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The cytosolic pattern recognition receptor NLRP3 senses host-derived danger signals and certain microbe-derived products in both humans and rodents. NLRP3 activation assembles an inflammasome complex that contains the adapter proteins ASC and caspase-1, whose activation triggers the maturation and release of the proinflammatory cytokines IL-1β and IL-18. S5 phosphorylation of NLRP3 prevents its oligomerization and activation, whereas dephosphorylation of this residue by the phosphatase PP2A allows NLRP3 activation. However, the protein kinase that mediates NLRP3 S5 phosphorylation is unknown. In this study, we show that AKT associates with NLRP3 and phosphorylates it on S5, limiting NLRP3 oligomerization. This phosphorylation event also stabilizes NLRP3 by reducing its ubiquitination on lysine 496, which inhibits its proteasome-mediated degradation by the E3 ligase Trim31. Pharmacologic manipulation of AKT kinase activity reciprocally modulates NLRP3 inflammasome-mediated IL-1β production. Inhibition of AKT reduced IL-1β production following the i.p. injection of LPS into mice. We propose that AKT, Trim31, and PP2A together modulate NLRP3 protein levels and the tendency to oligomerize, thereby setting a tightly regulated threshold for NLRP3 activation.

Apoptosis is a form of programmed cell death in multicellular organisms. Bcl-2 prevents apoptosis and promotes cellular survival by neutralizing BH3 domain-containing proteins, which directly activate the pore-forming proteins BAX and BAK. However, Bcl-2 is not known to regulate other cell death effectors such as gasdermin D (GSDMD) or mixed lineage kinase domain-like (MLKL), whose activation causes pyroptosis and necroptosis, respectively. Here, we identify a BH3-like domain in both GSDMD and MLKL that mediates an interaction with B-cell lymphoma 2 (Bcl-2). The presence of Bcl-2 reduced GSDMD cleavage at D275 by caspase-1, 4 or 5, and enhanced the GSDMD cleavage at D87. The GSDMD D87 cleavage inactivates the pyroptotic execution program. The presence of Bcl-2 also limited RIP3 mediated phosphorylation of MLKL, which reduced MLKL oligomerization and tempered the induction of necroptosis. Our observations suggest that the presence of Bcl-2 limits the induction of three forms of cell death apoptosis, pyroptosis, and necroptosis.

The SARS (severe acute respiratory syndrome) outbreak was caused by a coronavirus (CoV) named the SARS-CoV. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant activation of the innate immune response. Here, we identify several mechanisms by which a SARS-CoV open reading frame (ORF) activates intracellular stress pathways and targets the innate immune response. We show that ORF8b forms insoluble intracellular aggregates dependent on a valine at residue 77. Aggregated ORF8b induces endoplasmic reticulum (ER) stress, lysosomal damage, and subsequent activation of the master regulator of the autophagy and lysosome machinery, Transcription factor EB (TFEB). ORF8b causes cell death in epithelial cells, which is partially rescued by reducing its ability to aggregate. In macrophages, ORF8b robustly activates the NLRP3 inflammasome by providing a potent signal 2 required for activation. Mechanistically, ORF8b interacts directly with the Leucine Rich Repeat domain of NLRP3 and localizes with NLRP3 and ASC in cytosolic dot-like structures. ORF8b triggers cell death consistent with pyroptotic cell death in macrophages. While in those cells lacking NLRP3 accumulating ORF8b cytosolic aggregates cause ER stress, mitochondrial dysfunction, and caspase-independent cell death.

Many intracellular pathogens cause disease by subverting macrophage innate immune defense mechanisms. Intracellular pathogens actively avoid delivery to or directly target lysosomes, the major intracellular degradative organelle. In this article, we demonstrate that activator of G-protein signaling 3 (AGS3), an LPS-inducible protein in macrophages, affects both lysosomal biogenesis and activity. AGS3 binds the Gi family of G proteins via its G-protein regulatory (GoLoco) motif, stabilizing the Gα subunit in its GDP-bound conformation. Elevated AGS3 levels in macrophages limited the activity of the mammalian target of rapamycin pathway, a sensor of cellular nutritional status. This triggered the nuclear translocation of transcription factor EB, a known activator of lysosomal gene transcription. In contrast, AGS3-deficient macrophages had increased mammalian target of rapamycin activity, reduced transcription factor EB activity, and a lower lysosomal mass. High levels of AGS3 in macrophages enhanced their resistance to infection by Burkholderia cenocepacia J2315, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus, whereas AGS3-deficient macrophages were more susceptible. We conclude that LPS priming increases AGS3 levels, which enhances lysosomal function and increases the capacity of macrophages to eliminate intracellular pathogens.

The molecular mechanisms underlying the severe lung pathology that occurs during SARS-CoV infections remain incompletely understood. The largest of the SARS-CoV accessory protein open reading frames (SARS 3a) oligomerizes, dynamically inserting into late endosomal, lysosomal, and trans-Golgi-network membranes. While previously implicated in a non-inflammatory apoptotic cell death pathway, here we extend the range of SARS 3a pathophysiologic targets by examining its effects on necrotic cell death pathways. We show that SARS 3a interacts with Receptor Interacting Protein 3 (Rip3), which augments the oligomerization of SARS 3a helping drive necrotic cell death. In addition, by inserting into lysosomal membranes SARS 3a triggers lysosomal damage and dysfunction. Consequently, Transcription Factor EB (TFEB) translocates to the nucleus increasing the transcription of autophagy- and lysosome-related genes. Finally, SARS 3a activates caspase-1 either directly or via an enhanced potassium efflux, which triggers NLRP3 inflammasome assembly. In summary, Rip3-mediated oligomerization of SARS 3a causes necrotic cell death, lysosomal damage, and caspase-1 activation—all likely contributing to the clinical manifestations of SARS-CoV infection.

CD8(+) memory T (Tm) cells are a significant barrier to transplant tolerance induction in alloantigen-primed recipients, and are insensitive to existing clinical immunosuppressants. Here, we studied the inhibition of CD8(+) Tm cells by arsenic trioxide (As2O3) for the first time. Alloantigen-primed CD8(+) Tm cells were transferred to T cell immunodeficient nude mice. The mice were subjected to heart allotransplantation, and treated with As2O3. The transplant survival time was determined, and the inhibitory effects of As2O3 on CD8(+) Tm cell-mediated immune rejection were assessed through serological studies and inspection of the transplanted heart and lymphoid organs. We found that As2O3 treatment prolonged the mean survival time of the graft and reduced the number of CD8(+) Tm cells in the spleen and lymph nodes. The expression of the genes encoding interleukin (IL)-2, and IFN-γ was reduced, while expression of IL-10 and transforming growth factor-β was increased in the transplant. Our findings show that As2O3 treatment inhibits allograft rejection mediated by alloreactive CD8(+) Tm cells in the mouse heart transplantation model.

Coronaviruses (CoV) have recently emerged as potentially serious pathogens that can cause significant human morbidity and death. The severe acute respiratory syndrome (SARS)-CoV was identified as the etiologic agent of the 2002–2003 international SARS outbreak. Yet, how SARS evades innate immune responses to cause human disease remains poorly understood. In this study, we show that a protein encoded by SARS-CoV designated as open reading frame-9b (ORF-9b) localizes to mitochondria and causes mitochondrial elongation by triggering ubiquitination and proteasomal degradation of dynamin-like protein 1, a host protein involved in mitochondrial fission. Also, acting on mitochondria, ORF-9b targets the mitochondrial-associated adaptor molecule MAVS signalosome by usurping PCBP2 and the HECT domain E3 ligase AIP4 to trigger the degradation of MAVS, TRAF3, and TRAF 6. This severely limits host cell IFN responses. Reducing either PCBP2 or AIP4 expression substantially reversed the ORF-9b–mediated reduction of MAVS and the suppression of antiviral transcriptional responses. Finally, transient ORF-9b expression led to a strong induction of autophagy in cells. The induction of autophagy depended upon ATG5, a critical autophagy regulator, but the inhibition of MAVS signaling did not. These results indicate that SARS-CoV ORF-9b manipulates host cell mitochondria and mitochondrial function to help evade host innate immunity. This study has uncovered an important clue to the pathogenesis of SARS-CoV infection and illustrates the havoc that a small ORF can cause in cells.

The temporal relation of hepatitis C virus (HCV) infection to the development of type 2 diabetes remains unknown. The authors followed 4,958 persons aged > or =40 years without diabetes (3,486 seronegative, 812 anti-HCV+, 116 with hepatitis B virus/HCV coinfection, and 544 hepatitis B surface antigen (HBsAg)+) from a community-wide cohort in southern Taiwan for 7 years (1997-2003) to study the risk of diabetes associated with HCV infection. A total of 474 participants developed diabetes. The 7-year cumulative incidence was 7.5% for HBsAg+, 8.6% for seronegative, 14.3% for anti-HCV+, and 14.7% for coinfected participants. Compared with HCV- persons, HCV+ persons had a higher cumulative incidence of diabetes (log-rank test, p < 0.0001). A multivariate Cox proportional hazards model showed that anti-HCV+ (hazard ratio = 1.7, 95% confidence interval: 1.3, 2.1), coinfection (hazard ratio = 1.7), overweight, obesity, and increasing age were significantly associated with diabetes (p < 0.05). Gender, educational level, HBsAg+ status, alcohol consumption, and smoking were not significant. After stratification by age and body mass index, the risk ratio for diabetes in anti-HCV+ participants increased when age decreased and body mass index levels increased (p < 0.001). Results show that HCV infection is an independent predictor of diabetes, especially for anti-HCV+ persons who are younger or have a higher body mass index.

The efficacy of influenza vaccination is not well understood for major cause-specific mortality except pneumonia. For 10 months we followed the mortality data of 35,637 vaccinated elderly (>65 years old) in a county with 102,698 elderly in southern Taiwan. A multivariate Cox model showed that vaccination was significantly associated with lower mortality for all causes, [hazards ratio (HR)=0.56], stroke (HR=0.35), renal disease (HR=0.40), diabetes mellitus (HR=0.45), pneumonia (HR=0.47), COPD (HR=0.55), malignancy (HR=0.74), and heart diseases (HR=0.78), p

Signaling by G protein-coupled receptors coupled to Galpha(i) assists in triggering lymphocyte movement into and out of lymph nodes. Here, we show that modulating the signaling output from these receptors dramatically alters B cell trafficking. Intravital microscopy of adoptively transferred B cells from wild-type and Rgs1-/- mice revealed that Rgs1-/- B cells stick better to lymph node high endothelial venules, home better to lymph nodes, and move more rapidly within lymph node follicles than do wild-type B cells. In contrast, B cells from Gnai2-/- mice enter lymph nodes poorly and move more slowly than do wild-type B cells. The Gnai2-/- mice often lack multiple peripheral lymph nodes, and their B cells respond poorly to chemokines, indicating that Galpha(i1) and Galpha(i3) poorly compensate for the loss of Galpha(i2). These results demonstrate opposing roles for Rgs1 and Gnai2 in B cell trafficking into and within lymph nodes.

Background. The role of hepatitis C virus (HCV) infection in thrombocytopenia (defined as a platelet count of

The omega-3 (ω3) fatty acid docosahexaenoic acid (DHA) can suppress inflammation, specifically IL-1β production through poorly understood molecular mechanisms. Here, we show that DHA reduces macrophage IL-1β production by limiting inflammasome activation. Exposure to DHA reduced IL-1β production by ligands that stimulate the NLRP3, AIM2, and NAIP5/NLRC4 inflammasomes. The inhibition required Free Fatty Acid Receptor (FFAR) 4 (also known as GPR120), a G-protein coupled receptor (GPR) known to bind DHA. The exposure of cells to DHA recruited the adapter protein β-arrestin1/2 to FFAR4, but not to a related lipid receptor. DHA treatment reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB. DHA also reduced IL-1β levels by enhancing autophagy in the cells. As a consequence macrophages derived from mice lacking the essential autophagy protein ATG7 were partially resistant to suppressive effects of DHA. Thus, DHA suppresses inflammasome activation by two distinct mechanisms, inhibiting the initial priming step and by augmenting autophagy, which limits inflammasome activity.

The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also interacts with NLRP3 recruiting NLRP3 to mitochondria and facilitating inflammasome assembly. In this study we investigated whether cytosolic cytochrome c impacts NLRP3 inflammasome activation in macrophages. We report that cytochrome c binds to the LRR domain of NLRP3 and that cytochrome c reduces the interactions between NLRP3 and cardiolipin and between NLRP3 and NEK7, a recently recognized component of the NLRP3 inflammasome needed for NLRP3 oligomerization. Protein transduction of cytochrome c impairs NLRP3 inflammasome activation, while partially silencing cytochrome c expression enhances it. The addition of cytochrome c to an in vitro inflammasome assay severely limited caspase-1 activation. We propose that there is a crosstalk between the NLRP3 inflammasome and apoptosome pathways mediated by cytochrome c, whose release during apoptosis acts to limit NLRP3 inflammasome activation.

Regulator of G protein signaling (RGS) proteins modulate signaling through pathways that use heterotrimeric G proteins as transducing elements. RGS1 is expressed at high levels in certain B cell lines and can be induced in normal B cells by treatment with TNF-α. To determine the signaling pathways that RGS1 may regulate, we examined the specificity of RGS1 for various Gα subunits and assessed its effect on chemokine signaling. G protein binding and GTPase assays revealed that RGS1 is a Giα and Gqα GTPase-activating protein and a potential G12α effector antagonist. Functional studies demonstrated that RGS1 impairs platelet activating factor-mediated increases in intracellular Ca+2, stromal-derived factor-1-induced cell migration, and the induction of downstream signaling by a constitutively active form of G12α. Furthermore, germinal center B lymphocytes, which are refractory to stromal-derived factor-1-triggered migration, express high levels of RGS1. These results indicate that RGS proteins can profoundly effect the directed migration of lymphoid cells.

STE20-related kinases play significant regulatory roles in a range of cellular responses to environmental stimuli. GCKR (also referred to as KHS1) is a serine/threonine protein kinase that has an STE20-like protein kinase domain and that stimulates the stress-activated protein kinase (SAPK, also referred to as Jun kinase or JNK) pathway. GCKR has a large C-terminal regulatory domain that provides sites for interactions with other proteins. Adaptor proteins mediate the interactions between signaling molecules. In this study we showed that the adaptor proteins Crk and CrkL associated with GCKR. When Crk-I, Crk-II, or CrkL was transiently expressed in HEK 293T cells along with GCKR, each coimmunoprecipitated with GCKR. Furthermore, in the Bcr-Abl transformed cell line, K562 endogenous GCKR and CrkL coimmunoprecipitated, indicating a constitutive association. Detection of the CrkL-GCKR interaction required the SH3 domains of CrkL and 2 regions in GCKR—1 between amino acids 387 and 395 that contains a consensus SH3 binding motif and the other between amino acids 599 and 696. Crk or CrkL overexpression increased GCKR catalytic activity. A dominant negative form of Ras abolished Crk- or CrkL-induced GCKR activation, suggesting a dependence on Ras activation for their activation of GCKR. Finally, we showed impairment of the known ability of CrkL to activate the SAPK pathway by a catalytically inactive form of GCKR or by a GCKR antisense construct. Thus, GCKR associates with other proteins through interactions mediated by SH2/SH3 adaptor proteins, which can lead to GCKR and SAPK activation.

The Bcr-Abl oncogene, found in Philadelphia chromosome-positive myelogenous leukemia (CML), activates Ras and triggers the stress-activated protein kinase (SAPK or Jun NH2-terminal kinase [JNK]) pathway. Interruption of Ras or SAPK activation dramatically reduces Bcr-Abl–mediated transformation. Here, we report that Bcr-Abl through a Ras-dependent pathway signals the serine/threonine protein kinase GCKR (Germinal Center Kinase Related) leading to SAPK activation. Either an oncogenic form of Ras or Bcr-Abl enhances GCKR catalytic activity and its activation of SAPK, whereas inhibition of GCKR impairs Bcr-Abl–induced SAPK activation. Bcr-Abl mutants that are impaired for GCKR activation are also unable to activate SAPK. Consistent with GCKR being a functional target in CML, GCKR is constitutively active in CML cell lines and found in association with Bcr-Abl. Our results indicate that GCKR is a downstream target of Bcr-Abl and strongly implicate GCKR as a mediator of Bcr-Abl in its transformation of cells.

The Bcr-Abl oncogene, found in Philadelphia chromosome-positive myelogenous leukemia (CML), activates Ras and triggers the stress-activated protein kinase (SAPK or Jun NH2-terminal kinase [JNK]) pathway. Interruption of Ras or SAPK activation dramatically reduces Bcr-Abl–mediated transformation. Here, we report that Bcr-Abl through a Ras-dependent pathway signals the serine/threonine protein kinase GCKR (Germinal Center Kinase Related) leading to SAPK activation. Either an oncogenic form of Ras or Bcr-Abl enhances GCKR catalytic activity and its activation of SAPK, whereas inhibition of GCKR impairs Bcr-Abl–induced SAPK activation. Bcr-Abl mutants that are impaired for GCKR activation are also unable to activate SAPK. Consistent with GCKR being a functional target in CML, GCKR is constitutively active in CML cell lines and found in association with Bcr-Abl. Our results indicate that GCKR is a downstream target of Bcr-Abl and strongly implicate GCKR as a mediator of Bcr-Abl in its transformation of cells.

Autophagosomes delivers cytoplasmic constituents to lysosomes for degradation, whereas inflammasomes are molecular platforms activated by infection or stress that regulate the activity of caspase-1 and the maturation of interleukin 1β (IL-1β) and IL-18. Here we show that the induction of AIM2 or NLRP3 inflammasomes in macrophages triggered activation of the G protein RalB and autophagosome formation. The induction of autophagy did not depend on the adaptor ASC or capase-1 but was dependent on the presence of the inflammasome sensor. Blocking autophagy potentiated inflammasome activity, whereas stimulating autophagy limited it. Assembled inflammasomes underwent ubiquitination and recruited the autophagic adaptor p62, which assisted their delivery to autophagosomes. Our data indicate that autophagy accompanies inflammasome activation to temper inflammation by eliminating active inflammasomes.

Background: The risk of type 2 diabetes on the development of hepatocellular carcinoma remains inconclusive in different hepatitis statuses. Methods: We prospectively followed a community-based cohort with 5,929 persons in southern Taiwan from January 1997 through December 2004, made up of 4,117 seronegative, 982 anti–hepatitis C virus–positive [HCV(+)], 696 hepatitis B surface antigen–positive [HBsAg(+)], and 134 coinfected persons. Before the study, 546 participants had developed diabetes. Hepatocellular carcinoma diagnoses were from the National Cancer Registry. Results: After 50,899 person-years of follow-up, 111 individuals had developed hepatocellular carcinoma. The highest risk of hepatocellular carcinoma, compared with seronegative individuals without diabetes, was in anti-HCV(+) individuals with diabetes [incidence rate ratio (IRR), 76.0], then coinfected (IRR, 46.0), anti-HCV(+) without diabetes (IRR, 26.1), HBsAg(+) with diabetes (IRR, 21.4), and seronegative with diabetes (IRR, 7.2; P < 0.001). Anti-HCV(+) (n = 132) and seronegative individuals (n = 352) with diabetes had a higher cumulative incidence rate of hepatocellular carcinoma than those without diabetes (log-rank test, P < 0.001). Multivariate Cox proportional hazards analysis showed that gender, age, body mass index ≥30, HBsAg(+) [hazards ratio (HR), 12.6], anti-HCV(+) (HR, 18.8), coinfection (HR, 25.9), and diabetes [HR, 2.7; 95% confidence interval (95% CI), 1.7-4.3] were independent predictors of hepatocellular carcinoma (P < 0.05). After stratifying hepatitis status in multivariate Cox analysis, diabetes was significant for seronegative (HR, 5.4; 95% CI, 1.7-17.1) and anti-HCV(+) individuals (HR, 3.1; 95% CI, 1.7-5.4). Body mass index ≥30 was significant for HBsAg(+) individuals (HR, 3.3; 95% CI, 1.3-8.1). Conclusion: Type 2 diabetes is a strong independent predictor of hepatocellular carcinoma in anti-HCV(+) and seronegative individuals but not in HBsAg(+) individuals. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2054–60)

Past studies of the relation between hepatitis C virus (HCV) infection and type 2 diabetes conflict. The authors aimed to elucidate the relation by using a large community-based sample with a wide range of liver conditions. Between October 1997 and February 1998, 2,327 consecutive subjects (aged > or =35 years) were enrolled at the public health facility in Taiwan. Blood sugar, hepatitis B surface antigen, and antibody for HCV (anti-HCV) were tested. Abdominal sonography was performed on viral-hepatitis-positive subjects. In univariate analysis, older age, lower educational levels, sedentary work, body mass index of > or 25 kg/m2, and anti-HCV positivity were significantly associated with type 2 diabetes (p

We performed a community-based study of 12 villages of southern Taiwan's A-Lein Township to investigate the epidemiology of hepatitis B and hepatitis C virus (HCV) infections. Of 6,095 patients, 13.8% were positive for hepatitis B surface antigen positive (HBsAg(+)) and 17.0% were positive for anti-HCV (anti-HCV(+)). Infection was found to be inversely related to educational level and to be directly related to the frequency of the receipt of parenteral injection for medical purposes. Risk factors for HBsAg positivity were male sex, ageor = 50 years, and a family history of hepatocellular carcinoma. Risk factors for HCV seropositivity were lower education level, frequent parenteral injections, blood transfusion, menial occupations, smoking, and age50 years. Therefore, risk factors for HBsAg(+) and anti-HCV(+) were different in these Taiwanese communities. Safe medical injections and improved health education for high-risk groups are imperative for preventing HCV transmission.

For economic reasons, the few influenza vaccination programs seen in developing countries are aimed at the high-risk elderly. To evaluate its efficacy and cost-effectiveness, we conducted a 2-month influenza vaccination campaign in southern Taiwan’s A-Lein township for all the elderly. Significant differences in hospitalization and mortality between the vaccinated and unvaccinated groups were found. Age, sex, and risk group were significant for hospitalization and mortality, but only vaccination was significant for prevention. Savings for each person vaccinated were at least three times the cost of vaccination. We strongly recommend that all the elderly—not only high-risk elderly—receive an annual influenza vaccination.

Background Antibody to hepatitis C virus (anti-HCV) is a widely accepted method for the diagnosis of HCV infection. However, it is too expensive to use in large-scale health surveys. Objective To investigate the use of the serum alanine aminotransferase (ALT) level to predict the prevalence of HCV infection. Patients and Methods A sample of 6095 residents aged 35 years old or older in a small township of southern Taiwan, Republic of China, were examined in a community health survey. These persons were walk-ins to the government-sponsored stations after an intensive health promotion for this survey. Blood samples were obtained and analyzed for serum ALT levels. The presence of hepatitis B surface antigen and anti-HCV were determined by enzyme immunoassay methods. Results The overall prevalences of hepatitis B surface antigens(+), anti-HCV(+), and elevated ALT levels were 11.8%, 15.0%, and 7.5%, respectively. Among the 13 villages in this community, the prevalence of hepatitis B surface antigen(+) ranged from 6.8% to 17.3%, anti-HCV(+) ranged from 7.2% to 37.6%, and an elevated ALT level ranged from 5.8% to 16.5%. A strong positive correlation was found between the prevalence of an elevated ALT level and anti-HCV(+) ( r = 0.91, Spearman rank correlation; P r = −0.05, P = .87) was obtained between the prevalence of an elevated serum ALT level and hepatitis B surface antigen(+). Conclusion The prevalence of an elevated serum ALT level in a community is a strong indicator of its prevalence of anti-HCV(+), even in areas where there is a similar prevalence of hepatitis B virus infection. This result is useful for economically identifying hyperendemic communities with HCV infection.

This is a study of the differences in the risk factors for being either hepatitis B surface antigen positive [HBsAg(+)] or antibody to hepatitis C virus positive [Anti-HCV(+)] in A-Lein, a rural area in southern Taiwan, an area which also has a high hepatoma mortality rate. Three hundred eighty-five patients age > or =40 years participated in hepatoma screening at the A-Lein Community Health Center during 1995. Those who were HBsAg(-) and anti-HCV(-) or had coinfection of HBsAg(+) and anti-HCV(+) were excluded, leaving 293 patients: 109 HBsAg(+) and 184 anti-HCV(+). The anti-HCV(+) patients had a lower socioeconomic status (as defined by level of education and type of occupation) and were older than HBsAg(+) patients (P < 0.05). Those with higher alanine aminotransferase levels (ALT) also had a higher anti-HCV(+) to HBsAg(+) odds ratio (OR), and a dose response relationship was found, P < 0.0001. Anti-HCV(+) patients were more likely than HBsAg(+) patients to have a spouse who shared the infection, OR = 5.11; 95% CI, 2.30-11.28. Anti-HCV(+) patients were more likely than HBsAg(+) patients to have had blood transfusions (OR = 2.66; 95% CI, 1.20-5.89), frequent medical injections (OR = 2.64; 95% CI, 1.62-4.31), or injections by non-licensed medical providers (OR = 1.91; 95% CI, 1.18-3.09). Multiple logistic regression analysis showed that the significant factors for anti-HCV(+) patients vs. HBsAg(+) patients are drinking habit (OR = 3.45; 95% CI, 1.02-11.60), age (OR = 6.33; 95% CI, 2.93-13.68), and frequent medical injections (OR = 2.88; 95% CI, 1.65-5.03). The transmission of hepatitis C in A-Lein is closely related to low socioeconomic status, age, alcohol abuse, spouses being anti-HCV(+), and frequent medical injections, especially from non-licensed medical providers, including both pharmacists and those with no medical licensing whatsoever. These nonlicensed medical providers sometimes reuse needles to save money, which is a likely route of infection.

BACKGROUND Both hepatitis B and C are major health concerns in Taiwan. The goal of this study was to determine how risk factors for hepatitis B and C differed in this study population. It was also hoped that the data might help determine how age and place of residence affect hepatitis risk factors. METHODS Complete serum and hepatitis marker analysis (HBsAg and AntiHCV) was done for 282 individuals over 65 years old. Of these, 254 were interviewed for risk factor analysis. RESULTS Of the 282 subjects, 8.2% were HBsAg+, 27.3% were AntiHCV+, and 3.2% were both HBsAg+ and AntiHCV+. AntiHCV+ subjects were more likely than AntiHCV-subjects to have had frequent medical injections, odds ratio (OR) = 2.94, 95% confidence interval (CI) (1.68, 5.12), and it was the only independent risk factor for determining AntiHCV+, OR = 3.26, 95% CI (1.85, 6.11) (N = 254). The AntiHCV+ group had higher alanine and asparate aminotransferase levels but lower cholesterol and triglyceride levels than AntiHCV- and HBsAg+ groups (p < .0001). Abnormal ALT existed in 40.3% of AntiHCV+ and 10.7% of AntiHCV- cases. ALT was associated with AntiHCV and sex, although abnormal AST was only associated with AntiHCV. CONCLUSIONS AntiHCV was closely related with frequent medical injections and was the primary risk factor for abnormal ALT and AST levels in this study population. It appears that frequent medical injections are an important risk factor because of the previously common habit of reusing syringes. This is of major concern to elders in Taiwan because of their much greater likelihood of repeated exposure.

Alcohol consumption is a well-known risk factor for elevated ALT levels, but the role of cigarette smoking is unclear.We collected a cross-sectional sample of 6095 inhabitants 35 years or older in a community with hyperendemic hepatitis B and C virus infections. We assayed levels of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and anti-hepatitis C virus antibody (anti-HCV). Multivariate logistic regression was performed to determine the factors for elevated ALT levels (or =40 U/L) among people with different hepatitis infection statuses.Prevalence of elevated ALT levels in individuals who were seronegative for both infections or seropositive for HBsAg or anti-HCV was 3.9%, 11.1%, and 30.8%, respectively. Subjects with elevated ALT levels were more likely to be seropositive for anti-HCV, male, and seropositive for HBsAg; to drink alcohol; to smoke; and to have undergone blood transfusion (P.05). An association was found between elevated ALT levels and the consumption of cigarettes and alcohol among anti-HCV-seropositive subjects. In multivariate logistic analyses, alcohol consumption (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.1) and smoking (OR, 1.8; 95% CI, 1.1-2.7) were significantly associated with elevated ALT levels among anti-HCV-seropositive subjects, but no such association was found among HBsAg-seropositive subjects. The odds of elevated ALT levels were 7 times higher (95% CI, 2.7-18.8) for the anti-HCV-seropositive patients who smoked 1 or more packs of cigarettes per day and frequently drank alcohol than for those who did not.Smoking and alcohol consumption are independently associated with elevated ALT levels among anti-HCV-seropositive individuals but not among HBsAg-seropositive individuals. Patients who are seropositive for anti-HCV are strongly advised not to smoke and drink alcohol to reduce the possible risk for aggravating the liver dysfunction.