Glomerulosclerosis and viral gene expression in HIV-transgenic mice: role of nef.

BACKGROUND: Human immunodeficiency virus (HIV)-associated nephropathy is characterized by focal segmental glomerulosclerosis and microcystic tubular dilation. We have previously described a mouse transgenic for a Deltagag-pol HIV-1 genome, which develops glomerulosclerosis, cutaneous papillomas, and cataracts. METHODS: We developed mice transgenic for a Deltagag-pol-nef HIV genome in order to investigate the role of the nef gene in these phenotypes. RESULTS: One transgenic line, X5, expressed HIV mRNA in kidney and consistently manifested focal segmental glomerulosclerosis and tubular dilation by six weeks of age. Northern analysis indicated that renal transgene expression was higher in the Deltagag-pol-nef mice compared with the Deltagag-pol mice. In situ hybridization and immunostaining demonstrated HIV RNA and protein expression within the glomerular epithelial cells and tubular epithelial cells. These cell types showed histologic evidence of toxicity, including vacuolation and detachment from basement membrane, and exhibited increased rates of apoptosis. These data suggest that the renal disease seen in the Deltagag-pol-nef transgenic mouse may be caused by the expression of HIV genes within renal epithelial cells, that this expression may induce cellular toxicity, including apoptosis, and that nef is not required for the induction of renal disease. We have previously described mice bearing the nef gene, which do not manifest renal disease. In further experiments, Deltagag-pol-nef mice were bred with nef mice; these dual-transgenic mice developed renal disease that generally resembled that seen in Deltagag-pol-nef mice, but with somewhat more severe glomerulosclerosis and less severe tubulointerstitial injury. RESULTS: The results of these transgenic studies suggest that the role of nef is complex and may act both to reduce transgene expression and to potentiate glomerular injury induced by other HIV-1 gene products.

[Amantadine usage for influenza A during an influenza outbreak in a nursing home].

An outbreak of an influenza like illness was found in a nursing home in Fukuoka in January, 1999. Results of hemagglutinin inhibition tests with paired sera of patients and rapid diagnosis kit for influenza A indicated that an influenza A (H3N2) outbreak had occurred. A total of 15 patients with influenza like illness from one residential area of the nursing home were administered amantadine, 100 mg per day for five days. Clinical records of 264 residents were surveyed retrospectively from the tenth to the thirty-first of January, 1999. Influenza like illness was found in 112 residents (42.4%). The incidence of influenza like illness differed by residential area, ranging from 27.6% to 54.0%. The mean duration of fever was 3.6 days among patients administered amantadine. The mean duration was 4.4 days for patients not administered amantadine. The incidence of influenza like illness decreased rapidly after amantadine administration in the residential area where amantadine administration was done. These results suggest that amantadine is effective in mitigating influenza symptoms in the elderly. Amantadine may be useful for diminishing the influence of influenza A outbreaks in nursing homes.

Prevalence of liver abnormalities in the general population of Okinawa, Japan.

A total of 2,825 Japanese over 20 years of age living in the Yaeyama District of Okinawa, Japan were investigated in 1983 and 1984 to determine the prevalence and risk factors of liver abnormalities. Obesity index, hepatitis B virus markers, hepatitis C virus marker and serum transaminase were measured and the history of alcohol intake was recorded. People with elevated transaminase levels were assumed to have abnormalities of the liver. The overall prevalence of liver abnormalities was 3.6% and was significantly higher in men than in women (p < 0.001). Logistic regression analysis showed that the strongest predictors of liver abnormalities were alcohol for the men and obesity for the women. Hepatitis B virus was the second most prevalent risk factor in both sexes.

Alcohol consumption and seroconversion from hepatitis B e antigen in the Okinawa Japanese.

A total of 1,113 hepatitis B surface antigen (HBsAg) carriers of Yaeyama District in Okinawa, Japan, were investigated in attempts to elucidate effects of alcohol consumption on seroconversion from hepatitis B e antigen (HBeAg). All of HBsAg carriers were tested for HBeAg. The subjects over 20 years of age were asked about their habitual intake of alcohol and were ranked into three categories: nondrinkers, light drinkers (1-59 g/day), and heavy drinkers (> or = 60 g/day). The prevalence of HBeAg decreased with advancing age and did not differ between the sexes. Logistic regression analyses of the data revealed prevalence curves of HBeAg, depending on the age of subjects. The prevalence curves tended to be higher and decrease more slowly in heavy drinkers than in the nondrinkers. Thus, the possibility that heavy alcohol drinking prolongs seroconversion from HBeAg seems worthy of further consideration.

Sexual transmission of human T-lymphotropic virus type I among female prostitutes and among patients with sexually transmitted diseases in Fukuoka, Kyushu, Japan.

The authors investigated the prevalence of antibody to human T-lymphotropic virus type I (anti-HTLV-I) in 409 female prostitutes, 446 patients with an episode of sexually transmitted diseases, and 17,345 control blood donors. All subjects were Japanese and all studies were done in Fukuoka, Kyushu, Japan, in 1989. The prevalence of anti-HTLV-I was significantly higher in the prostitutes (5.1%, p < 0.001), in the male patients (2.8%, p < 0.05), and in the female patients (5.7%, p < 0.05) than in the controls (males 1.4%, females 2.2%). Prevalence of anti-HTLV-I in the prostitutes increased with the number of years spent in prostitution, but the increase was not statistically significant. Among the subjects with sexually transmitted diseases, female prostitutes with syphilis, male patients with non-gonococcal urethritis, female patients with syphilis, and female patients with gonorrhea had a significantly higher prevalence of anti-HTLV-I than did the controls. A longitudinal study was done on the 168 prostitutes. Two (1.3%) of the 158 initially seronegative subjects seroconverted over the period of 2 years. These data suggest that the risk of male-to-female transmission of HTLV-I through sexual contact is high among high risk groups in Japan, and they support the possibility of female-to-male transmission of HTLV-I.

Development of human monoclonal antibodies to rabies.

A total of nine human monoclonal antibodies (MAbs) to rabies virus were generated from peripheral B lymphocytes of subjects immunized with human diploid cell rabies vaccine by somatic cell hybridization. The MAbs were analyzed for their antigen-binding specificities using ELISA, Western blot, and immunoprecipitation assays. The different assays made it possible to identify MAbs directed to the surface glycoprotein, nucleoprotein, nominal phosphoprotein, and matrix protein. One of the MAbs that recognized the surface glycoprotein neutralized rabies virus.

cDNA sequence and genomic organization of mouse secretin.

A murine insulinoma library was constructed by subtracting glucagonoma cDNAs from insulinoma cDNAs. Comparison of the nucleotide sequence of one of the clones with sequences from the GenBank database showed that it was a member of the secretin family. The clone, 490 bp long, encodes a protein of 133 amino acids consisting of a signal peptide, a N-terminal peptide, secretin, and a C-terminal peptide, which showed 88% and 80% homology with rat and porcine secretin precursor proteins, respectively. The translated secretin peptide showed a unique Met to Thr substitution at position 5 as compared to the secretins from other species. That the Met to Thr substitution was not tumor-related was demonstrated by the fact that an identical sequence was found in cDNA from normal mouse intestine. Studies on the mouse secretin gene revealed that it contains four exons separated by 81 bp, 110 bp, and 96 bp introns.

Prevalence of antibody to human T-cell lymphotropic virus type I in Okinawa, Japan, after an interval of 9 years.

To clarify events related to age dependence of human T-cell lymphotropic virus type I (HTLV-I) seroprevalence, the authors carried out two seroepidemiologic studies at a 9-year interval on residents of Yonaguni Island, Okinawa, Japan. The overall prevalence was 17.8% (345/1,943) in 1980 and 17.1% (264/1,543) in 1989-1990. The authors studied the relation of the HTLV-I infection rate to the birth year of 967 individuals tested in both years. Of the 967 individuals, 209 were positive for anti-HTLV-I in the 1980 survey. By the 1989-1990 survey, only 7 of the 758 anti-HTLV-I negative cases (0.9%) had become positive for anti-HTLV-I, and all 7 were over 40 years of age. For persons born in the same period, there was almost no difference between the prevalence of HTLV-I found in the 1980 survey and that found in the 1989-1990 survey. These data show that there were few new cases of HTLV-I infection and none in the lower age groups over the 9 years, which suggests that higher rates of HTLV-I infection in adults reflect past higher rates of infection as infants.

Sexual transmission of hepatitis C virus among female prostitutes and patients with sexually transmitted diseases in Fukuoka, Kyushu, Japan.

The authors investigated the prevalence of antibody to hepatitis C virus (anti-HCV) in 404 female prostitutes, 428 clinic patients with a history of at least one episode of sexually transmitted disease, and 8,944 blood donors who served as the controls. All subjects were Japanese, and all studies were carried out in Fukuoka, Kyushu, Japan, in 1989. The prevalence of anti-HCV was significantly higher in the prostitutes (6.2%), in the female patients with sexually transmitted diseases (6.1%), and in the male patients with sexually transmitted diseases (2.9%) than in the controls (1.5%). Prevalence of anti-HCV increased with age in prostitutes and in the controls. The prevalence of anti-HCV in those who had been involved in prostitution for 1 year or more (8.1%) was higher than in those who had been involved in prostitution for less than 1 year (1.4%), but the difference was not statistically significant. One of the 152 anti-HCV negative prostitutes seroconverted between 1 and 2 years later. Among the subjects with sexually transmitted diseases, patients with a history of at least one episode of syphilis had a significantly higher prevalence of anti-HCV (4.4%) than the controls. Patients with acute urethritis and cervicitis also showed a high prevalence of anti-HCV (3.6% and 6.7%, respectively). These data support the possibility of sexual transmission of hepatitis C virus.

The effects of breastfeeding and presence of antibody to p40tax protein of human T cell lymphotropic virus type-I on mother to child transmission.

We examined the effects of various factors, including duration of breastfeeding, the status of mother's anti-p40tax, and titre of mother's anti-human T cell lymphototropic virus type-I (HTLV-I) on mother to child transmission of HTLV-I in 76 HTLV-I carrier mothers and 175 of their children. The overall prevalence of anti-HTLV-I among children was 16.0%. The prevalence of anti-HTLV-I among children breastfed for over 3 months was significantly higher (27.6%) than that of those breastfed for under 3 months (5.1%; P = 0.012). Of the 78 bottle-fed children, 10 (12.8%) were positive for anti-HTLV-I. In the children breastfed for over 3 months, the prevalence of anti-HTLV-I among 37 children of anti-p40tax positive mothers was 37.8% and that of 21 children of anti-p40tax negative mothers was 9.5%, a significant difference (P = 0.044). These data suggest that about 13% of bottle-fed children born to carrier mothers are infected with HTLV-I by routes other than breast milk, and that the mother's anti-p40tax can serve as a marker of infectivity of HTLV-I in the case of breastfeeding for over 3 months.

[Evaluation of micro particle enzyme immunoassay (MEIA) for the demonstration of antibody to hepatitis B surface antigen].

A fully automated microparticle enzyme immunoassay (IMx AUSAB, Abbott) has been recently introduced for the detection of the presence of antibody to hepatitis B surface antigen (anti-HBs). The present trial was carried out to determine the feasibility of using the IMx AUSAB with sera and plasma, and for comparison with RIA (AUSAB, Abbott) and EIA (AUSAB EIA, Abbott). According to the kinds of vaccines used and locations of residents, the subjects were divided into six groups. Results obtained were as follows; In the test of 642 sera from 446 vaccines and 196 other inhabitants of Okinawa and Miyazaki prefectures, 388 (87.0%) were found positive for anti-HBs using IMx, 392 (87.9%) with RIA and 359 (80.5%) with EIA. Among those vaccinated with recombinant vaccines, 96.6% were found positive with IMx, 96.2% with RIA and 89.4% with EIA. Among subject vaccinated with plasma derived vaccines, 72.9% were found positive with IMx, 75.7% with RIA, and 68.5% EIA. Quantitative agreement between IMx and RIA among the six groups gave linear correlation coefficients ranging from 0.459 to 0.821. In the group vaccinated with the recombinant vaccine by K company (r = 0.459), anti-HBs was confirmed in many sera by IMx compared to that confirmed by RIA and EIA. In addition, anti-HBs was assayed within one hour by IMx and the procedure was simplified by autoanalyser equipped for this method. The results indicate that the sensitivity of IMx is equal to that of RIA and more than that of EIA, and that quantitative linear correlations were obtained between IMx and RIA, and IMx and EIA.

[Evaluation of micro particle enzyme immunoassay technique (MEIA)-IMx for the detection of IgM class antibody to hepatitis B core antigen].

The new Micro Particle Enzyme Immunoassay technique (MEIA, IMx HBc-M, Abbott) had been recently introduced for the detection of IgM class antibody to hepatitis B core antigen (IgM anti-HBc). To evaluate the feasibility of using the IMx HBc-M, we carried out comparison tests between this method. RIA and EIA using sera from acute hepatitis B and type B chronic liver disease. Results obtained were as follows: In the test of 98 sera from acute hepatitis B patients, 92 (93.9%) were positive for IgM anti-HBc by IMx HBc-M, 96 (98.0%) by RIA and 82 (83.7%) by EIA. The four sera which were positive by RIA, but not by IMx were ones obtained from 5 to 12 month after onset. In the test of 267 sera from B type chronic liver disease patients, 93 (34.8%) were positive by IMx HBc-M, 109 (40.8%) by RIA and 23 (8.6%) by EIA. There was a difference in the positive rate between IMx HBc-M and RIA among type B chronic liver disease: the positive rate was higher in RIA than in IMx HBc-M among type B active chronic hepatitis, but only a little higher in IMx HBc-M than RIA among hepatocellular carcinoma. IgM anti-HBc titer was significantly higher in acute hepatitis type B than in chronic liver disease, and was so even in the phase of HBsAg negative in acute hepatitis. IgM anti-HBc was assayed within 45 minutes by IMx, and the procedure was simple because of the auto analyser used in this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycyrrhizin withdrawal followed by human lymphoblastoid interferon in the treatment of chronic hepatitis B.

Seventeen patients with chronic hepatitis B were treated with a 4-week administration of glycyrrhizin followed by a 4-week treatment with human lymphoblastoid interferon, then followed for 6 months after the end of treatment. All were positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B virus-associated DNA polymerase (DNA-p) for at least 6 months before entry. All patients were Japanese and none of them were homosexuals. Eleven patients lost DNA-p activity and 10 of them lost HBeAg. Three of these 10 patients had antibody to HBeAg. In 10 patients who became HBeAg-negative, alanine aminotransferase levels after glycyrrhizin administration were higher and initial DNA-p activities relatively lower than the levels found in seven patients who remained HBeAg-positive. The immunomodulator provided by a short course of glycyrrhizin before administration of human lymphoblastoid interferon may be an effective treatment for patients with chronic hepatitis B.

[Evaluation of micro particle enzyme immunoassay technique (MEIA)-IMx for the detection of antibody to hepatitis B core antigen].

The new Micro Particle Enzyme Immunoassay technique (MEIA, IMx HBc, Abbott) has been recently introduced for the detection of the antibody to hepatitis B core antigen (anti-HBc). To evaluate the feasibility of using the IMx-HBc, we carried out comparison tests with this method and RIA using various sera. Results obtained were as follows: In the test of 813 sera, 427 (52.3%) were positive by both IMx and RIA, two (0.2%) were positive by RIA only, and the remaining 384 (47.3%) were negative by both methods. A good correlation between IMx and RIA was observed with a coincidence rate of 99.8% and a correlation coefficient of 0.969. Examination of diluted sera using IMx revealed that IMx can be used as efficiently was RIA: high anti-HBc titer was found among HBsAg carriers, but not among non HBsAg carriers. Anti-HBc was assayed within 45 minutes by IMx, and the procedure was simple because of the auto analyser used in this method. These results indicate that the sensitivity of IMx is equivalent to that of RIA, and that it is easier to use than RIA.

Prevalence of antibody to hepatitis C virus in hemodialysis patients.

The prevalence of hepatitis C virus infection in hemodialysis patients in Japan was examined using sera from 418 patients from six dialysis units in 1989. The authors made use of an enzyme-linked immunosorbent assay (Ortho Diagnostics). Antibody to hepatitis C virus (anti-HCV) was detected in 127 patients (30.4%), the frequency varying from 20.0% to 34.9% in different units. The mean prevalence of anti-HCV was 20 times higher than that in blood donors. Anti-HCV positivity was not associated with antibody to hepatitis B core antigen, which was not a surrogate marker for non-A, non-B hepatitis agents in this study. Another striking finding of this study was that 84.3% of the anti-HCV-positive patients had normal liver function. Anti-HCV positivity correlated positively with the number of blood transfusions and increased with the duration of hemodialysis; however, it was 22.1% even in 113 patients never given blood transfusion. Acquisition of hepatitis C virus by dialysis patients is, therefore, not only through blood transfusions but also because of hepatitis C virus present within the unit itself. Liver dysfunction in the anti-HCV-positive patients was rare.

[An epidemiologic study of anti-HTLV-I (antibody to human T cell lymphotropic virus type I) by category of disease in the Kushima district of Miyazaki prefecture].

HTLV-I seroprevalence in the southern part of Miyazaki prefecture was reported to be high in many seroepidemiological surveys. In order to determine the distribution of antibody to Human T-cell lymphotropic virus type I (anti-HTLV-I) in the Kushima district of Miyazaki prefecture and evaluate the relation between the HLTV-I carrier and disease, determination of anti-HTLV-I status of patients in a hospital in Kushima City, Miyazaki prefecture was carried out from March to July, 1985. Sera from 542 patients was tested for presence of anti-HTLV-I by particle agglutination (PA) and indirect immunofluorescence (IF). Results obtained area as follows 1) Overall prevalence of anti-HTLV-I was 31.2 per cent (169 of 542 individuals). It increased gradually with age and elevated remarkably in the 60-69 age group, showing the highest rate of 39.6 per cent. 2) Prevalence of anti-HTLV-I was 28.6 per cent (65 of 227) in males and 33.0 per cent (104 of 315) in females. A significant difference by sex was not recognized. 3) No significant difference was found in the geographical distribution of anti-HTLV-I, but prevalence in the Toi area was relatively low. 4) Anti-HTLV-I was prevalent in the patients with tuberculosis (46.2 per cent), most of whom had a history of blood transfusion. In this study, the relation between HTLV-I carriers and diseases was not analysed. 5) Seroprevalence of anti-HTLV-I in the patients who had had blood transfusions was significantly higher than that of those who had not had blood transfusions (p less than 0.01).

Marked decrease of hepatitis B virus infection among children in Okinawa, Japan.

During the period 1980-1989 in Okinawa, Japan, serologic markers of hepatitis B infection (hepatitis B surface antigen; HBsAg, antibody to hepatitis B core antigen; anti-HBc) were investigated in nursery school children (1-4 years of age). Prevalences of HBsAg were 1.1-1.5% in the period from 1980-1984, but decreased to under 1.0% in the period from 1985. In 1989 there were two carriers in nursery schools, both born in 1985 or fathers who were HBsAg carriers. Prevalences of anti-HBc were 3.3-7.1% in the period from 1980-1983 with a decrease to 0.5% by 1988. Since hepatitis B vaccine was available for neonates whose mothers were HBsAg carriers with hepatitis Be antigen (HBeAg) and for nursery school children in 1983, hepatitis B virus infection among nursery school children and HBsAg carriers due to transmission from mother-to-child were markedly reduced. This strategy for immunization is useful in endemic areas. Immunization for children whose fathers are HBsAg carriers may also be necessary.

[An epidemiologic study of anti-ATLA (antibody to adult T-cell leukemia-associated antigen) by category of disease in the Karatsu and Higashimatsuura districts of northern Kyusyu by enzymeimmunoassay].

The Kyusyu district is known as an endemic area of HTLV-I. But the prevalence of anti-ATLA in Saga prefecture was reportedly relatively low. In this study, in order to determine the distribution of antibody to ATL-associated antigen (anti-ATLA) in the Karatsu and Higashimatsuura districts of the northern Kyusyu, the determination of anti-ATLA status of patients in Karatsu Red Cross Hospital was carried out from September to October, 1985. Sera from 757 patients were tested for presence of anti-ATLA by Enzyme immunoassay (EIA) prepared by Eisai Co., Ltd. Tokyo, Japan. Results obtained are as follows: 1) Overall prevalence of anti-ATLA was 13.7 per cent (104 of 757 individuals). Prevalence of anti-ATLA increased with age, reaching a maximum of 21.1 per cent for people from 60 to 69 years old. 2) Prevalence of anti-ATLA was 9.5 per cent (36 of 376) in males and 17.8 per cent (68 of 381) in females. A significant difference by sex was recognized. (p less than 0.001) 3) The positive rates of patients with non-malignant diseases were high in the Chinzei, Hizen, and Hamatama areas facing the Sea of Genkai. The positive rate of the seaside area was significantly higher than that of the mountain area. (p less than 0.001). 4) Anti-ATLA was most prevalent in the patients with neoplasms (26.1%). The positive rate of ATL patients was 100 per cent, and that of patients with malignancies other than ATL was 25.9 per cent. These results suggest that HTLV-I infection is likely to increase the incidence of other types of malignancy.

Antibody to p40tax protein of human T cell leukemia virus 1 and infectivity.

To investigate the physiologic significance of antibody to human T cell leukemia virus type 1 (HTLV-1) tax gene product (p40tax), 147 male and 243 female HTLV-1 carriers were examined for anti-p40tax, and 104 carriers were checked for anti-p40tax an average of 5.4 times during an 8-year period. Prevalence of anti-p40tax was significantly higher in female (62.6%) than in male subjects (51.0%; P less than .05). Anti-p40tax status did not change in most during the observation period. There were significantly more HTLV-1 carriers among children of anti-p40tax-positive mothers (45.3%) than among those from anti-p40tax-negative mothers (20.0%; P less than .01). However, no significant difference was observed between wives of p40tax-positive and -negative men. The p40tax antibody may be a marker of relative infectivity of HTLV-1, albeit an imperfect one.

Prevalence of IgM anti-HBc among HBsAg carriers in Okinawa, Japan.

To evaluate the presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) in hepatitis B surface antigen (HBsAg) carriers, serial serum specimens of 698 carriers in Okinawa, Japan, from infants to adults, were studied by radioimmunoassay. IgM anti-HBc was detected in 7.6% of these carriers, with no difference between the sexes. The prevalence of IgM anti-HBc was higher in the age groups 0-9, 50-59 and over 60 than in the age group 20-29 and 30-39 years. In hepatitis B e antigen (HBeAg) positive carriers, the prevalence of IgM anti-HBc was 15.4%, a value significantly higher than in the HBeAg-negative carriers at 6.6%. In carriers with liver damage, the prevalence of IgM anti-HBc was 33.3%, a level significantly higher than the 6.3% in carriers without liver damage. However, IgM anti-HBc was detected in 34 carriers with neither HBeAg nor liver damage. These carriers are being closely followed. We discussed the presence of IgM anti-HBc in association with HBeAg or liver damage. The presence of IgM anti-HBc among HBsAg carriers was closely associated with liver damage.