Hiroko Nomiyama

A novel recombinant adeno-associated virus vaccine induces a long-term humoral immune response to human immunodeficiency virus

Recombinant adeno-associated virus (AAV) has attracted tremendous interest as a promising vector for gene delivery. In this study we have developed an HIV-1 vaccine, using an AAV vector expressing HIV-1 env, tat, and rev genes (AAV-HIV vector). A single injection of the AAV-HIV vector induced strong production of HIV-1-specific serum IgG and fecal secretory IgA antibodies as well as MHC class I-restricted CTL activity in BALB/c mice. The titer of HIV-1-specific serum IgG remained stable for 10 months. When AAV-HIV vector was coadministered with AAV-IL2 vector, the HIV-specific cell-mediated immunity (CMI) was significantly enhanced. Boosting with AAV-HIV vector strongly enhanced the humoral response. Furthermore, the mouse antisera neutralized an HIV-1 homologous strain, and BALB/c mice immunized via the intranasal route with an AAV vector expressing the influenza virus hemagglutinin (HA) gene showed protective immunity against homologous influenza virus challenge. These results demonstrate that AAV-HIV vector immunization may provide a novel and promising HIV vaccination strategy.

Respiratory retention, uptake and excretion of organic solvents in man

SummaryMechanisms of respiratory retention of organic solvents are discussed. Respiratory retention, uptake and excretion were estimated separately in 66 men and women volunteer students exposed to benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol.After 2 hrs exposure, respiratory retention reached constant levels; these differed for each of the 7 organic solvents tested. No sex difference in retention was observed. Respiratory excretion values differed as 100 × concentration in expired air immediately following breathing of solvent free air/concentration of solvent in air breathed during exposure. Men excreted more toluene and trichloroethylene than did women. Uptake varied 27–60%.

Effects of dietary cadmium on rabbits. I. Early signs of cadmium intoxication.

Abstract Rabbits were fed diets containing 300 ppm cadmium for up to 54 weeks, and signs of cadmium intoxication were studied. The earliest signs of intoxication were amino-aciduria and enzymuria, both of which were detected after 14–16 weeks. Anemia was observed after 27 weeks, and later proteinuria and glycosuria appeared. Loss of body weight and appetite were also seen after 42 weeks of cadmium feeding. Osteomalacia was not observed. The above data suggest that early cadmium intoxication can be detected by determining urinary excretion of amino acids and enzymes. Proteinuria and glycosuria indicate a later stage of cadmium intoxication.

Respiratory elimination of organic solvents in man

SummaryRespiratory elimination of benzene, toluene, n-hexane, trichloroethylene, acetone, ethyl acetate and ethyl alcohol were studied after exposure in human volunteers to those solvents.1.Solvent concentration in expired air decreased rapidly with time after the cessation of exposure and the decrease was expressed as an equation. Ethyl acetate and ethyl alcohol in expired air decreased faster than did other organic solvents. The decrease was very slow in acetone.2.Large amounts of retained acetone, benzene and n-hexane were eliminated through the lungs as unchanged solvents, while the amount of eliminated ethyl acetate was almost negligible.3.The ratio of respiratory elimination to the inhaled (environmental) organic solvent suggested that the determination of respiratory concentration is helpful for estimating environmental benzene, acetone, trichloroethylene and toluene concentration.

Does CSF copper level in Wilson disease reflect copper accumulation in the brain

The levels of copper and ceruloplasmin in the cerebrospinal fluid (CSF) of patients with Wilson disease were investigated. Ceruloplasmin concentrations in the CSF of all patients were almost the same but were lower than those of the controls. CSF copper concentrations in patients without neurologic signs were within the normal range, 22 +/- 6 ng/ml. In contrast, CSF copper concentrations in patients with neurologic signs (69-98 ng/ml) were significantly higher than the normal levels before and at the beginning of the treatment with D-penicillamine; it gradually decreased in response to treatment. These results suggest that the appearance of neurologic manifestations in Wilson disease is not related to the CSF ceruloplasmin concentration. The CSF copper concentration in this disease appears to reflect copper accumulation in the brain and may be useful as a marker for monitoring therapy.

Metabolism of trichloroethylene in human

SummaryRetention and respiratory elimination of trichloroethylene, and urinary excretion of trichloroethylene metabolites were determined in ten volunteer students exposed to 250–380 ppm trichloroethylene for 160 min.1.Retention amounted to 36% of the inhaled trichloroethylene.2.Trichloroethylene was eliminated through respiration after exposure, and the concentration in expired air decreased exponentially with a rate constant k∶:0.14 hour−1. Respiratory elimination of trichloroethylene was 16% of the retained trichloroethylene.3.Urinary excretion of total trichloro-compounds decreased exponentially with k∶:0.23 day−1 in males and 0.20 in females.4.Urinary excretion of trichloroacetic acid and trichloroethanol were 32.6% and 48.6% in males, and 43.9% and 42.7% of the retained trichloroethylene in females.5.Trichloroacetic acid in females was found to be 2–3 times more than that in males for the first 24 hours after exposure. Trichloroethanol, on the contrary, was excreted twice more in males than in females for the first 12 hours. Therefore, the trichloroethanol to trichloroacetic acid ratio was significantly different between males and females by 5.5 times for the first 24 hours after exposure.6.These findings suggest a sex difference in human metabolism of trichloroethylene. Urinary total trichloro-compounds form a better index of trichloroethylene exposure than urinary trichloroacetic acid.

Cadmium-induced renal dysfunction: New mechanism, treatment and prevention

Cadmium-induced renal dysfunction has hitherto been regarded as noncurative, with the renal dysfunction occurring when the cadmium concentration in the renal cortex exceeded a critical concentration for the renal cortex, 200 μg/g wet weight. However, we have identified a mechanism that is quite different from the above working hypothesis: cadmium induces hepatic dysfunction through cadmium-induced free radicals in the liver. Hepatic cadmium-thionein is released into the bloodstream upon hepatic dysfunction and enters the renal tubular lumen by freely passing through the renal glomeruli to result in injury to the brush border membrane of the proximal convoluted tubules. The critical concentration of plasma cadmium, an alternative biomarker for cadmium-thionein in the renal proximal tubules, for inducing renal dysfunction was found to be 100 &mu Cd/L and was quite independent of the cadmium level in the renal cortex. Cadmium-induced renal dysfunction was therefore considered reversible following cessation of cadmium exposure, when the renal dysfunction was not so serious, probably as a result of decreased levels of plasma cadmium-thionein. We also succeeded in improving cadmium-induced renal dysfunction through subcutaneous glycyrrhizin administrations, by lowering the plasma cadmium-thionein due to alleviation of the destruction of hepatic cells. We further succeeded in ameliorating cadmium-induced renal dysfunction through administration of acetazolamide, a carbonic anhydrase blocker, due to the depressed plasma cadmium-thionein associated with improvement of the hepatic dysfunction. J. Trace Elem. Exp. Med. 11:275–288, 1998.

Normal chromium levels in urine and blood of Japanese subjects determined by direct flameless atomic absorption spectrophotometry, and valency of chromium in urine after exposure to hexavalent chromium.

Two hundred and thirty one urine and 20 blood samples of Japanese subjects from 4 geographic areas without known chromium pollution were assayed for chromium by direct flameless atomic absorption spectrophotometry. Normal chromium level in urine of Japanese subjects was 0.41 microg/L on an average. Urine level was less than 0.8 microg/L for all age and sex groups. Chromium levels in 2 hour urines did not correlate with those in 24 hours urine. Blood level of chromium was 2.9 ng/mL. A rabbit given an oral administration of 100 mg hexavalent chromium excreted 8.2 mg in 15 days after administration. No hexavalent chromium could be detected in urine. Ninety percent of the urinary excretion occurred within 2 days of administration.

Three fatal cases of thinner-sniffing, and experimental exposure to toluene in human and animals

SummaryThree fatal cases of organic solvent abuse revealed high levels of toluene in blood and alveolar air and a high level of hippuric acid, metabolite of toluene, in urine. The lethal concentration of toluene was estimated to be 2,000 ppm.Furthermore, 10 male and female volunteer students were exposed to 107 ±12 ppm toluene for 4 hours. Hippuric acid in urine increased with the exposure time and reached maximum 2 hours after initiation of toluene exposure and remained at the same level thereafter. Following cessation of exposure to toluene, hippuric acid in urine showed a rapid decrease and recovered almost to the normal level 4 hours after cessation of exposure.Urinary excretion of hippuric acid in 7 rabbits exposed to 350 ppm for 100 minutes or to 4,500 ppm toluene for 10 minutes, reached its maximum 1.5–2 hours after initiation of exposure and decreased rapidly after cessation of exposure to toluene to recover to the normal level 4 hours later.

Dose-response relationship for trichloroethylene in man.

SummaryTwelve volunteer students were experimentally exposed to 0, 27, 81 or 201 ppm trichloroethylene for 4 hours, and suffered from irritation to mucous membrane of eyes and throat at over 27 ppm trichloroethylene. No headache or physiological responses were reported at 27 ppm; headache occurred at levels over 81 ppm. Accumulated urinary excretion of total trichloro-compounds, trichloroacetic acid and trichloroethanol for 6 days after trichloroethylene exposure increased linearly with environmental trichloroethylene concentration in volunteers experimentally exposed to 0–315 ppm trichloroethylene.In 39 trichloroethylene workers also no changes were observed in the metabolic pattern of trichloroethylene in relation to environmental concentration corresponding to excretion of total trichloro-compounds in urine of 0–180 mg/4 hours namely.Those data might support a threshold limit value of 50 ppm for trichloroethylene. This conclusion, however, is based only on the appearance of toxic symptoms, but not on critical changes in trichloroethylene metabolism above 50 ppm.