Income-based inequality in nationwide general health checkup participation in Japan.

OBJECTIVE: In Japan, it is mandatory for employers to provide general health checkup opportunities to employees. Although many companies have subsidized checkups for employees' dependent family members, their participation is low. We assessed income-based inequality in the participation of employees' dependents in the general health checkup. STUDY DESIGN: This is a cross-sectional descriptive study. Annual participation rate in general health checkup and various factors including income, age, and sex were collected and analyzed to examine the income-based inequality of participation rate in general health checkup. METHODS: The data for the present study were sourced from the Fukuoka Branch of the Japan Health Insurance Association, a large medical insurer in Japan. We extracted data of 196,057 dependents aged 40-74 years. We conducted a multiple logistic regression analysis using participation from April 2015 to March 2016 as dependent variable and income category ranging from 1 (lowest) to 4 (highest) between April and June 2015 as independent variable (adjusted for sex and age). We computed slope index of inequality (SII) and relative index of inequality (RII) based on income category. RESULTS: Higher the income, the more likely were dependents to participate in the general health checkup. SII for the participation rate of general health checkup ranged between -0.02 (95% confidence interval [CI]: -0.07 to 0.03) and 0.06 (0.03-0.09) for men; 0.03 (0.01-0.06) and 0.10 (0.09-0.11) for women. RII for the participation rate of general health checkup ranged between -0.19 (95% CI: -0.66 to 0.29) and 0.88 (0.15-1.61) for men; 0.22 (0.05-0.39) and 0.68 (0.60-0.76) for women. The highest inequality existed for men in their 50s and 60s and women in their 50s; the lowest inequality was among men and women aged 70-74 years. CONCLUSION: There was income-based inequality in participation in the general health checkup among dependents (family members) of the insured persons. The degree of inequality differed with age group. It cannot be explained solely by financial barrier among low-income group, rather it may reflect Japanese unique context in medical insurance system.

The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies.

The mechanisms by which hepatitis C virus (HCV) induces chronic infection in the vast majority of infected individuals are unknown. Sequences within the HCV E1 and E2 envelope genes were analyzed during the acute phase of hepatitis C in 12 patients with different clinical outcomes. Acute resolving hepatitis was associated with relative evolutionary stasis of the heterogeneous viral population (quasispecies), whereas progressing hepatitis correlated with genetic evolution of HCV. Consistent with the hypothesis of selective pressure by the host immune system, the sequence changes occurred almost exclusively within the hypervariable region 1 of the E2 gene and were temporally correlated with antibody seroconversion. These data indicate that the evolutionary dynamics of the HCV quasispecies during the acute phase of hepatitis C predict whether the infection will resolve or become chronic.

Evidence for a bidirectional promoter complex within the X gene of woodchuck hepatitis virus.

The genetic organization of hepadnaviruses is unusual in that all cis-acting regulatory sequences are located within genes. Thus, in the mammalian hepadnavirus genome, the presurface, surface, and X transcript promoters reside within the polymerase gene while the pregenome transcript promoter is located within the X gene. In this study we have identified two additional promoters within the woodchuck hepatitis virus (WHV) X gene that stimulate production of transcripts in vitro. First, we cloned regions of the WHV X gene into a promoterless expression vector (pGL2) to examine their ability to promote expression of firefly luciferase and mapped a previously unidentified promoter to positions 1475-1625 of the WHV8 genome. Deletion analysis revealed that the essential domain of this promoter, termed the ORF5/deltaX transcript promoter, mapped to nucleotides 1525-1625. Analysis revealed that this transcript initiated at nucleotide 1572 in both human (HuH-7) and woodchuck (WLC-3) hepatoma cell lines. Consistent with this finding, DNA footprinting analysis revealed protection of nucleotides 1567-1578 on the positive strand of the WHV8 genome. The function of this transcript in vivo is unclear, however, it may be used to produce a truncated form of the X protein that initiates at an AUG codon at position 1743-1745 on the WHV8 genome. Next, a second promoter was identified at positions 1625-1975 that was responsible for production of an antisense transcript. The activity of this promoter was comparable to that of the previously characterized surface transcript promoter of WHV in the absence of an enhancer. The antisense transcript promoter resides immediately upstream of open reading frame (ORF) 6, a previously identified ORF on the strand opposite of the known WHV protein-encoding sequences, that is thought to represent a vestigial gene. Analysis indicates that the antisense transcript had multiple start sites: nucleotides 1683 and 1762 on the WHV8 genome when assayed in HuH-7 cells, and nucleotide 1786 when assayed in WLC-3 cells. These data are consistent with footprinting analysis of supercoiled WHV DNA that revealed that the regions encompassing nucleotides 1696-1685, 1781-1766, and 1801-1787 on the negative sense DNA strand were protected from nuclease degradation. It is possible that such a transcript was once used in protein expression in an ancestral virus and may now be used for genetic control of WHV replication and/or gene expression. Overall, these data are consistent with the presence of a bidirectional promoter complex within the WHV X gene.

Central actions of AD-1211, an analgesic lacking common opiate features.

The site of the analgesic action of AD-1211, the less active stereoisomer, and its pharmacological features were investigated. AD-1211, as well as pentazocine and morphine, blocked the reflex hypertension caused by injection of both bradykinin and bradykinin plus PGE1 into the splenic artery of dogs. In the rat or mouse writhing test, the analgesic activity of AD-1211 after intraperitoneal and intracisternal administration was equal to and more than 40 times, respectively, that after intravenous administration. The analgesic activity of AD-1211, unlike that of pentazocine and morphine, was incompletely reversed by naloxone and was not attenuated even by its repeated administration for 7 days in the mouse writhing and tail pressure test, respectively. AD-1211, unlike pentazocine and/or morphine, lacked some effects on central nervous, respiratory and cardiovascular function in conscious animals. These results demonstrate that AD-1211 produces its analgesic action through a central mechanism but lacks some of the common pharmacological actions shown by morphine-like analgesics.

Interferon-alpha modulates resistance to cisplatin in three human hepatoma cell lines.

We investigated the expression of the drug resistance-related genes, multidrug resistance gene 1 (MDR1), multidrug resistance associated protein gene (MRP), and the DNA topoisomerase IIalpha, DNA topoisomerase IIbeta, and glutathione-S-transferase pi gene (GST-pi) in three human hepatoma cell lines (HepG 2, HuH 7, SK-Hep-1) with or without drug treatment with interferon-alpha (IFN-alpha) and cisplatin (CDDP), by a reverse transcription-polymerase chain reaction (RT-PCR) method and a competitive PCR method. The signals of the MDR1, MRP, topoisomerase IIalpha, and topoisomerase IIbeta genes in HepG2 were weakened when IFN-alpha was added to CDDP. In SK-Hep-1, the administration of CDDP alone increased the signals of MDR1 while the addition of IFN-alpha decreased the signals, and the signals of GST-pi were decreased by IFN-alpha plus CDDP. In summary, our results concerning the expression of drug resistance-related genes in three human hepatoma cell lines demonstrate that IFN-alpha may modulate the mechanism of resistance to CDDP in liver cancer.

High-risk groups and screening strategies for early detection of hepatocellular carcinoma in patients with chronic liver disease.

Characteristics of high-risk groups for hepatocellular carcinoma (HCC) in Japan were studied to establish screening strategies for early detection of the tumor. Some 93% of patients with HCC were associated with chronic liver disease. On the other hand, 67% of patients with liver cirrhosis had HCC at autopsy. Most were related to current hepatitis virus infection. An analysis of risk factors among 120 patients with chronic hepatitis revealed that age and histological findings were independent risk factors, while HBsAg, anti-HCV, sex, history of heavy drinking, history of blood transfusion were not independent risk factors. Multivariate analysis of 239 patients with liver cirrhosis demonstrated that age, positivity for HBsAg and/or anti-HCV, family history of liver disease, hepatic reserve, and a history of radical resection were independent factors related to the development of HCC. A screening schedule for cirrhotic patients was established in accordance with these results; ultrasonography was done every three months, and tumor markers measured every two months. The screening strategy proved to be effective for the early detection of HCC and improvement of the prognosis.

[Comparison between HGV genome and HGBV-C genome].

New hepatitis viruses, hepatitis G virus(HGV) and hepatitis GB virus C(HGBV-C), were reported from two groups of researchers. Now these two are thought to be similar but HGV genome(U44402) and HGBV-C genome(U36380) do not have the same sequence. We compare these two sequences in both nucleotide and aminoacid analyses. Homology of nucleotide between HGV and HGBV-C is 83.8% in 5'NC region, 88.8% in core, 85.1% in E1, 85.7% in E2, 85.1% in NS2-3, 84.5% in NS4A, 86.8% in NS4B-5A, 88.6% in NS5B and 18.0% in 3'NC. The length of 3'NC is quite different between HGV and HGBV-C. Homology of aminoacid between these two viruses is 82.9% in core region, 87.3% in E1, 91.0% in E2, 97.4% in NS2-3, 93.8% in NS4A, 96.2% in NS4B-5A and 96.6% in NS5B. Especially helicase and replicase regions are highly conserved in 99.0% and 92.7% of aminoacid homology, respectively.

Morphological studies on cerebral cortical lesions induced by transient ischemia in Mongolian gerbil--diffuse and peripheral pallor of the neuronal perikarya.

Unilateral transient cerebral ischemia was produced in Mongolian gerbils by clipping the left common carotid artery for 1 h. About 60% of the gerbils with neurological symptoms had post-ischemic seizures. The majority of those that had seizures died within a few days, and sections of their cerebral cortices contained many dark and shrunken neurons. However, the gerbils that did not have seizures survived without any severe complications. In the cerebral cortex of the latter, the neurons with diffuse or peripheral pallor of the perikarya were seen along with a small number of dark and shrunken neurons. Diffuse pallor occurred within a few hours following ischemia in layers III, V, and VI, and disappeared 1 or 2 days after recirculation. Electron microscopically, these neurons showed dispersion of ribosomes, simple and elongated profiles of rough endoplasmic reticulum (r-ER), clustered vacuoles, and mild to moderate mitochondrial swelling. Occasional net-like tubulomembranous structures, probably derived from r-ER, were observed. On the other hand, peripheral pallor became apparent after 5 days following ischemia, usually involving layer II first and gradually extending to the deeper layers. Concomitantly, the amount of neuropil decreased and the dendrites exhibited tortuosity and irregularity in layer II. Electron microscopically, these neurons showed marked swelling of peripheral perikarya and polyribosomes and organelles were located peripherally to the nuclei. In addition, numerous degenerated axon terminals and distended dendrites were observed around the neurons. These observations indicate that diffuse pallor represents damage directly induced by ischemia and subsequent recirculation, while peripheral pallor is the delayed and remote effect of ischemia, probably due to degeneration of neuronal processes.

TNF inhibitor with a low molecular weight found in the human sera.

We found a TNF inhibitory factor with a molecular weight of 5 to 10 kDa in the human sera. The activity was detected by inhibiting the activity of serum to TNF-induced cytotoxicity against target cells. It was found in sera of all the healthy donors tested without any febrile diseases. Moreover, our results demonstrated that TNF inhibitory factor decreases in the semum of patients on regular hemodialysis treatment and in the serum of diabetes mellitus patients. The activity found in human sera was eluted from DEAE-cellulose column (Mono Q) at 0.25 and 0.45 M NaCl, and was labile to incubation for 60 min at 56 degrees C and susceptible to treatment with trypsin, which destroyed 60% of its biological activity. TNF inhibitory factor may act as a regulator of the biological activity of TNF and could have beneficial effects in certain inflammatory conditions, and therefore, could be useful in clinical application.

Central and peripheral analgesic action of non-acidic non-steroidal anti-inflammatory drugs in mice and rats.

The site of the analgesic action of non-acidic (basic), non-steroidal anti-inflammatory drugs (NSAIDs) was investigated in the acetic acid writhing test. In rats the anti-writhing potency ratio of i.p. to i.v. administered aminopyrine, tiaramide HCl or mepirizole was 4.96, 1.87 and approximately 4, respectively, suggesting an involvement of both central and peripheral mechanisms of their anti-writhing action. In mice the ratio of intracisternally (i.c.) to i.v. administered aminopyrine, tiaramide HCl or mepirizole was approximately 5.8, approximately 50 and approximately 7, respectively. Since the above ratio for morphine and methadone was higher than 10 and tolmetin sodium, an acidic NSAID, did not produce any anti-writhing effect when given i.c., it could be assumed that the anti-writhing action of these non-acidic NSAIDs was at least partially mediated via the central nervous system. In common with tolmetin sodium, aminopyrine showed more of anti-inflammatory potency when administered i.p. than i.v. and it did not reduce vascular permeability in mice when administered i.c. These results suggest that non-acidic NSAIDs produce their anti-writhing action through both central and peripheral mechanisms.

Minute carcinoid tumor of the uterine cervix associated with microinvasive adenocarcinoma, with reference to its histogenesis.

A rare case of carcinoid tumor of the uterine cervix associated with adenocarcinoma was reported. The carcinoid tumor was composed of round to polygonal cells showing solid or trabecular proliferation. Most of these cells and a small number of isolated cells wedged in neoplastic glands were positive with either Grimelius or Fontana-Masson stains, and also positive for serotonin by immunostain (PAP method). Positively stained cells were thus considered to have the same histochemical nature as enterochromaffin cell. The carcinoid tumor was minute, about 2 X 2 mm and the adenocarcinoma was a microinvasive one. In some parts, smooth transition between both tumor components was observed. From these findings, it is suggested that both the carcinoid tumor and the adenocarcinoma in the present case were derived from a primitive precursor cell of common mesodermal origin.

Hepadnavirus enhancer and its binding proteins.

In the hepadnavirus enhancer region, a 33 bp DNA sequence is strongly conserved among mammalian hepadnavirus genomes. To elucidate the role of the sequence, we tested enhancer activities and capability to form DNA-protein complex of several synthetic DNAs. Not only two tandem copies of a 46 bp DNA covering the sequence but also two tandem copies of a 23 bp in the sequence exhibit enhancer activity. Also the activity was augmented by treatment of a tumor promoter, TPA. DNA binding proteins complexes with the 23 bp DNA were augmented in extracts of HepG2 or HeLa cells stimulated with TPA. These results imply that the conserved sequence of hepadnavirus enhancer is a TPA-inducible enhancer which is transactivated by ubiquitous DNA-binding proteins. We presented results showing that DNA-protein complexes with a 23 bp DNA are similar to but distinct from those with a TPA-responsive element DNA, the recognition site for c-jun/fos products. We also presented results suggesting that hepadnavirus X protein may not directly or indirectly affect DNA-protein complex formation with the conserved sequence in the hepadnavirus enhancer.