Takehiro Matsumoto

Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis

Abstract: Background: Although the pathogenesis of non‐alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients.

Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis

The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-α, -β, -γ, interleukin (IL)-1β, -4, -6, -10, -12p40, -18, tumor necrosis factor-α) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-α, -β and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-α, -β) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-α is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-β and TLR-3. Furthermore, the level of IFN-α mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC.

Relationship between sustained elevation of serum alanine aminotransferase and progression from cirrhosis to hepatocellular carcinoma: comparison in patients with hepatitis B virus- and hepatitis C virus-associated cirrhosis.

Abstract  Most patients with hepatocellular carcinoma (HCC) in Japan have hepatitis B virus (HBV)‐or hepatitis C virus (HCV)‐associated cirrhosis. In the present study, the risk of HCC in patients with cirrhosis was analysed by the levels of serum alanine aminotransferase (ALT). One hundred and one (78%) of 129 patients with cirrhosis registered from April 1979 were followed at monthly intervals with the measurement of serum ALT. Of 101 patients, 38 tested positive for hepatitis B surface antigen (HBsAg) but negative for antibody to HCV (anti‐HCV; HBV group), 47 tested negative for HBsAg but positive for anti‐HCV (HCV group) and nine tested positive and seven tested negative for both. Mean serum ALT during follow‐up was calculated on the basis of monthly values during the observation period that started at enrolment and ended with the detection of HCC or at the end of March 1994. By the end of March 1994, 37 (37%) patients developed HCC; 12 were in the HBV group, 21 in the HCV group and four were in the group positive for both. Mean serum ALT during the observation period was similar in patients who developed HCC and those who did not develop HCC in the HBV group. In contrast, the value was significantly higher in patients who developed HCC than in patients who did not develop HCC in the HCV group (P < 0.05).

Prevalence and clinical characteristics of TT virus (TTV) in patients with sporadic acute hepatitis of unknown etiology

BACKGROUND/AIMS Recently, a novel DNA virus was isolated from the serum of a patient with post-transfusion non-A-G hepatitis and named TT virus. The aim of this study was to determine the prevalence and clinical characteristics of TT virus infection in patients with sporadic acute hepatitis of unknown etiology. METHODS TT virus was investigated in the serum of 66 patients with sporadic acute hepatitis non-A-G and 50 healthy controls by semi-nested PCR with previously published primers. RESULTS TT virus was detected in 17 (26%) of the 66 patients with sporadic acute hepatitis non-A-G and in a slightly higher rate (34%,17/50) in the control group. No significant differences in alanine aminotransferase or bilirubin concentrations were observed between the groups of patients with or without TT virus infection. Eighty per cent (12/15) of patients for whom follow up was possible had persistent viremia from 4 to 36 months, and 67% (8/12) of these patients had already normalized their levels of alanine aminotransferase. A phylogenetic tree constructed by the Neighbor Joining Method revealed that all isolates in this study were grouped within genotype 1a and 1b, without showing any association between genetic type and development of hepatic disease. CONCLUSIONS Our results suggest that TT virus DNA is present not only in patients with sporadic acute hepatitis non-A-G but also in a large proportion of the general population. This virus was not likely to be the causative agent of hepatitis among the patients in this study.

Two cases of hepatopulmonary syndrome with improved liver function following long-term oxygen therapy

Hepatopulmonary syndrome (HPS) is a complication of liver disease that is characterized by hypoxemia and intrapulmonary vascular dilatations. The only established therapy for this disorder is liver transplantation. Here, we report two patients (a 63-year-old woman and a 72-year-old man) with HPS associated with hepatitis C virus-related cirrhosis. We gave the patients low-dose oxygen supplementation to improve their respiratory symptoms. Surprisingly, their liver function improved from Child Pugh class C to class A, and ascites disappeared after a year of oxygen supplementation. We believe that long-term oxygen therapy contributed to the improvement of liver function in these two cases. Long-term oxygen therapy might offer a new therapeutic approach to improve liver function in patients with cirrhosis with hypoxemia.

Detection of HBV RNA in peripheral blood mononuclear cells in patients with and without HBsAg by reverse transcription polymerase chain reaction.

We examined RNA of hepatitis B virus (HBV) in peripheral blood mononuclear cells (PBMCs) by the reverse transcription polymerase chain reaction (RT PCR) in 61 patients associated with HBV infection, in order to analyze the relationship between the transcriptional activity of HBV in PBMCs and the clinical characteristics. The presence of HBV RNA in PBMCs was detected in 19/51(37.1%) patients with HBsAg positive and in 1/10 (10.0%) patient with HBsAg negative patients. Six healthy controls were all negative. The frequency of HBV RNA positivity was detected in patients with high ALT level (P<0.05), serum HBeAg positivity (P<0.01) and serum HBV DNA level>/=0.7 Meq/ml (P<0.05). Moreover, HBV RNA in PBMCs was detected in one patient followed up for 2 years after HBsAg disappearance in serum, who had not HBV DNA but anti-HBc IgG, in serum. These results suggested that the transcription of HBV in PBMCs, was frequently detected in the patients with higher replication of the virus, but HBV RNA in PBMCs might be detected in a few patients who had no evidence of HBV replication serologically.

Efficacy of immunization of high-risk infants against hepatitis B virus evaluated by polymerase chain reaction

The polymerase chain reaction (PCR) is a rapid and very sensitive method to detect viral genomes. In the present study, the efficacy of immunization against hepatitis B virus (HBV) of high‐risk infants was evaluated by PCR. Twenty‐nine infants born to 24 HBeAg‐positive carrier mothers were given hepatitis B immune globulin (HBIG) at birth and thereafter received repeated inoculations of plasma‐derived vaccine or HBIG, or both, within 1 year. Serum samples at 1 year following immunization were stored at −40°C for later analysis using PCR to detect HBV‐DNA. When HBV genomes were detected in infants, the DNA sequences in the S gene of HBV were determined. Of 29 infants, 2 were positive for HBV‐DNA at the 1 year following immunization; one had the HBV containing only the wild‐type sequence in the S gene and became negative for HBV‐DNA during the follow‐up period. In contrast, another had the HBV, which contained nucleotide substitutions that altered the expression of the common group‐specific determinant “a” of the S gene and resulted in clinical hepatitis with viral persistence. PCR analysis suggests that immunization against HBV prevents effectively high‐risk infants from mother‐to‐child transmission. Even then, however, it is possible that amino acid substitutions in the “a” determinant of the S gene are associated with failure of conventional immunization against HBV. J. Med. Virol. 53:255–260, 1997.

Relationship of α-fetoprotein levels and development of hepatocellular carcinoma in hepatitis C patients with liver cirrhosis

α-fetoprotein (AFP) is a tumor marker of hepatocellular carcinoma (HCC) and has also been reported to reflect the effectiveness of long-term low-dose interferon (IFN) therapy in hepatitis C virus (HCV)-infected patients with chronic liver disease. The correlation between AFP levels and the incidence of HCC has been discussed over a long period. We investigated whether high levels of AFP at the time of diagnosis were associated with an increased incidence of HCC in patients with HCV. A total of 107 HCV patients with liver cirrhosis without other risks were evaluated for the predictive value of non-invasive risk factors for HCC, including age, gender, alcohol intake, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count and AFP levels at study entry, as well as the IFN therapy received. During the follow-up period, HCC developed in 68 (63.6%) patients. Kaplan-Meier estimates were made to assess the cumulative risk of HCC. The 10-year cumulative incidence rate of HCC was 80%. Cox regression analysis was performed on several variables, including age, gender, alcohol consumption, experience of IFN therapy and biochemical parameters. The following factors were identified as exhibiting an increased risk of HCC by univariate analysis: aspartate transaminase (AST) ≥71 IU/l, alanine transaminase (ALT) ≥60 IU/l, AFP ≥6 ng/ml and IFN therapy. Multivariate analysis identified that the AFP level [6–19 ng/ml: hazard ratio (HR), 2.22; P=0.006 and ≥20 ng/ml: HR, 2.09; P=0.003] was an independent and significant risk factor for the development of HCC. A slightly elevated (6–19 ng/ml) AFP level may be a risk factor for HCC in certain cases. By contrast, AFP levels <6 ng/ml indicate a low risk of HCC development in HCV patients with liver cirrhosis.

An effective medical partnership in Nagasaki, Japan for patients with rheumatoid arthritis.

Abstract Objectives: A clear division of the roles of inpatient facilities and outpatient clinics treating patients with rheumatoid arthritis (RA) is needed. To address this, we created a medical partnership between a university hospital and 43 community clinics in Nagasaki, Japan. Methods: We recruited the clinic physicians and compiled a list of the RA medications used (i.e. methotrexate [MTX], other disease-modifying antirheumatic drugs [DMARDs], and biologics). When a patient’s low disease activity or remission was confirmed at the university hospital, the hospital/clinic partnership provided double follow-up/medical care with semiannual meetings between the hospital and clinic physicians. Results: We enrolled 149 patients who maintained clinical remission at 43 clinics over a 54-month period, without rare serious events. Among the nine patients who returned to the university hospital due to relapse, 66.7% had exacerbated RA within 18 months. An average 8.8–9.6 mg/week (max. 14 mg/week) MTX dose was prescribed at the clinics. The biologic usage rate was 22.1%, with a yearly increase. Among the patients treated with biologics, the DAS28ESR at enrollment was 2.65, with 58% treated with an MTX/biologic combination. A significant reduced number of patients with RA per rheumatologist were observed. Conclusions: Maintenance of DAS remission without major adverse events was attained in the medical partnership.

Privacy-conscious detection of roll-over based on thermography measurement

Because of the accident of falling out of the bed of inpatients / recipients of care occurs constantly in nursing /care facilities, the technique of roll-over detection / posture state estimation are required. In this paper, we developed the detection technique of roll-over with the thermographic watching system with the respect of a persons privacy The detection of roll-over is the method which finds out the errant characteristic value of the thermography. By using the Higher-order Local Auto-Correlation (HLAC) as the characteristic value, several of rollover and awaking was detected.