Diseases of bile duct in children

Several diseases originate from bile duct pathology.Despite studies on these diseases,certain etiologies of some of them still cannot be concluded.The most common disease of the bile duct in newborns is biliary atresia,whose prognosis varies according to the age of surgical correction.Other diseases such as Alagille syndrome,inspissated bile duct syndrome,and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction.The majority of these diseases present with cholestatic jaundice in the newborn or infant period,which is quite difficult to differentiate regarding clinical acumen and initial investigations.Intraoperative cholangiography is potentially necessary to make an accurate diagnosis,and further treatment will be performed synchronously or planned as findings suggest.This article provides a concise review of bile duct diseases,with interesting cases.

New insights into the immunology and evolution of HIV

Fewer than one million HIV infected individuals are currently receiving anti-retroviral therapy. Thelimitations of such treatment have underscored the need to develop more effective strategies to control thespread and pathogenesis of HIV. Typically, naturally occurring protective immune responses provide theparadigm for such development. It is now clear however that HIV can utilise the millieu of an activatedimmune system to its own replicative advantage. Mobilisation of the immune response, intended to thwartof HIV contributes to lack of immune control and the development of progressive disease in the majority ofinfected, untreated individuals. Further delineation of the intimate interactions between the HIV and theimmune system will be critical and recent advances in this direction are discussed.

Attenuation of MET-mediated migration and invasion in hepatocellular carcinoma cells by SOCS1

AIM To investigate the role of suppressor of cytokine signaling 1(SOCS1)in regulating MET-mediated invasive potential of hepatocellular carcinoma(HCC)cells.METHODSStable derivatives of mouse(Hepa1-6)and human(hep3B,Hep G2)HCC cell lines expressing SOCS1or control vector were evaluated for their ability to migrate towards hepatocyte growth factor(HGF)in the transwell migration assay,invade extracellular matrix in response to HGF stimulation in a 3-D invasion assay by confocal microscopy,and to undergo anchorageindependent proliferation in semisolid agar.Following intravenous and intrasplenic inoculation into NOD.scid.gamma mice,the ability of Hepa cells to form othotopic tumors was evaluated.Following HGF stimulation of Hepa and Hep3B cells,expression of proteins implicated in epithelial-to-mesenchymal transition was evaluated by western blot and qR T-PCR.RESULTS SOCS1 expression in mouse and human HCC cells inhibited HGF-induced migration through matrigel.In the 3-D invasion assay,HGF stimulation induced invasion of HCC cells across type-Ⅰcollagen matrix,and SOCS1expression significantly reduced the depth of invasion.SOCS1 expression also reduced the number and size of colonies formed by anchorage-independent growth in semisolid agar.Following intravenous inoculation,control Hepa cell formed large tumor nodules that obliterated the liver whereas the SOCS1-expressing Hepa cells formed significantly smaller nodules.Tumors formed by SOCS1-expressing cells showed reduced phosphorylation of STAT3 and ERK that was accompanied by reduced levels of MET protein expression.HGF stimulated Hepa cells expressing SOCS1 showed increased expression of E-cadherin and decreased expression of EGR1,SNAI1and ZEB1.Comparable results were obtained with Hep3B cells.SOCS1 expressing HCC cells also showed reduced levels of EGR1 and SNAI1 transcripts.CONCLUSION Our findings indicate that loss of SOCS1-dependent control over epithelial-to-mesenchymal transition may contribute to MET-mediated migration,invasion and metastatic growth of HCC.

Anti-rods/rings autoantibody generation in hepatitis Cpatients during interferon-α/ribavirin therapy

Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α(IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies(ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings(RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings(antiRR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2(IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.

Prevalence and clinical significance of antiphospholipid antibodies among hospitalized COVID-19 patients

Objective:To describe the prevalence of antiphospholipid antibodies in coronavirus disease-19(COVID-19)and to find potential associations between antiphospholipid antibody positivity and clinical outcomes.Methods:From September to November 2020,clinical and laboratory data were collected from 50 COVID-19 patients hospitalized at Saiful Anwar General Hospital in Malang,Indonesia.Antiphospholipid antibodies were measured by finding Ig M anti-β2 glycoprotein,lupus anticoagulant,and Ig M/Ig G anticardiolipin.Clinical characteristics,thrombotic events,ICU admission,and mortality during hospitalization were recorded.Disease severity was defined by the Guidelines for the Prevention and Control of COVID-19,Indonesia.Results:Among 50 patients,5 patients(10.0%)were positive for antiphospholipid antibodies:4 patients(80.0%)had Ig M anti-β2 glycoprotein and 1 patient had Ig G anti-cardiolipin(20.0%)and Ig M anti-cardiolipin(20.0%),none of lupus anticoagulant was detected.Antiphospholipid antibodies were associated with anosmia(OR 8.1;95%CI 1.1-57.9;P=0.018),nausea and vomiting(OR 12.4;95%CI 1.2-122.6;P=0.010),diarrhea(OR 9.8;95%CI 1.3-70.9;P=0.010),cardiovascular disease(OR 1.4;95%CI 1.0-1.9;P=0.001),chronic kidney disease(OR 12.0;95%CI 1.6-90.1;P=0.05),acute coronary syndrome(OR 29.3;95%CI 2.0-423.7;P=0.001),moderate(OR 0.11;95%CI 0.01-1.10;P=0.031)and severe(OR 18.5;95%CI 1.8-188.4;P=0.002)disease severity,and in-hospital mortality(OR 8.1;95%CI 1.1-57.9;P=0.018).However,there is no correlation between the presence of antiphospholipid antibody and ICU admission.Conclusions:In summary,the prevalence of antiphospholipid antibodies in COVID-19 patients is low,mainly against Ig M anticardiolipin,and is associated with an acute coronary syndrome,gastrointestinal manifestations,moderate and severe disease severity,and increased risk of mortality.

Studies on the allostimulatory function of dendritic cells from HCV-HIV-1 co-infected patients

There is increasing recognition of the potential morbidity and mortality associated with HIV-1 and hepatitis C (HCV)co-infection. HIV appears to adversely affect HCV disease while the reciprocal effect of HCV on HIV remains controversial.We therefore studied the effect of co-infection on dendritic cell function versus HIV infection alone, as previous work has shown that HCV impairs dendritic cell (DC) function. HIV-1 positive individuals with HCV were matched for CD4count, HIV- 1 RNA viral load and therapy, to HIV- 1 positive patients without HCV. Monocyte-derived DC were generated and mixed leukocyte reactions were performed. We assessed allostimulatory capacity with and without administration of exogenous Thl cytokines, using thymidine uptake and cell division analyses with the vital dye CFSE. We found that monocyte-derived DC from co-infected individuals showed no significant differences in allostimulatory capacity to ex vivo generated DC from HIV-1 infected individuals without HCV. Unlike the situation with HCV infection alone, this impairment was not reversed by increasing concentrations of either interleukin-2 or -12. Monocyte-derived DC from HIV-1 and HCV co-infected individuals have a similar allostimulatory capacity to DC from matched patients with HIV-1alone. These findings are compatible with results of prior clinical studies that found no evidence that HCV co-infection altered HIV disease progression and has implications for immunotherapeutic approaches in co-infected individuals.

Trichosanthin functions as Th2-type adjuvant in induction of allergic airway inflammation

It is important to understand the pathogenesis of asthma induced by natural allergens, which could exclude the interference of artificial adjuvant and provide insights of natural immune response in the disease. In the present study, we show that Trichosanthin （TCS） could induce airway inflammation even without the help of alum. Furthermore, TCS appeared capable of replacing alum to promote OVA-specific airway inflammation. TCS induced accumulation of IL-4-producing eosinophils in peritoneum at an early stage and the adjuvant function of TCS was eliminated by blockage of IL-4 at this stage. Finally, the eosinophils triggered by TCS from WT mice, but not from IL-4- deficient mice were shown to function as adjuvant for the induction of OVA-specific Th2 responses. Our data indicate that TCS is not only an allergen, but also a Th2-typc adjuvant modulating the switching of immune responses to a Th2 pathway. This chain of events results from IL-4 production by eosinophils at an early stage of TCS-priming. In conclusion, TCS may be useful as a Th2 adjuvant, and innate immune cells, such as eosinophils, may be a good target to study the initiation of Th2 response.

Basic Study Hepatitis B virus detected in paper currencies in a densely populated city of India: A plausible source of horizontal transmission?

BACKGROUND The recent rise in the incidence of hepatitis B virus(HBV)infections in a densely populated city of eastern India(“mixing vessel”of people of varied socioeconomic and immune status)prompted this study.Applying saliva on fingers for enumerating bank notes is a common practice in the Indian subcontinent.Paper notes may be a potential source of“horizontal”transmission of this virus,especially if there are cuts/bruises on the oral mucous membrane or skin.AIM To investigate whether paper currencies could be a plausible mode of horizontal transmission of HBV infection.METHODS Polymerase chain reactions(PCR)followed by nucleotide sequencing was done for the detection of HBV.Hepatitis B virus surface antigen enzyme-linked immunosorbent assay(HBsAg ELISA)was performed on all HBV deoxyribonucleic acid-positive samples to check the detectability of the virus.Atomic force microscopy(AFM)was carried out for visual confirmation of HBV particles in ultracentrifuged/immunoprecipitated samples from currency paper washings.RESULTS HBV-specific PCRs on pellets obtained after ultracentrifugation/immunoprecipitation of the currency paper washings detected potentially intact/viable HBV(genotype D2)in 7.14%of samples(n=70).AFM gave the visual confirmation of HBV particles in ultracentrifuged/immunoprecipitated samples from currency paper washings.However,HBV isolates from the currency notes could not be detected by HBsAg ELISA.CONCLUSION It is a common practice in the Indian subcontinent to count paper currencies by applying saliva on fingertips.Paper notes may be a potential source of“horizontal”transmission of this virus,especially if there are cuts/bruises on the oral mucous membrane or skin,but it was practically not possible to demonstrate experimentally such transmission.Detection of potentially intact/viable and“occult”HBV from currency poses potential risk of silent transmission of this virus among the general population.

Inflammation and cardiovascular disease

Cardiovascular disease(CVD) has been associated with the so-called traditional risk factors, such as hypertension, hypercholesterolemia and cigarette smoking.Chronic inflammation, exemplified by elevated high sensitivity C-reactive protein, has been added to these risk factors for CVD as non-traditional risk factor. There are two aspects in this association. The first is whether inflammation plays a pathogenic role in traditional risk factors-mediated CVD or it is just an epiphenomenon. The second is whether chronic inflammation caused by an inflammatory disease has any impact on CVD. Accumulated data have shown that inflammation has a central and inciting role in the development of atherosclerosis leading to increased CVD risk. How inflammation contributes to CVD is a topic of continuous research where mechanisms involving both innate and adaptive immune pathways are involved. Endothelial dysfunction, oxidative stress in vascular endothelial cells, macrophage accumulation, formation of inflammasome, production of tumor necrosis factor(TNF)-a, IL-1 and IL-6 characterize the inflammatory process leading to atherogenesis. Recently clonal hematopoiesis of indeterminate potential represents a surprising and novel mechanism underlying atherogenesis. Data from chronic rheumatic inflammatory diseases exemplify the complexity of mechanisms leading to increased CVD, while they also provide evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL6 agents, could control atherogenesis and ameliorate CVD risk. Recent groundbreaking work using biologic anti-IL-1 b therapy to treat men and women who have had a prior heart attack provides the best proof of the pathogenic contribution of inflammation in the development of CVD.

In utero transplantation: Disparate ramifications

In utero stem cell transplantation,which promises treatment for a host of genetic disorders early in gestationbefore disease effect stems from Ray Owen's seminalobservation that self-tolerance,is acquired duringgestation.To date,in utero transplantation(IUT)hasproved useful in characterizing the hematopoietic stemcell.Recent observations support its use as an in vivomethod to further understanding of self-tolerance.Preclinical development continues for its application asa treatment for childhood hematolymphoid diseases.In addition,IUT may offer therapeutic options in thetreatment of diabetes among other diseases.ThusIUT serves as a technique or system important in botha basic and applied format.This review summarizesthese findings.

Precision medicine in sepsis and septic shock:From omics to clinical tools

Sepsis is a heterogeneous disease with variable clinical course and several clinical phenotypes.As it is associated with an increased risk of death,patients with this condition are candidates for receipt of a very well-structured and protocolized treatment.All patients should receive the fundamental pillars of sepsis management,which are infection control,initial resuscitation,and multiorgan support.However,specific subgroups of patients may benefit from a personalized approach with interventions targeted towards specific pathophysiological mechanisms.Herein,we will review the framework for identifying subpopulations of patients with sepsis,septic shock,and multiorgan dysfunction who may benefit from specific therapies.Some of these approaches are still in the early stages of research,while others are already in routine use in clinical practice,but together will help in the effective generation and safe implementation of precision medicine in sepsis.

<i>Mycobacterium vaccae</i>Immunization to Pregnant BALB/c Mice Ameliorated Lung Histopathology and Bone Marrow Eosinophila in Ovalbumin Sensitized Offsprings

Context: One of the treatment strategies for atopic diseases is to skew immune response away from Th2 dominance by using Mycobacterial strains. Objective: We wanted to find out whether M. vaccae administration to pregnant mice had any preventive effect on the offsprings in the development of a murine asthma model. Materials and Methods: Pregnant BALB/c mice were divided into two groups;first group received heat-killed M. vaccae subcutaneously on 12th day of pregnancy and the latter group received PBS. After delivery, newborn mice of each group were further divided into two subgroups as M. vaccae/Ovalbumin (OVA), M. vaccae/control, PBS/OVA and PBS/ control. To establish experimental murine asthma model, mice were intraperitoneally sensitized and challenged intratracheally with Ovalbumin. We analysed airway histopathology, bone marrow eosinophil progenitors and splenic cell cytokine profiles of the offsprings. Results: Comparison of offsprings in M. vaccae/OVA group were not different than PBS controls with respect to thicknesses of airway epithelium, basement membrane, subepithelial smooth muscles and number of hyperplasic goblet cells as well as bronchial associated lymphoid tissue density and eosinophil progenitors in the bone marrow. Comparison of M. vaccae/OVA group to asthma model revealed significant differences and lower levels of OVA-induced IL-5. Conclusions: We propose that immunization of pregnant BALB/c with M. vaccae could prevent histopathological alterations in the airways related to the asthma model and down-regulates IL-5 secretion from splenocytes of offsprings.

Acquisition and dissemination mechanisms of CTXΦ in Vibrio cholerae : New paradigm for dif residents

Vibrio cholerae(V. cholerae) genome is equipped with a number of integrative mobile genetic element(IMGE) like prophages, plasmids, transposons or genomic islands, which provides fitness factors that help the pathogen to survive in changing environmental conditions. Metagenomic analyses of clinical and environmental V. cholerae isolates revealed that dimer resolution sites(dif) harbor several structurally and functionally distinct IMGEs. All IMGEs present in the dif region exploit chromosomally encoded tyrosine recombinases, Xer C and Xer D, for integration. Integration takes place due to site-specific recombination between two specific DNA sequences; chromosomal sequence is called att B and IMGEs sequence is called att P. Different IMGEs present in the att P region have different attP structure but all of them are recognized by Xer C and Xer D enzymes and mediate either reversible or irreversible integration. Cholera toxin phage(CTXΦ), a lysogenic filamentous phage carrying the cholera toxin genes ctx AB, deserves special attention because it provides V. cholerae the crucial toxin and is always present in the dif region of all epidemic cholera isolates. Therefore, understanding the mechanisms of integration and dissemination of CTXΦ, genetic and ecological factors which support CTXΦ integration as well as production of virion from chromosomally integrated phage genome and interactions of CTXΦ with other genetic elements present in the genomes of V. cholerae is important for learning more about the biology of cholera pathogen.

Kirsner's inflammatory bowel disease

Very few medical textbooks have so thoroughly dominated,and even defined a field, as has Inflammatory Bowel Diseases by Joe Kirsner. Originally co-edited with Roy Shorter of Mayo Clinic, this book, beginning with its first edition in 1975, encapsulated the science and art of caring for patients with Crohn's disease and ulcerative colitis. Thus it is with considerable respect, and indeed some awe and trepidation,that we eagerly embraced the opportunity to assume the editorship of this preeminent textbook and the obligation to transition it to reflect the changing, increasingly complex pathophysiology and treatment of these diseases.

Xenobiotics-Induced Liver Damage Is Biochemically Abrogated by Treatment with Lipophilic Extracts of <i>Moringa oleifera in Vivo</i>

Context Drug-induced hepatotoxicity represents a significant proportion of liver disease cases. Currently, there is no effective treatment. To date efforts to identify treatment regimen that can reverse progressive damage have not been successful. We have previously shown that extract from Moringa (M) oleifera possesses clinically relevant antidiabetic and electrolyte modulators. Objective The aim of the current studies is to create experimental model of xenobiotic induced liver damage and investigate if treatment with lipophilic extract of M. oleifera could biochemically reverse progressive liver damage. Materials and Method For two groups of healthy rats, 7 in each group received 200 mg of extract or vehicle twice daily for 14 days. Acute toxicity, hepatotoxicity and hematologic/endothelial toxicity were monitored. Then 30 rats weighing 130 - 200 g received repeated dose of acetaminophen (xenobiotics) (640 mg/kg) for 5 days. Hepatotoxicity was confirmed biochemically by an established protocol. Treatment with M. oleifera extract resulted in mean weight of 132.2 ± 5.05 compared to the control with 134.1 ± 5.08 (P > 0.8115) among the healthy rats. Their LDH levels were 170.7 ± 13.02 and 133.8 ± 7.17 (P > 0.0698) for controls group, while the mean serum (ALT) level was 12.4 ± 1.2 or 25.6 ± 5.644 (P M. oleifera resulted in 100% biochemical recovery from hepatitis compared to the control group (P M. oleifera could effectively and biochemically abrogate xenobiotics induced liver damage in animal model.

Tuberculosis Case Notification and Treatment Outcomes in West Gojjam Zone, Northwest Ethiopia: A Five-Year Retrospective Study

Introduction: Tuberculosis (TB) is a major public health concern in Ethiopia. Analysis of TB case notification and treatment outcomes is crucial to understand the TB control program performance. The current study was carried out to assess trends of TB case notifications, treatment success rate and factors associated with unsuccessful treatment outcome among TB patients in West Gojjam Zone of Amhara Region, Ethiopia. Method: A retrospective cohort study was conducted in West Gojjam Zone. Demographic and clinical data were reviewed for all TB patients registered between July 2007 and June 2012 at 30 randomly selected public health facilities of the study zone. In addition, annual case notification reports of the study zone were used to analyze trends in TB case notifications. Logistic regression analysis was used to assess the association between potential predictor variables and unsuccessful treatment outcomes. Results: Tuberculosis case notification for all forms of TB decreased from 203/100,000 population in 2007 to 155/100,000 population in 2012. Among patients whose treatment outcomes were evaluated, 94.4% were successfully treated, 0.3% had treatment failure, 1.5% defaulted and 3.7% died. In multivariate analysis, the odds of unsuccessful treatment outcome was higher among retreatment cases than new cases (adjusted OR, 3.44;95% CI: 1.92, 6.19). HIV co-infected cases were more likely to have unsuccessful treatment outcome compared to HIV negatives (adjusted OR, 2.68;95% CI: 1.92, 3.72). Conclusion: Tuberculosis case notification rates showed a decreasing trend between 2007 and 2012. The treatment success rate exceeded the 90% treatment success rate target as set by the WHO. Special attention is required for patients with high risk of unsuccessful treatment outcome. Therefore, retreatment cases, and HIV positive cases need strict follow up throughout their treatment period.

澳門地區丙型肝炎病毒基因型分析

應用逆轉錄——DNA聚合酶鏈反應(RT-PCR)及DNA序列分析,對採自澳門地區的43例抗——丙型肝炎病秦(HCV)抗體陽性的慢性肝炎患者及55例血液透析患者血清進行了HCV RNA檢測及基因型分析。結果顯示,15例慢性肝炎患者中,8例為Ⅱ/Ⅰb基因型,7例為6a型。在11例HCV RNA陽性的血液透析患者中,1例為Ⅰ/Ⅰa型,5例為Ⅱ/Ⅰb型,1例為6a型。這種基因型分佈與在中國内地城市所得結果明顯不同,提示丙型肝炎病毒在中國内地及相鄰地區的廣泛傅播可能僅是近半個多世紀的事件。

Risk perception and knowledge of COVID-19 in patients with celiac disease

BACKGROUND We recently demonstrated that the odds of contracting coronavirus disease 2019(COVID-19)in patients with celiac disease(CeD)is similar to that of the general population.However,how patients with CeD perceive their COVID-19 risk may differ from their actual risk.AIM To investigate risk perceptions of contracting COVID-19 in patients with CeD and determine the factors that may influence their perception.METHODS We distributed a survey throughout 10 countries between March and June 2020 and collected data on demographics,diet,COVID-19 testing,and risk perceptions of COVID-19 in patients with CeD.Participants were recruited through various celiac associations,clinic visits,and social media.Risk perception was assessed by asking individuals whether they believe patients with CeD are at an increased risk of contracting COVID-19 when compared to the general population.Logistic regression was used to determine the influencing factors associated with COVID-19 risk perception,such as age,sex,adherence to a gluten-free diet(GFD),and comorbidities such as cardiac conditions,respiratory conditions,and diabetes.Data was presented as adjusted odds ratios(aORs)RESULTS A total of 10737 participants with CeD completed the survey.From them,6019(56.1%)patients with CeD perceived they were at a higher risk or were unsure if they were at a higher risk of contracting COVID-19 compared to the non-CeD population.A greater proportion of patients with CeD perceived an increased risk of contracting COVID-19 when compared to infections in general due to their CeD(56.1%vs 26.7%,P<0.0001).Consequently,34.8%reported taking extra COVID-19 precautions as a result of their CeD.Members of celiac associations were less likely to perceive an increased risk of COVID-19 when compared to non-members(49.5%vs 57.4%,P<0.0001).Older age(aOR:0.99;95%CI:0.99 to 0.99,P<0.001),male sex(aOR:0.84;95%CI:0.76 to 0.93,P=0.001),and strict adherence to a GFD(aOR:0.89;95%CI:0.82 to 0.96,P=0.007)were associated with a lower perception of COVID-19 risk and the presence of comorbidities was associated with a higher perception of COVID-19 risk(aOR:1.38;95%CI:1.22 to 1.54,P<0.001).CONCLUSION Overall,high levels of risk perceptions,such as those found in patients with CeD,may increase an individual’s pandemic-related stress and contribute to negative mental health consequences.Therefore,it is encouraged that public health officials maintain consistent communication with the public and healthcare providers with the celiac community.Future studies specifically evaluating mental health in CeD could help determine the consequences of increased risk perceptions in this population.