A major obstacle to understanding the pathogenesis of Alzheimer's disease is the lack of easily studied animal models. Our approach is to apply transgenic methods to humanize mice and rats, employing methods that introduce large genomic transgenes, because this improves the level of transgene protein expression and the tissue specificity of expression. Our plan is to reproduce AD pathology in rodents by making them transgenic for several human proteins involved in AD. This report describes transgenic animal lines that we have produced, and summarizes our current approach and future plans. Two human genes known to be involved in AD pathology are the amyloid precursor protein (APP) and the E4 isoform of apolipoprotein E (apoE4). So far, we have produced and analyzed a transgenic line carrying the entire human APP gene cloned in a yeast artificial chromosome. We have also produced but not yet analyzed a mouse carrying the human apoE4 gene. Work is in progress to produce a transgenic line carrying a disease-causing mutation in the human APP gene. As we produce these animals, we are breeding them together, and also breeding them with a mouse line that lacks endogenous apoE, to produce an animal model carrying several human proteins whose interaction is believed to be instrumental in development of AD pathology. These transgenic animals will be useful for dissecting the biochemical and physiological steps leading to AD, and for development of therapies for disease intervention.

Alzheimer Disease↗

PubMedDate not supplied

Electromagnetic fields inhibit endothelin-1 production stimulated by thrombin in endothelial cells.

Electromagnetic field (EMF) radiation has been found to induce arteriolar dilatation, but the mechanism of action remains largely unknown. This study investigated the effect of EMF radiation on the production of endothelin-1 (ET-1), a potent vasoconstrictor, by cultured endothelial cells. EMF radiation reduced ET-1 basal levels in human umbilical vein and microvascular endothelial cells, but failed to reduce ET-1 basal levels in bovine and human aortic endothelial cells. EMF radiation significantly inhibited thrombin-stimulated ET-1 production in all four endothelial cell types in a dose-dependent manner. EMF radiation significantly inhibited thrombin-induced endothelin-1 mRNA expression in all four cell types. The inhibitory effect of EMF radiation on ET-1 production was abolished by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (10(-3) mol/1). These results demonstrate that EMF radiation modulates ET-1 production in cultured vascular endothelial cells and the inhibitory effect of EMF radiation is, at least partly, mediated through a nitric oxide-related pathway.

Animals↗

PubMedDate not supplied

Chemopreventive effects of ferulic acid on oral and rice germ on large bowel carcinogenesis.

Effects of ferulic acid (FA) known as a major constituent of rice bran or germ on 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis were examined in 4 groups of male rats. The incidences of tongue carcinomas and preneoplastic lesions (severe dysplasia) in rats of the group given FA in the diet at a dose of 500 ppm after exposure to 4NQO for 5 weeks in drinking water at a dose of 20 ppm, was significantly lower on termination of the experiment (32 weeks) in the group with the carcinogen alone (P < 0.005 and P < 0.001 respectively). The results suggest chemopreventive activity for this phenolic compound on oral cancer. Modifying effects of rice germ on azoxymethane (AOM)-induced formation of aberrant crypt foci (ACF) were also examined, in 8 groups of male F344 rats. Numbers of ACF/colon, ACF/cm2 and aberrant crypts/colon in the group treated with AOM (15 mg/kg s.c. once a week for 3 weeks) and gamma-amino butylic acid (GABA)-enriched defatted rice germ (2.5% in diet) or the group with AOM and rice germ (2.5% in diet) were smaller than those of the group with AOM alone (P < 0.005). Exposure to defatted rice germ or rice germ during the initiation phase or the post-initiation phase also decreased incidences of AOM-induced large bowel neoplasms (P < 0.05). These results suggest chemopreventive potential for rice germ on colonic neoplasia.

4-Nitroquinoline-1-oxide↗

PubMedDate not supplied

[An adult case of primary antiphospholipid syndrome presenting recurrent anterior spinal artery syndrome].

A 50-year-old man suffered from sudden onset of paraplegia, sensory impairment of the lower extremities and difficulty urinating. These symptoms spontaneously resolved, and he was able to walk again within 10 days. After 2 months' observation, he experienced a relapse with identical symptoms. Neurological examination revealed paraplegia, hypalgesia and hypesthesia in the lower extremities and difficulty urinating. Position and vibration senses were preserved in the extremities. Knee jerk was mildly hyperreflexic on the left, but pathological reflexes were not present. He had such risk factors for arteriosclerosis as diabetes mellitus, hypercholesterolemia and smoking. Although antinuclear antibodies were negative, he repeatedly showed high anticardiolipin antibody titers. MRI showed a T2-hyperintense lesion of the anterior portion of the spinal cord at Th9-10 levels. Neither arteriovenous malformation nor fistula was found on MR angiography. Abdominal CT revealed no abnormality in the descending aorta. Cervical ultrasonogram showed arterioslerotic lesions on the right common carotid artery. This is the first report of recurrent spinal cord infarction in an adult patient associated with primary antiphospholipid syndrome. Recurrence of the spinal cord infarction in this case may have been facilitated by the presence of risk factors for arteriosclerosis.

Anterior Spinal Artery Syndrome↗

PubMedDate not supplied

[A variant form of septo-optic-pituitary dysplasia (SOPD) complicated with acute optic neuritis].

We herein report a case of a variant form of septo-optic-pituitary dysplasia (SOPD). A 40-year-old man was admitted due to sudden occurrence of left blurred vision and lasting polyuria. He showed short statue of height of 144 cm and the neurological examination revealed hypesthesia of the left trigeminal nerve and temporal pallor in the left fundus oculi. Brain MR imaging demonstrated agenesis of the septum pellucidum and hypoplasia of the corpus callosum with subcortical spotty lesions, but optic nerve hypoplasia was not detected. The left eye showed a prolonged P100 latency of pattern reversal VEPs. He was diagnosed as having hypopituitarism since growth hormone-releasing factor did not stimulate growth hormone secretion and restriction of water-intake did not induce secretion of antidiuretic hormone. Thus we regarded this case as a variant form of SOPD. The mutation of HESX 1 gene, however, was not detected in the case. P100 of the left eye showed a reduction in latency four months after discharge. This case was considered to be a variant form of SOPD complicated by acute optic neuritis.

Acute Disease↗