ABSTRACT
Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.
ABSTRACT
In clinical psychiatric cases, the placement of a nasogastric tube is occasionally considered. If a patient who presents with mania or other psychiatric conditions refuses to take drugs, they are administered via the nasogastric tube. The tablet is crushed, suspended, passed via the nasogastric line, and reaches the stomach directly. However, the effects of these processes on blood drug concentrations remain unclear. Herein, we report a patient with bipolar I disorder who presented with low blood lithium carbonate (Li) concentrations after receiving the drug via the nasogastric tube. Case: A 26-year-old woman developed manic symptoms with grandeur delusion. She was admitted to a psychiatric hospital three times after diagnosis. Her manic symptoms with delusion improved with Li and aripiprazole (ARP). Her condition stabilized with Li 800 mg/day and ARP 9 mg/day. After the Li dose was reduced to 600 mg/day, she maintained remission, with the blood level range of Li being 0.31 â¼ 0.42 mEq/L. After 1 year, she was admitted to our hospital due to a jaw deformity. During the perioperative period, treatment with oral Li was discontinued by the surgeons, and her manic symptoms recurred. During therapy with olanzapine 20 mg and Li 800 mg, her blood Li concentration was 0.67 mEq/L. The symptoms remained. Hence, the Li dose increased to 1,000 mg/day. However, she refused to take the medication. Thus, a nasogastric tube was used to administer medicines. Thereafter, the blood Li concentration decreased to 0.43 mEq/L, which was lesser than 800 mg/day. Each blood sample was collected approximately 18 h after the administration. Her symptoms remained. Thereafter, she agreed to take the medication, and the Li concentration reached 0.78 mEq/L. Then, the symptoms partly improved. Conclusion: After the administration of Li via the nasogastric tube, the Li concentration decreased, which was lower than expected. This phenomenon could be attributed to the fact that the medication was crushed, suspended, and administered via the nasogastric tube. Therefore, pulverizing and administering Li tablets via the nasogastric tube can be applied for the management of mania, however, caution should be observed because of the risk of fluctuations in blood Li levels, as in this case.