The Impact of an Undergraduate Community-Based Medical Education Program in a Japanese Urban City.

INTRODUCTION:  With an aging global population posing healthcare challenges, especially in community healthcare, training professionals for community healthcare remains a global educational challenge, including in Japan. While previous research shows increased student interest in community healthcare through practical experiences, the focus has primarily been on rural areas, leaving a gap in understanding urban-based community medical education. This study aimed to evaluate the impact of urban community-based medical education on students' understanding and attitudes toward community healthcare. METHODS:  This study was conducted at Kyushu University in Fukuoka City, the sixth-largest city in Japan. For fifth-grade medical students, a community-based medical education program is mandatory, with a one-week schedule that includes orientation, one day in a clinic, and three days in a community hospital. The program aimed to expose students to various healthcare settings, emphasizing outpatient care, inpatient management, home health care, home nursing, and rehabilitation. A self-administered questionnaire referencing the Model Core Curriculum for medical education was administered immediately before and after the program, and the differences in students' perceptions were assessed using the Student's t-test. RESULTS:  Findings from 188 students completing both pre- and post-program questionnaires revealed significant improvements in perceptions of students' knowledge and skills related to community healthcare. After the training, there was a noteworthy positive shift in attitudes toward community healthcare and increased interest in primary care physicians as a career choice. Although students maintained a preference for urban areas, there was a notable inclination towards rural settings. The study highlights the program's success in enhancing students' understanding and positive attitudes toward community healthcare within an urban context. It challenges prior notions regarding work-life balance and urban-rural preferences in career choices. CONCLUSIONS:  Urban community-based medical education significantly improved students' perceptions and attitudes toward community healthcare. It offers valuable insights for curriculum planners, emphasizing the need for continued research into sustained effects and broader applicability.

A case of mediastinal abscess and infected aortic aneurysm caused by dissemination of Mycobacterium abscessus subsp. massiliense pulmonary disease.

An 81-year-old man was admitted to our hospital because of fever and malaise that had persisted for 3 months. The patient had undergone two aortic valve replacements, 10 and 5 years previously, because of aortic valve regurgitation and infectious endocarditis. He also had had asymptomatic Mycobacterium abscessus complex (MABC) pulmonary disease for the two previous years. Contrast-enhanced computed tomography showed a mediastinal abscess and an ascending aortic aneurysm. Mycobacterium abscessus subsp. massiliense was cultured from his blood, suggesting the aortic aneurysm was secondary to infection of an implanted device. After enlargement over only a few days, a leakage of contrast medium to the mediastinal abscess was found on computed tomography. The patient was diagnosed with rupture of an infectious aortic aneurysm, and emergency aortic replacement and drainage of the mediastinal abscess were successful. The patient was treated with several antibiotics, including meropenem, amikacin, and clarithromycin, and his general condition improved. Cultures from both the mediastinal abscess and a pericardial patch that was placed at the time of surgery 5 years previously revealed MABC. In our case, the infected aortic aneurysm most likely resulted from MABC pulmonary disease rather than from previous intraoperative contamination. This route of infection is rare. Physicians should be aware of the possibility of dissemination and subsequent infection of implants related to MABC pulmonary disease.

A case of severe COVID-19 with pulmonary thromboembolism related to heparin-induced thrombocytopenia during prophylactic anticoagulation therapy.

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words).

Kyushu and Okinawa Population Study (KOPS): a large prospective cohort study in Japan.

PURPOSE: The Kyushu and Okinawa Population Study (KOPS) was established to investigate gene-environmental interactions in non-communicable diseases in Japan. Besides collecting blood samples and anthropometric measurements, we also obtained medical histories, psychological status and lifestyle habits, including physical activities and dietary patterns. PARTICIPANTS: KOPS is a community-based prospective cohort study and consists of participants from four southwestern areas in Japan. Baseline surveys were conducted between 2004 and 2007 (wave 1), and 2009 and 2012 (wave 2) at the sites of municipality-based health check-ups. A total of 17 077 participants were included, comprising 10 697 participants of wave 1 and 6380 participants of wave 2; the median age in both groups was 61 years. Among them, 3006 individuals participated in both wave 1 and wave 2 surveys. FINDINGS TO DATE: We have focused on either risk or confounding factors for non-communicable diseases. We have assessed the clinical utility of the newly developed biomarkers for impaired glucose tolerance, such as urinary myo-inositol and glycated albumin, and atherosclerosis, such as small dense low-density lipoprotein cholesterol. We have conducted an international collaborative study with Framingham Offspring Study to investigate ethnic differences in impaired glucose tolerance and cardiovascular diseases. We have found that insulin resistance and deficiency might account for the ethnic differences in impaired glucose tolerance and cardiovascular disease risks. As gene-environmental interaction analyses, we found a synergic effect of interleukin 28B single nucleotide polymorphisms (SNPs) and gender on the spontaneous elimination of hepatitis C, and a beneficial interaction of SNPs of high-density lipoprotein cholesterol and gender on the impact of physical activity. In addition, we reported eight novel loci contributing to the development and severity of coronary artery disease from a large genome-wide association study. FUTURE PLANS: We plan to investigate further the clinical utility of the newly developed biomarkers and the gene-environmental interactions using prospective data.

Association between steatohepatitis biomarkers and hepatocellular carcinoma after hepatitis C elimination.

BACKGROUND: A strong association between chronic hepatitis C (CHC) and hepatic steatosis has been reported. However, the influence of steatohepatitis on hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) elimination remains unclear. AIM: To evaluate the development of HCC after HCV cure using a new steatohepatitis-related biomarker. METHODS: This cohort study analysed the prospective database of 290 CHC patients without a history of HCC who achieved HCV elimination by direct-acting antivirals. We calculated the FibroScan-aspartate aminotransferase (FAST) score 12 weeks after the end of treatment (pw12). The risk of HCC was analysed using the multivariable Cox proportional hazard model. RESULTS: HCV genotype (GT)1 was most prevalent at 72.4%, followed by GT2 (26.6%). Median follow-up period was 4.2 years (IQR 3.1-4.5). The cumulative HCC incidence for a FAST score ≥ 0.35 was significantly higher than that for a FAST score < 0.35 (log-rank test: P < 0.001). The annual HCC incidence rate for a FAST score ≥ 0.35 was significantly higher than that for a FAST score < 0.35, in patients with liver stiffness measurement (LSM) ≥10 kPa (adjusted hazard ratio [HR] 4.41, 95% confidence interval [CI] 1.30-15.0, P = 0.018). After adjusting for variables, including age, albumin, alpha-fetoprotein, the patatin-like phospholipase domain-containing the 3 (PNPLA3) rs738409 genotype, and pw12 fibrosis markers with FIB-4, non-alcoholic fatty liver disease fibrosis score, and LSM, FAST score ≥ 0.35 was associated with the development of HCC (adjusted HR 4.42, 95% CI 1.02-19.9, P = 0.043). CONCLUSIONS: Steatohepatitis-related biomarkers with the FAST score are helpful for predicting the development of HCC after HCV elimination.

The Expression Level of Neutrophil CD64 Is a Useful Marker of Systemic Inflammation Associated with HIV Infection.

CD64 is an Fc-gamma-receptor type 1. The expression level of neutrophil CD64 (nCD64) is a known bacterial infection marker, and it also increases in viral infections. We examined the absolute nCD64 before and after the initiation of antiretroviral therapy (ART) to determine its role as an infection and inflammation marker of human immunodeficiency virus (HIV) infection. In this prospective observational study, 94 HIV-infected patients were enrolled and classified into ART (n = 62), ART naive (n = 24), and acute/early phase groups (n = 8). The median nCD64 was 1,430 molecules/cell in the ART group, 2,994 in the ART naive group, 4,625 in the acute/early phase group, and 1,196 in the healthy control group. The nCD64 in the ART group was significantly higher compared with the healthy controls (p = .041), and the nCD64 in the ART naive and acute/early phase groups was significantly higher compared with the ART group (both p < .001). In the ART naive group, nCD64 was significantly higher in patients with than without concomitant infections (3,942 ± 1,519 vs. 2,300 ± 784, p = .004). However, this was influenced by the fact that nCD64 elevated as the stage of HIV infection progressed. nCD64 decreased significantly during the 24 weeks after starting ART (p = .004), although an upward trend in nCD64 was observed at weeks 2 and 4, without symptoms. When immune reconstitution inflammatory syndrome occurred, nCD64 elevated with a wider range than did C-reactive protein. This preliminary study suggests that nCD64 would be useful as a marker of the systemic inflammation of HIV-infected patients.

The relation of postprandial plasma glucose and serum endostatin to the urinary albumin excretion of residents with prediabetes: results from the Kyushu and Okinawa Population Study (KOPS).

BACKGROUND: Previous clinical studies have shown that the circulating level of endostatin is related to kidney injury. We hypothesized that the impact of HbA1c, fasting, and postprandial plasma glucose on urinary albumin excretion would be related to the serum endostatin level. METHODS: A cross-sectional, community-based population study of 1057 Japanese residents was conducted. Of these subjects, 162 with a fasting plasma glucose value between 5.5 and 6.9 mmol/L and an HbA1c level of <6.5 % received an oral glucose tolerance test, had serum endostatin measured, and had the urinary albumin/creatinine ratio (UACR) calculated. RESULTS: In multivariate analysis, 2-h postprandial plasma glucose (ß = 0.26, P < 0.01) was significantly associated with log-transformed UACR, independently of fasting plasma glucose (ß = 0.14, P = 0.28) and HbA1c (ß = -0.08, P = 0.57). When divided by the median value of endostatin (82.2 ng/mL), 2-h postprandial plasma glucose (ß = 0.38, P = 0.01) remained significantly associated with the log-transformed UACR of the participants below the median, while the fasting plasma glucose (ß = 0.34, P = 0.046) was independently associated with the log-transformed UACR of participants above the median. CONCLUSION: Postprandial plasma glucose was independently associated with the urinary albumin excretion of the residents with prediabetes. Moreover, this relationship was limited to residents with a serum endostatin level below the median.

Association of IL28B rs8099917 genotype and female sex with spontaneous clearance of hepatitis C virus infection: a Japanese cross-sectional study.

Hepatitis C virus (HCV) infection is a serious global health problem. Previous studies have suggested that the interleukin 28B (IL28B) rs8099917 genotype is related to spontaneous clearance of HCV in Caucasian populations. Our objective was to investigate the association of the IL28B rs8099917 genotype with spontaneous clearance of HCV by community-dwelling Japanese. A cross-sectional community-based population study of 993 Japanese residents was conducted. Based on anti-HCV antibody and HCV RNA levels, 50 subjects were assigned to the spontaneous-clearance group, 155 to the chronic-infection group, and 788 to the control group. Logistic regression analysis was done to examine the roles of the IL28B rs8099917 genotype and sex. To analyze the interactions between these factors, an "IL28B rs809991 genotype × sex" interaction term was included in the multivariate analysis. Significantly more subjects in the spontaneous-clearance group than in the chronic-infection group had the favorable IL28B rs8099917 genotype and were female. Multivariate logistic regression analysis extracted the favorable IL28B rs8099917 TT genotype (odds ratio [OR] 9.39; 95% confidence interval [CI], 2.16-40.83, P = 0.003) and female sex (OR, 2.27; 95% CI, 1.16-4.45, P = 0.017) as factors contributing to the spontaneous clearance of HCV. No significant interaction was found between the IL28B rs8099917 genotype and sex (P for interaction = 0.428). Both the favorable IL28B rs8099917 genotype and female sex were associated with the spontaneous clearance of HCV in this Japanese population.

Importance of virological response in the early stage of telaprevir-based triple therapy for hepatitis C.

AIM: To investigate the efficacy of virological response (VR) to telaprevir (TVR)-based triple therapy in predicting treatment outcome of hepatitis C. METHODS: This prospective, multicenter study consisted of 253 Japanese patients infected with hepatitis C virus (HCV) genotype 1b. All received 12 wk of TVR in combination with 24 wk of pegylated-interferon-α (IFN-α) and ribavirin. Serum HCV RNA was tested at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. VR was defined as undetectable serum HCV RNA. Sustained virological response (SVR) was VR at 24 wk after the end of treatment and was regarded as a successful outcome. RESULTS: Of 253 patients, 207 (81.8%) achieved SVR. The positive predictive value of VR for SVR was 100% at week 2, after which it gradually decreased, and was over 85% to week 12. The negative predictive value (NPV) gradually increased, reaching 100% at week 12. The upslope of the NPV showed a large increase from week 4 (40.6%) to week 6 (82.4%). There was a moderate concordance between the SVR and VR at week 6 (kappa coefficient = 0.44), although other VRs had poor concordance to SVR. Multiple logistic regression analysis extracted VR at week 6 (P < 0.0001, OR = 63.8) as an independent factor contributing to SVR. In addition, the interleukin-28B single nucleotide polymorphism and response to previous pegylated-IFN-α and ribavirin therapy were identified as independent factors for SVR. CONCLUSION: VR at week 6, but not at week 4, is an efficient predictor of both SVR and non-SVR to TVR-based triple therapy.

Glycated albumin as a diagnostic tool for diabetes in a general Japanese population.

OBJECTIVE: Diabetes mellitus is a major cause of cardiovascular, kidney, neurologic, and eye diseases, and may be preventable in some cases by lifestyle modification. Screening tests for diabetes mellitus include fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Our objective was to evaluate the utility of plasma glycated albumin (GA) in the diagnosis of diabetes mellitus. DESIGN AND METHODS: A cross-sectional, community-based population study of 908 non-diabetic Japanese residents was conducted. Of these subjects, 176 with FPG value between 5.5 and 6.9mmol/l, and an HbA1c level of <6.5% received an oral glucose tolerance test (OGTT). RESULTS: The OGTT results were used for the diagnosis of diabetes mellitus using World Health Organization criteria. Receiver operating characteristic (ROC) analyses demonstrated that optimal threshold values for the diagnosis of diabetes in this population were 15.2% for GA and 5.9% for HbA1c, respectively. Using these cutoff levels, the sensitivity of GA at 62.1% for detecting diabetes was the same as that of HbA1c. However the specificity for GA for detecting diabetes was 61.9%, while for HbA1c it was higher at 66.7%. CONCLUSIONS: Our results indicate that the measurement of glycated albumin may serve as a useful screening test for diabetes in a general Japanese population.

A thymine-adenine dinucleotide repeat polymorphism near IL28B is associated with spontaneous clearance of hepatitis C virus.

BACKGROUND: Genome-wide association studies have revealed several single-nucleotide polymorphisms around interleukin 28B (IL28B) that are strongly associated with hepatitis C virus (HCV) clearance. However, their predictive value is not perfect, which suggests that other genetic factors may also be involved in HCV clearance. We previously reported a wide variation in the length of a thymine-adenine (TA) dinucleotide repeat in the promoter region of IL28B and that the transcriptional activity of the promoter increased gradually in a TA repeat length-dependent manner. METHODS: We determined the length of the TA repeats of 1,060 Japanese and 201 African-American samples to investigate the relation to spontaneous HCV clearance. RESULTS: The distribution of the TA repeats greatly differed between the two ethnicities. The variation ranged from 10 to 18 repeats, and the most frequent allele, 12, accounted for over 80% for Japanese. The African-American data showed a gently sloping distribution, and the allele with six repeats was detected only in the African-American sample. The TA repeats 11 or greater were correlated with spontaneous clearance. Multiple logistic regression analysis extracted the genotype of the TA repeats as an independent factor in both the Japanese [p = 0.0004, odds ratio (OR) = 13.02 95% confidence interval (CI) = 2.59-237.0] and African-American (p = 0.027, OR = 3.70 95% CI = 1.16-11.8) populations. CONCLUSIONS: A long TA repeat in the promoter region of IL28B was associated with spontaneous HCV clearance. Although its efficacy may be limited in Japanese population because of its allele distribution, this novel genetic factor will be useful for predicting HCV clearance especially for the African Americans.

The kinetics of the hepatitis B surface antigen level after the initiation of antiretroviral therapy for hepatitis B virus and human immunodeficiency virus coinfected patients.

BACKGROUND: Hepatic flares (HF), which reflect hepatitis B virus (HBV)-related immune reconstitution inflammatory syndrome (IRIS), frequently occur in patients with HBV and human immunodeficiency virus (HIV) coinfection after the start of antiretoroviral therapy (ART). The rate of hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss is higher for patients with HF after the initiation of ART. METHODS: We retrospectively examined the kinetics of the HBsAg and HBeAg levels of six HBV/HIV coinfected patients after the commencement of ART that included tenofovir. All were male and HBeAg positive. RESULTS: Three patients developed HF after the initiation of ART. All subsequently lost HBeAg and one of them lost HBsAg after HF. None who did not experience HF lost HBeAg. The HBsAg and HBeAg levels remarkably decreased when HF occurred, but the decline of HBsAg was very slow in the periods before and after HF. The median decline of the HBsAg level at 48 weeks was 2.20 Log IU/mL for patients with HF, but only 1.00 Log IU/ml for patients without HF. Little decline was seen for either group in the median decline of the HBsAg level from 48 weeks to 96 weeks, 0.28 Log IU/mL in the HF group and 0.06 Log IU/mL in the non-HF group. CONCLUSION: The immune reconstitution of a HBV/HIV coinfected patient plays an important role in the clearance of HBV. If HBsAg and HBeAg levels decrease rapidly when HF occurs, the hepatic flare would be due to HBV-related IRIS.

Subclinical carotid atherosclerosis and triglycerides predict the incidence of chronic kidney disease in the Japanese general population: results from the Kyushu and Okinawa Population Study (KOPS).

OBJECTIVE: To examine whether or not subclinical atherosclerosis independently predicts the incidence of chronic kidney disease (CKD) in the Japanese general population. METHODS: This study is part of the Kyushu and Okinawa Population Study (KOPS), a survey of vascular events associated with lifestyle-related diseases. Participants who attended both baseline (2004-2007) and follow-up (2009-2012) examinations were eligible. The common carotid intima-media thickness (IMT) was assessed for each participant at baseline. The end point was the incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) during the follow-up of participants without CKD at baseline. RESULTS: During the five-year follow-up, 224 of the 1824 participants (12.3%) who developed CKD had higher carotid IMT (0.74 ± 0.22 vs. 0.65 ± 0.14 mm, P < 0.001), higher triglycerides (1.6 ± 0.8 vs. 1.3 ± 0.7 mmol/L, P < 0.001), and lower high density lipoprotein cholesterol (1.5 ± 0.4 vs. 1.6 ± 0.4 mmol/L, P < 0.001) at baseline than those who did not. In logistic regression analysis adjusted for significant covariates, eGFR (Odds ratio [OR] 0.83, 95% confidence interval (CI) 0.80-0.85, P < 0.001), carotid IMT (0.10 mm increase: OR 1.17, 95% CI 1.04-1.33, P = 0.010), and triglycerides (OR 1.35, 95% CI 1.06-1.73, P = 0.015) at baseline were independent predictors for the development of CKD. CONCLUSIONS: Higher carotid IMT and hypertriglyceridemia were independently associated with the development of CKD in the population studied.

Hepatitis B virus-related immune reconstitution inflammatory syndrome in two patients coinfected with human immunodeficiency virus diagnosed with a liver biopsy.

Hepatic flares occurred in two patients with HBV/HIV coinfection following the commencement of antiretroviral therapy (ART). At that time, the HIV RNA and HBV DNA levels had decreased. The results of liver biopsies showed lymphocytic infiltration that was diffusely positive for CD8(+) T cells in the portal areas and lobules. These findings suggested HBV-related immune reconstitution inflammatory syndrome (IRIS). The alanine aminotransferase levels of both patients gradually decreased with the continuation of ART. Because there are few reports of the liver histology of HBV-related IRIS, these cases provide a better understanding of the pathogenesis of HBV-related IRIS.

A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy.

Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy.

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.

Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/ribavirin therapy in chronic hepatitis C patients.

BACKGROUND: Genetic variation around interleukin-28B (IL28B), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes. METHODS: The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data. RESULTS: We found that BDCA-4(+) plasmacytoid and BDCA-3(+) myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment (p = 1.0 × 10(-10)), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %). CONCLUSIONS: Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype.

Serum cholesterol and triglyceride reference ranges of twenty lipoprotein subclasses for healthy Japanese men and women.

AIM: This epidemiological study was done to generate normal ranges for the cholesterol and triglyceride levels in serum lipoprotein subclasses isolated from healthy adults based on gender and menopausal status. METHODS: Cholesterol and triglyceride levels in 20 lipoprotein subclasses as separated by high performance liquid chromatography were measured in serum obtained from 825 fasting healthy subjects (267 men, 558 women). RESULTS: For serum cholesterol, 13.7% was found in very low density lipoprotein (VLDL) subclasses, 55.6% in low density lipoprotein (LDL) subclasses, and 30.4% in high density lipoprotein (HDL) subclasses. For serum triglycerides, these values were 52.1%, 27.9%, and 17.4%, respectively. Levels of cholesterol in some VLDL subclasses were inversely correlated with the levels of some HDL subclasses, while for triglycerides, elevated levels in any one subclass were generally strongly associated with elevated levels in all other subclasses. Men had significantly higher large VLDL-cholesterol levels than women (P < 0.05), while women had significantly higher small VLDL-cholesterol levels than men (P < 0.001). Women had significantly higher large LDL- and large and medium HDL-cholesterol levels than men (P < 0.001). Men had significantly higher chylomicron (CM), large and medium VLDL-, and small LDL-triglyceride levels than women (P < 0.001). Women had significantly higher very large and large HDL-triglyceride levels than men (P < 0.01). Postmenopausal women had significantly higher CM, all VLDL, and large, medium and small LDL-cholesterol levels, and significantly higher all VLDL, LDL, and HDL-triglyceride levels than premenopausal women (P < 0.001). CONCLUSIONS: Our data document important gender and menopausal status differences in cholesterol and triglyceride subclass levels, as well as significant correlations between values in the various serum lipoprotein subclasses.

Raloxifene hydrochloride is an adjuvant antiviral treatment of postmenopausal women with chronic hepatitis C: a randomized trial.

BACKGROUND & AIMS: Early menopause in women with chronic hepatitis C virus (HCV) infection is associated with a low likelihood of a sustained virological response (SVR) in conjunction with their antiviral treatment. This is potentially related to their reduced estrogen secretion. The study was done to determine whether selective estrogen receptor modulator administration might improve the efficacy of the current standard of care (SOC) treatment, pegylated interferon (PegIFN) α2a plus ribavirin (RBV), for postmenopausal women. METHODS: One hundred and twenty-three postmenopausal women with genotype 1b chronic hepatitis C were randomly assigned to one of two treatment groups: raloxifene hydrochloride (RLX) (60 mg/day) plus SOC (PegIFNα2a 180 µg/week and RBV 600-1,000 mg/day) (n=62) or SOC only (n=61). Genotyping was performed of the polymorphism in the interleukin-28B (IL28B) gene region (rs8099917) of DNA collected from each patient. RESULTS: One RLX-treated patient discontinued RLX because of a systemic rash following 2 weeks of treatment. Twenty-four weeks after treatment, the SVR rate was significantly higher for RLX plus SOC patients (61.3%) than for SOC only patients (34.4%) (p=0.0051). Further, the SVR rate was significantly higher for RLX plus SOC patients with IL28B TT (72.5%) than for SOC only patients with IL28B TT (39.2%) (p=0.0014), but no such relationship was observed in patients carrying the minor IL28B allele. CONCLUSIONS: RLX improved the efficacy of SOC in the treatment of postmenopausal women with chronic hepatitis C. RLX shows promise as an adjuvant to the standard antiviral treatment of such patients.