Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis

An innate immune response to bacterial components is speculated to be involved in the pathogenesis of primary biliary cirrhosis (PBC). Recently, CD4-positive T helper type 17 (Th17) cells, characterized by the secretion of interleukin (IL)-17, have been implicated in the pathogenesis of autoimmune diseases. Human Th17 cells are generated from Th0 cells by IL-6 and IL-1β and maintained by IL-23. In this study, the role of IL-17 in PBC and its association with biliary innate immunity were examined. Using cultured human biliary epithelial cells (BECs), the expression of Th17-related cytokines and chemokines and changes therein on treatment with pathogen-associated molecular patterns (PAMPs) and IL-17 were examined. Immunohistochemistry for IL-17 and Th17-related cytokines was performed using tissue samples of human liver. Consequently, the expression of IL-6, IL-1β, IL-23p19 and IL-23/IL-12p40 mRNAs, and their up-regulation by PAMPs, were found in BECs. Moreover, BECs possessed IL-17-receptors and stimulation with IL-17 induced production of IL-6, IL-1β, IL-23p19 and chemokines. Several IL-17-positive cells had infiltrated damaged bile ducts and the expression of IL-6 and IL-1β was enhanced in the bile ducts of PBC patients. In conclusion, IL-17-positive cells are associated with the chronic inflammation of bile ducts in PBC which is associated causally with the biliary innate immune responses to PAMPs.     

Tardive seizure and antibiotics: case reports and review of the literature

Tardive seizure is a serious adverse reaction of electroconvulsive therapy (ECT). However, it was rarely reported in ECT sessions for psychiatric patients who needed concurrent antibiotic treatments. We present 2 cases of patients with schizophrenia who manifested a catatonic syndrome and were indicated for ECT, along with antibiotic therapies for infectious diseases with piperacillin and cefotiam, respectively. The beta-lactam antibiotics are reported to induce convulsions caused by the suppression of inhibitory GABAergic functions. In addition, there is a report on prolonged ECT seizure related to ciprofloxacin, which has an epileptogenic property with a similar action to beta-lactam antibiotics. Thus, tardive seizures in our cases are thought to be related to piperacillin and cefotiam.     

Silhouette sutures for treatment of facial aging: facial rejuvenation, remodeling, and facial tissue support

During facial aging, a series of physical and biochemical changes leading to tissue hypotrophy, sagging, and wrinkles takes place not only at the level of the skin but also in the fatty tissue, muscle, and other structures. One of these changes is the decrease in volume and elasticity of the tissue because of alteration of collagen fiber formation. The intermittent use of silhouette sutures (partially reabsorbable) is aimed at preventing and treating the tissue sagginess and reinforcing the soft tissue of the face.     

Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia

Background/Aims: Biliary epithelial cells (BECs) possess negative regulatory mechanisms of Toll‐like receptor (TLR)‐based tolerance to bacteria (e.g. endotoxin tolerance). Viral infections of the Reoviridae genus with a dsRNA genome are suspected to be part of the aetiology of biliary atresia (BA), but the negative biliary mechanisms remain unexplored. Methods: Cultured human intrahepatic BECs (HIBECs) pretreated with polyinosinic–polycytidylic acid [poly(I:C)] (a synthetic analogue of viral dsRNA) for 24 h were exposed to poly(I:C) in fresh medium. The activation of nuclear factor‐κB (NF‐κB) and the expression of myxovirus resistance protein A (MxA) and tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL) mRNAs were evaluated. Moreover, after the pretreatment, the transition of these molecules was examined in poly(I:C)‐free conditions. Results: Treatment with poly(I:C) significantly upregulated NF‐κB activity in fresh HIBECs, and pretreatment failed to show tolerance to poly(I:C). The production of MxA and TRAIL was also preserved. Moreover, upregulation in the pretreated HIBECs was well preserved in poly(I:C)‐free medium for at least 72 h. Conclusions: BECs fail to show tolerance to poly(I:C), and once innate immunity is activated it is sustained in poly(I:C)‐free conditions, suggesting that the initiation of the immune response to dsRNA in HIBECs and its presence after the clearance of virus are closely associated with the progression of BA.     

Isolated vascular “v” lesions in liver allografts: How to approach this unusual finding

According to the Banff criteria for kidney allografts, isolated vascular or “v” lesions are defined as intimal inflammation, age‐inappropriate fibro‐intimal hyperplasia, or both, without the presence of associated interstitial T cell‐mediated rejection (TCMR). In general, these lesions portend a worse outcome for kidney allografts, particularly in those where the “v” lesions are identified in patients with coexistent donor specific antibodies (DSA) or later after transplantation. Although affected arteries are rarely sampled in liver allograft biopsies, we identified nine patients at a mean of 1805 days posttransplantation and compared these to matched controls. Almost half (4 of 9) of the study patient biopsies showed inflammatory arteritis associated with focal or diffuse C4d positivity, which was not observed in matched controls. One “v” lesion patient progressed to rejection‐related graft failure and two developed moderate/severe TCMR in subsequent biopsies, whereas only one rejection episode occurred in follow‐up biopsies, and no rejection‐related deaths or graft failures were detected in controls. In conclusion, patients with liver allograft isolated “v” lesions should undergo further evaluation and closer follow‐up for impending TCMR and/or underlying co‐existent chronic antibody‐mediated rejection (AMR).     

HBV- and HCV- infected workers in the Japanese workplace

Around three million Japanese are persistently infected with HBV or HCV. Though most of them work in various industries, little is known about the actual conditions in their workplaces. To clarify the workplace conditions of workers with hepatitis, three kinds of questionnaire surveys, answered by occupational health physicians and workers with hepatitis, were carried out. The rates of workers recognized as workers with hepatitis B or C by occupational health physicians were 0.82% and 0.48% of 130,092 workers, respectively. About 30% of workers with hepatitis were engaged in "hazardous work". The percentage of workers engaged in various types of hazardous work among workers with hepatitis was nearly the same as that among all Japanese workers. About 30% of occupational health physicians witnessed exacerbation of hepatitis in the workers at their workplaces, and 22% of workers with hepatitis experienced exacerbation of hepatitis. The rate of workers with hepatitis who had experienced exacerbation was not significantly different between workers with and without hazardous work. Workers with hepatitis have strong concerns about the relationship between work and exacerbation. As causes of exacerbation, occupational health physicians cited "unknown", "drinking" and "quit treatment" while workers with hepatitis answered "work-related causes", besides "unknown" and "drinking."     

International comparison of sensitizing chemical substances

Some occupational and environmental chemicals cause allergic diseases. To prevent chemical allergies, it is essential to identify the chemical substances that cause sensitization and to eliminate such sensitizers from daily life. As an occupational countermeasure, information for evaluating sensitization of chemical substances is needed. The aims of this article are to compare the criteria for sensitizers among national organizations in various countries and international organizations, and to make out a list of these chemical substances. The definition of sensitizing chemicals and the designation of respective sensitizers according to the PRTR law, Japan Society for Occupational Health (JSHO), American Conference of Governmental Industrial Hygienists (ACGIH), European Union (EU), Deutsche Forschungsgemeinshaft (DFG) and Japanese Society of Occupational and Environmental Allergy were studied. There are 1,389 chemical substances which are designated as sensitizers by any of the laws and five organizations. We specify each chemical substance in the list.     

Digital transplantation pathology: combining whole slide imaging, multiplex staining and automated image analysis

Conventional histopathology is the gold standard for allograft monitoring, but its value proposition is increasingly questioned. "-Omics" analysis of tissues, peripheral blood and fluids and targeted serologic studies provide mechanistic insights into allograft injury not currently provided by conventional histology. Microscopic biopsy analysis, however, provides valuable and unique information: (a) spatial-temporal relationships; (b) rare events/cells; (c) complex structural context; and (d) integration into a "systems" model. Nevertheless, except for immunostaining, no transformative advancements have "modernized" routine microscopy in over 100 years. Pathologists now team with hardware and software engineers to exploit remarkable developments in digital imaging, nanoparticle multiplex staining, and computational image analysis software to bridge the traditional histology-global "-omic" analyses gap. Included are side-by-side comparisons, objective biopsy finding quantification, multiplexing, automated image analysis, and electronic data and resource sharing. Current utilization for teaching, quality assurance, conferencing, consultations, research and clinical trials is evolving toward implementation for low-volume, high-complexity clinical services like transplantation pathology. Cost, complexities of implementation, fluid/evolving standards, and unsettled medical/legal and regulatory issues remain as challenges. Regardless, challenges will be overcome and these technologies will enable transplant pathologists to increase information extraction from tissue specimens and contribute to cross-platform biomarker discovery for improved outcomes.     

Re‐examination of the Lymphocytotoxic Crossmatch in Liver Transplantation: Can C4d Stains Help in Monitoring?

C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.     

The risk for hepatitis A, B, and C at two institutions for children in Somalia with different socioeconomic conditions.

The prevalence of serologic markers for hepatitis A, B, and C was investigated in children from two residential institutions in Somalia. Among 596 individuals at one residence (Shebeli), the prevalences were 96% for antibody to hepatitis A virus (anti-HAV), 75% for total hepatitis B virus (HBV) markers, 16% for hepatitis B surface antigen (HBsAg), and 1.5% for antibody to hepatitis C virus (anti-HCV). Corresponding figures for the 76 individuals at a smaller residence (Societe Organisation Sociale, SOS) were 59%, 20%, 3.9%, and 0%, respectively. At Shebeli, the HBsAg carrier rates in the 1-10-year-old age group was 28% for boys and 16% for girls. These rates were significantly higher than in the older children (16% and 7.4% for boys and girls, respectively). Fifty-eight percent of the HBsAg carriers were positive for hepatitis B e antigen. Total HBV markers were significantly more frequent in girls from Shebeli, when their duration of residence was longer than five years (89% versus 63%). The duration of stay did not influence the prevalences of HBsAg, HAV, or HCV antibodies. A followup study of children initially seronegative for HBV markers was carried out after two years. For children at Shebeli 1-10 years old, the annual seroconversion rates to HBV markers (95% confidence interval) was 60.5% (42.7-77.0%). The corresponding rate for children at SOS was 10.2% (5.2-17.5%). The differences between the two institutions in the prevalence of serologic markers for hepatitis A and B, and in the annual seroconversion rate to HBV markers reflected different rates of horizontal transmission.(ABSTRACT TRUNCATED AT 250 WORDS)