Neurotoxicity and carcinogenicity of N-methylolacrylamide in F344 rats and B6C3F1 mice

Toxicology and carcinogenicity studies of N-methylolacrylamide were conducted by administering the chemical by gavage in water to both sexes of F344/N rats and B6C3F1 mice 5 times per week for 16 d, 13 wk, or 2 yr. In 16-d studies, rats receiving doses of 200 mg/kg or higher and mice receiving 400 mg/kg died. In 13-wk studies, all rats given 100 mg/kg or higher doses died. Rats receiving 50 mg/kg or higher doses developed hindlimb ataxia progressing to paralysis. In neurobehavioral assessments, decreased forelimb and hindlimb grip strength occurred in rats at doses as low as 12.5 mg/kg. Landing footspread was also increased in dosed rats compared to controls. Axon filament and myelin sheath degeneration in the spinal cord and/or peripheral nerves occurred in rats receiving doses of 25 mg/kg or higher. Necrosis in the granular cell layer of the cerebellum was seen in rats given 200 mg/kg. Mice receiving 200 mg/kg in 13-wk studies died. Decreased grip strength was noted in mice at doses as low as 25 mg/kg, and rotarod performance was also affected by N-methylolacrylamide administration, but no neuropathology was seen microscopically. Testicular weights were decreased at doses as low as 12.5 mg/kg, and hepatocellular necrosis, thymic lymphocyte necrosis, and hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were seen in mice that died (200 mg/kg). In 2-yr studies, survival and weight gains in male and female rats receiving doses of 6 or 12 mg/kg/d were minimally affected. No biologically important clinical signs or neoplastic or nonneoplastic lesions were attributed to N-methylolacrylamide administration to rats, suggesting that higher doses could have been tolerated. In mice, survival was not different between dosed and control groups (0, 25, or 50 mg/kg/d). Body weights were higher by as much as 25% in dosed compared to control groups. No compound-related clinical signs were observed, but increases in neoplasms of the harderian gland, liver, and lung were clearly related to chemical administration in both sexes of mice. Benign granulosa-cell neoplasms of the ovary were also increased in dosed female mice.     

Myocardial sestamibi single-photon emission tomography: Variations in reference values with gender, age and rest versus stress?

Reference data files support the evaluation of myocardial perfusion single-photon emission tomography (SPET). The aim of this study was to create a large reference data base for technetium-99m sestamibi SPET, age and gender matched to the general patient population. One hundred and twenty-eight healthy volunteers (76 males and 52 females) with a likelihood of coronary artery disease of less than 5% underwent rest and maximal exercise^99mTc-sestamibi SPET with a 2-day protocol and 180° elliptical rotation. The normalized activity values of^99mTc-sestamibi in the inferior wall differed significantly between men and women. Age variations were found for men in the anterior wall. Normalized activity values in all four walls were strikingly similar during rest and stress. Our results suggest that the use of reference files in^99mTc-sestamibi SPET requires a gender- and, for males, possibly an age-matched reference population. Different reference files at rest and during stress might not be necessary.     

An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninaemia

Summary The study included 16 adolescents with optimally controlled hyperphenylalaninaemia (McKusick 26160), of whom six did not require treatment according to conventional criteria. All except the two patients with lowest median serum phenylalanine level throughout childhood (most values at 200–300 µmol/L) had white matter abnormalities detectable with magnetic resonance imaging. The lesions were particularly prominent in the watershed regions between the posterior and middle cerebral arteries. In most patients with moderate or severe hyperphenylalaninaemia frontal white matter lesions were present as well. Normal proton magnetic resonance spectra indicated that the lesions were stable. Occipital EEG abnormalities were frequent, and deficient performance on a pattern-recognition test was a characteristic neuropsychological finding. Serum phenylalanine levels at about 300 µmol/L or below throughout childhood and early adolescence may be required to avoid lesions. The present study demonstrates the limitations of even an optimally controlled dietary regimen in hyperphenylalaninaemia.