Familial dysautonomia is caused by mutations of the IKAP gene.

The defective gene DYS, which is responsible for familial dysautonomia (FD) and has been mapped to a 0.5-cM region on chromosome 9q31, has eluded identification. We identified and characterized the RNAs encoded by this region of chromosome 9 in cell lines derived from individuals homozygous for the major FD haplotype, and we observed that the RNA encoding the IkappaB kinase complex-associated protein (IKAP) lacks exon 20 and, as a result of a frameshift, encodes a truncated protein. Sequence analysis reveals a T-->C transition in the donor splice site of intron 20. In individuals bearing a minor FD haplotype, a missense mutation in exon 19 disrupts a consensus serine/threonine kinase phosphorylation site. This mutation results in defective phosphorylation of IKAP. These mutations were observed to be present in a random sample of Ashkenazi Jewish individuals, at approximately the predicted carrier frequency of FD. These findings demonstrate that mutations in the gene encoding IKAP are responsible for FD.

[A six-month intraperitoneal repeated dose toxicity study of tazobactam/piperacillin and tazobactam in rats].

Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. A six-month intraperitoneal repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female rats. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effect on clinical finding of survival rats was evident. 2. There was no dose-related increases of food consumption in both the males and females given TAZ/PIPC and PIPC. Slight reductions in body weight gain occurred in males given 800 mg/kg/day of TAZ/PIPC. 3. Decreases in erythrocyte, hemoglobin and hematocrit, and increases in reticulocytes were seen only at study termination in the group given 800 mg/kg/day of TAZ/PIPC. Increases in reticulocytes were seen only at study termination in the females given 80 or 160 mg/kg/day of TAZ. 4. A decrease in triglyceride levels was observed in the males given 800 mg/kg/day of TAZ/PIPC or 160 mg/kg/day of TAZ. 5. The ophthalmoscopic examination or urinalysis show no test article-related changes. 6. Enlarged ceca in all groups of animals given TAZ/PIPC and in the females given 160 mg/kg/day of TAZ were observed. 7. An increase of relative organ weight in liver was noted in the males and females given 800 mg/kg/day of TAZ/PIPC, in the males given 80 or 160 mg/kg/day of TAZ and in the females given 160 mg/kg/day of TAZ. 8. In the hepatocytes, accumulation of PAS-positive materials which was identified histochemically and ultrastructurally as glycogen, was present in the males given 800 mg/kg/day of TAZ/PIPC and in the males given 80 or 160 mg/kg/day of TAZ. 9. After a one-month recovery period, the changes of liver had generally disappeared, suggesting that they were reversible. 10. From the histopathological changes of liver, the no-toxic dose level in both the males and females was 400 mg/kg/day and 40 mg/kg/day for TAZ/PIPC and TAZ, respectively.

Subchronic and chronic inhalation toxicity of antimony trioxide in the rat.

Fischer 344 rats were exposed by inhalation to Sb2O3 (antimony trioxide) dust at exposure levels of 0, 0.25, 1.08, 4.92, and 23.46 mg/m3 for 6 hr/day, 5 days/week for 13 weeks followed by a 27-week observation period. Subsequently, an inhalation oncogenicity study was conducted at exposure levels of 0, 0.06, 0.51, and 4.50 mg/m3 for 12 months followed by a 12-month observation period. The Sb2O3 in the subchronic study had a mass median aerodynamic diameter (MMAD) of 3.05 +/- 0.21 microns (mean +/- SD) with a geometric standard deviation (GSD) of 1.57 +/- 0.06. In the chronic study, the MMAD was 3.76 +/- 0.84 and the GSD was 1.79 +/- 0.32. Except for the eyes, no adverse clinical observations were attributed to Sb2O3 in either study. In the subchronic study, corneal irregularities were seen after about 2 weeks of exposure and did not abate during the observation period. In the chronic study, ophthalmoscopic evaluation at 24 months revealed a dose-related increase in cataracts of 11, 24, 28, and 32% (both sexes combined) for each group, respectively. Body weights were significantly lower (6%) than the control group's weights in the 23.46 mg/m3 males in the subchronic study. These rats did not recover this weight during the 27-week observation period. Body weights of the females in both studies and males in the chronic study were unaffected. There were no Sb2O3 effects on clinical chemistry or hematology in either study. Mean absolute and relative lung weights were significantly increased in the 4.92 and 23.46 mg/m3 groups in the subchronic study. The 23.46 mg/m3 group's lung weights did not recover to control levels during the 27-week observation period. Lung weights for rats in the chronic study were unaffected. Microscopic changes in the lungs in the subchronic and chronic study were limited to subacute-chronic interstitial inflammation, increased numbers of alveolar-intraalveolar macrophages, foreign material in the alveolar-intraalveolar macrophages in the peribronchial and perivascular (chronic study only) lymphoid aggregates and in the peribronchial lymph nodes, granulomatous inflammation/granulomas, and fibrosis. In the chronic study, any observed neoplasms occurred with comparable incidence among all groups and were within the historical range for controls. Clearance of Sb2O3 from the lung was burden dependent and was reduced by 80% in the 4.50 mg/m3 group in the chronic study. The previously reported studies, which found Sb2O3 to be a carcinogen, were run at higher lung burdens. Under the exposure conditions of the current study, Sb2O3 was not a carcinogen.

Subchronic oral toxicity of cellulose acetate in rats.

Cellulose acetate was administered by way of a dietary admixture to Sprague-Dawley rats (20/sex/group) at dose levels of 0, 500, 2500 and 5000 mg/kg body weight/day for 94-96 days. Physical observations, body weight and food consumption measurements were made before testing and throughout the study. Ophthalmoscopic examinations were conducted on all animals before testing and just prior to study termination. Haematology, clinical chemistry and urinalysis were performed at 1.5 and 3 months on 10 animals/sex/group. After 3 months of treatment the animals were killed, terminal body weights and organ weights were measured and ratios calculated. Histopathological examination of tissues from the control and high-dose groups was conducted. The evaluation of physical observations, ophthalmology, body weight, food consumption, haematology, clinical chemistry, organ-to-body-weight ratios, gross pathology and histopathology revealed no evidence of an adverse effect related to treatment with cellulose acetate.

Subchronic inhalation toxicity of ethylbenzene in mice, rats, and rabbits.

Mice, rats, and rabbits (five/sex/group) were exposed by inhalation to ethylbenzene (EB) vapors for 6 hr/day, 5 days/week for 4 weeks (20 exposures). Rats and mice received 0, 99, 382, or 782 ppm EB while rabbits received 0, 382, 782, or 1610 ppm. No changes were evident in mortality patterns, clinical chemistries, urinalyses, or treatment-related gross/microscopic (including ophthalmologic) lesions. Rats exhibited sporadic lacrimation and salivation, as well as significantly increased liver weights at 382 and 782 ppm, and small increases in leukocyte counts at 782 ppm. Males at this exposure level also showed marginal elevations in platelet counts. In mice, females showed statistically increased absolute and relative liver weights at 382 and 782 ppm, while males had statistically increased relative liver-to-brain weight ratios only at 782 ppm. Female rabbits at the high exposure level of 1610 ppm gained weight more slowly than controls (not statistically significant); males showed a similar transient downward trend after 1 week, but showed no differences from controls at study's end. A no observed adverse effect level (NOAEL) of 382 ppm appears appropriate for rats and mice with a lowest observed adverse effect level (LOAEL) of 782 ppm. A NOAEL of 782 ppm and LOAEL of 1610 ppm are appropriate for rabbits.

Subchronic inhalation and oral toxicity of hydrogenated terphenyls in rats.

The subchronic toxicity of a commercial blend of partially hydrogenated terphenyl was evaluated in rats by inhalation and oral routes of exposure. Animals were exposed to target concentrations of 0, 10, 100, or 500 mg/m3 for 6 hr/day, 5 days/week or were offered diets daily with concentrations of 0, 50, 200, or 2000 ppm. Each study lasted approximately 14 weeks. The study designs included observations for clinical signs, body weights, ophthalmic exams, hematology and clinical chemistry, major organ weights, and gross and histopathology. No treatment-related effects were noted in the ophthalmic exams. Body weights were slightly depressed in high-dose males from the inhalation study and high-dose females in the dietary study. Liver and liver/body weights were increased in high-dose animals of both sexes and high- and mid-dose males in the dietary and inhalation studies, respectively. In the high-dose females of the dietary study, kidney and kidney/body weights were increased with increased adrenal and adrenal/body weights were also observed. No compound-related gross lesions nor pathological correlates to the organ weight changes were observed in either study. The no-adverse effect levels were considered to be 100 mg/m3 and 200 ppm (15.9 mg/kg) for the inhalation and dietary studies, respectively. These data indicate that a wide margin of safety exists for hydrogenated terphenyl workplace exposure.