: The low average levels of HCV RNA in biopsy samples can be explained by focal distribution of infected hepatocytes. HCV replication directly induces IFNb, which then activates ISGs. The apparent lack of a correlation between levels of IFNb and ISG expression indicates that control of the innate immune response during HCV infection

    Biomarkers of disease differentiation: HCV recurrence versus acute cellular rejection

    Get PDF
    The wound-healing process induced by chronic hepatitis C virus (HCV) infection triggers liver damage characterized by fibrosis development and finally cirrhosis. Liver Transplantation (LT) is the optimal surgical treatment for HCV-cirrhotic patients at end-stage liver disease. However, acute cellular rejection (ACR) and HCV recurrence disease represent two devastating complications post-LT. The accurate differential diagnosis between both conditions is critical for treatment choice, and similar histological features represent a challenge for pathologists. Moreover, the HCV recurrence disease severity is highly variable post-LT. HCV recurrence disease progression is characterized by an accelerated fibrogenesis process, and almost 30% of those patients develop cirrhosis at 5-years of follow-up. Whole-genome gene expression (WGE) analyses through well-defined oligonucleotide microarray platforms represent a powerful tool for the molecular characterization of biological process. In the present manuscript, the utility of microarray technology is applied for the ACR and HCV-recurrence biological characterization in post-LT liver biopsy samples. Moreover, WGE analysis was performed to identify predictive biomarkers of HCV recurrence severity in formalin-fixed paraffin-embedded liver biopsies prospectively collected

    Cell Culture Replication of a Genotype 1b Hepatitis C Virus Isolate Cloned from a Patient Who Underwent Liver Transplantation

    Get PDF
    The introduction of the genotype 2a isolate JFH1 was a major breakthrough in the field of hepatitis C virus (HCV), allowing researchers to study the complete life cycle of the virus in cell culture. However, fully competent culture systems encompassing the most therapeutically relevant HCV genotypes are still lacking, especially for the highly drug-resistant genotype 1b. For most isolated HCV clones, efficient replication in cultured hepatoma cells requires the introduction of replication-enhancing mutations. However, such mutations may interfere with viral assembly, as occurs in the case of the genotype 1b isolate Con1. In this study, we show that a clinical serum carrying a genotype 1b virus with an exceptionally high viral load was able to infect Huh7.5 cells. Similar to previous reports, inoculation of Huh7.5 cells by natural virus is very inefficient compared to infection by cell culture HCV. A consensus sequence of a new genotype 1b HCV isolate was cloned from the clinical serum (designated Barcelona HCV1), and then subjected to replication studies. This virus replicated poorly in a transient fashion in Huh7.5 cells after electroporation with in vitro transcribed RNA. Nonetheless, approximately 3 weeks post electroporation and thereafter, core protein-positive cells were detected by immunofluorescence. Surprisingly, small amounts of core protein were also measurable in the supernatant of electroporated cells, suggesting that HCV particles might be assembled and released. Our findings not only enhance the current method of cloning in vitro HCV replication-competent isolates, but also offer valuable insights for the realization of fully competent culture systems for HCV

    Daytime variation in hepatitis C virus replication kinetics following liver transplant

    Get PDF
    Background: There is a growing interest in the role of circadian regulated pathways in disease pathogenesis. Methods: In a cohort of hepatitis C virus (HCV) infected patients undergoing liver transplantation, we observed differences in early viral infection kinetics of the allograft that associated with the time of liver transplant. Results: A higher frequency of subjects transplanted in the morning showed a rebound in viral RNA levels (n=4/6) during the first week post-surgery. In contrast, no viral rebound was observed in seven subjects transplanted in the afternoon. None of the other parameters previously reported to influence viral replication in the post-transplant setting, such as donor age, cold-ischemia time and length of surgery associated with viral rebound. Conclusions: These observation highlights a role for circadian processes to regulate HCV infection of the liver and warrants further investigation

    The diverse meteorology of Jezero crater over the first 250 sols of Perseverance on Mars

    Get PDF
    ASA’s Perseverance rover’s Mars Environmental Dynamics Analyzer is collecting data at Jezero crater, characterizing the physical processes in the lowest layer of the Martian atmosphere. Here we present measurements from the instrument’s first 250 sols of operation, revealing a spatially and temporally variable meteorology at Jezero. We find that temperature measurements at four heights capture the response of the atmospheric surface layer to multiple phenomena. We observe the transition from a stable night-time thermal inversion to a daytime, highly turbulent convective regime, with large vertical thermal gradients. Measurement of multiple daily optical depths suggests aerosol concentrations are higher in the morning than in the afternoon. Measured wind patterns are driven mainly by local topography, with a small contribution from regional winds. Daily and seasonal variability of relative humidity shows a complex hydrologic cycle. These observations suggest that changes in some local surface properties, such as surface albedo and thermal inertia, play an influential role. On a larger scale, surface pressure measurements show typical signatures of gravity waves and baroclinic eddies in a part of the seasonal cycle previously characterized as low wave activity. These observations, both combined and simultaneous, unveil the diversity of processes driving change on today’s Martian surface at Jezero crater

    NETWORK PHYSIOLOGY OF INTER-MUSCULAR INTERACTIONS

    No full text
    Maddie Sayre1, Celeste Childs1, Libby Connolly1, Maddie Davis1, Quinlyn Shannehan1, Gabriela Simpson1, Sergi Garcia-Retortillo1, Plamen Ch Ivanov2. 1Wake Forest University, Winston-Salem, NC. 2Boston University, Boston, MA. BACKGROUND: Skeletal muscles continuously coordinate to facilitate a wide range of movements. Muscle fiber composition and timing of activation account for distinct muscle functions and dynamics necessary to fine tune muscle coordination, generate movements, and adapt to fatigue. Here we investigate how distinct muscle fiber types dynamically synchronize and integrate as a network across muscles in response to fatigue. METHODS: Fourteen healthy adults performed three maximal body weight squat tests until exhaustion. Electromyography (EMG) signals from the following muscles were recorded simultaneously during the entire protocol: left and right vastus lateralis (LegL and LegR); left and right erector spinae (BackL and BackR). We first obtained 10 time series of EMG band power for each muscle, representing the dynamics of different muscle fiber types. To investigate cross-frequency interactions among EMG frequency bands that occur as a result of synchronous modulation of their spectral amplitudes, we calculated the bivariate equal-time Pearson’s cross-correlation for each pair of EMG band power time series across all Leg and Back muscles. RESULTS: Different muscle fiber types dynamically synchronize their activity across muscles following distinct patterns of cross-frequency communication. Specifically, with progression of fatigue, same-type muscle subnetworks (LegL-LegR and BackL-BackR) exhibit statically significant (i) global decline in links strength (p \u3c 0.05) and (ii) increase in links strength stratification (p \u3c 0.03), while (iii) preserving the general functional form of the network profile. In contrast, sub-networks of different-type muscles (Leg-Back) exhibit significant (i) global increase in links strength (p \u3c 0.05) and (ii) decline in links strength stratification (p \u3c 0.02), while (iii) changing the functional form of the network profile. CONCLUSION: This work addresses inter-muscular interactions among rhythms of myoelectrical activation, corresponding to the activity of different type muscle fibers, across muscles in response to fatigue. This dynamic network approach can lead to the development of network-based markers that will break new ground in the study of multilevel inter-muscular interactions, and will provide new understanding of diverse exercise-related phenomena such as performance, fatigue or muscle injuries

    Development and implementation of a continuing medical education program on non-alcoholic fatty liver disease for primary care practitioners in Europe

    No full text
    Background: Primary care has a crucial role to play in the prevention, early detection, referral, and risk factor management of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH). In 2021, a team of European collaborators developed a continuing medical education (CME) program on NAFLD/NASH that consolidates evidence and clinical best practices tailored to the primary care setting. This article reports on the methodology used to design and develop the CME and the results of a feasibility study.Methods: An expert advisory group representing both European specialists and general practitioners supported the design of the CME to be implemented in three European settings (Greece, Spain, and Netherlands). The CME features four training modules and problem-based learning using clinical case studies. The CME was tested regarding feasibility and acceptability among a sample of primary care providers (PCPs) in Greece (n = 28) with measurements occurring before, immediately after, and 1 month following the training. Outcome measures included satisfaction with the CME, changes in PCPs' knowledge, attitudes, confidence, and self-reported clinical practices related to NAFLD/NASH.Results: The CME is available as an open-access e-learning course on the European Society for Primary Care Gastroenterology education platform (1) in English, Greek, Spanish, and Dutch. The feasibility study documented high levels of satisfaction, with 96% of PCPs reporting they were extremely or very satisfied with the overall training. Statistically significant increases in PCPs' confidence in NAFLD/NASH-related clinical practices were documented between the pre- and post-assessments. At the follow-up, 62% of GPs reported that the CME had changed their clinical practices related to NAFLD/NASH to a great extent.Conclusion: This CME intervention developed by experts and tailored to PCPs in European settings may serve as an asset for increasing knowledge, confidence, and practice behaviors related to NAFLD/NASH
    corecore