Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy.

OBJECTIVES: The cause of hypocretin cell loss in human narcolepsy-cataplexy is unknown but has been suggested to be neurodegenerative in nature. To test this hypothesis, we evaluated the remaining hypocretin cells in human narcolepsy brains for the presence of aggregated protein inclusions, gliosis, and inflammation. METHODS: Brains were examined by routine histologic methods for potential comorbid neurodegenerative diseases and through immunohistochemical screening for protein inclusions in the hypothalamus. Hypothalamic sections of 4 subjects with narcolepsy and 5 nonneurologic controls were examined immunohistochemically with antibodies against ubiquitin (a marker of aggregated protein), allograft inflammatory factor 1 (AIF1, a microglial activation marker), glial fibrillary acidic protein (GFAP, a reactive astrocytic marker), and hypocretin. Hypothalami of subjects with narcolepsy were additionally examined for the presence of known components of protein aggregates (tau, alpha-synuclein, amyloid beta, and TDP-43). RESULTS: Hypocretin cells were markedly decreased in all 4 subjects with narcolepsy. Ubiquitinated inclusions were not observed in the total of 96 remaining hypocretin cells in these subjects. Further, we noted that even in patients with dementia neuropathology, the lateral hypothalamic hypocretin area was spared from ubiquitinated inclusions. AIF1 and GFAP staining in the perifornical area was unremarkable. CONCLUSIONS: Our findings suggest that hypocretin cell loss does not involve ubiquitinated inclusions, the hallmark of most neurodegenerative diseases. The lack of increased markers of inflammation also argues against a progressive and continuous neurodegenerative process.

[Treatment of 522 patients with sudden deafness performed oxygenation at high pressure].

INTRODUCTION: Oxygenation at high pressure (OHP) is thought to be useful, even though regional blood flow is decreased, because increasing dissolved oxygen prevents the death of nerve tissue. In this report, we retrospectively investigated the effect of OHP on sudden deafness. OBJECT AND METHOD: We reviewed 522 patients treated with OHP at Kagawa Rosai Hospital over a ten-year period (January 1989 to December 1998). We discussed some prognostic factors: comparison between cases which had been treated with OHP previously and those which had not, number of days between onset and beginning of the treatment which included OHP, age, initial averaged five-frequency hearing level, vertigo, tinnitus, complications of OHP, cases of relapse and the time of the onset, which is about season, month and week. OHP was administered at a pressure of 2.5 atmospheres for 80 minutes a day from 10 to 15 times. All patients also received a course of intravenous administration of steroid, vitamin B12, Prostaglandin E1, ATP, and low-molecular dextran. RESULTS: Overall, complete recovery occurred in 19.7% of the patients, definite improvement in 34.9% (complete recovery included), and slight improvement in 58.1% (definite improvement included). Most of the patients (78.0%) were referred by other hospitals, because our hospital was the only one in the Sikoku area which had a big equipment of OHP. All 161 patients had already been treated in other hospitals over 8 days, but they had shown little improvement after the initial therapy. Of this group, complete recovery after the second course of treatment occurred in 13.0% of the patients, definite improvement in 19.3%, and slight improvement in 39.1%. OHP was thus effective for about 40% of patients who had been unresponsive to the initial therapy. Delay in treatment usually produces poor hearing recovery. There was a significant difference between those patients treated within 14 days and those treated 15 days or more after onset. The improvement rate also decreased with age. The prognosis of patients with vertigo was worse than those without vertigo. Tinnitus had no influence on the prognosis. There were no severe complications during the course of OHP, but otitis media with effusion occurred in 90 patients, and paracentesis was performed for 53 patients. CONCLUSION: The treatment of sudden deafness with OHP has been discussed in this report. Important prognostic factors were time between onset and beginning of the treatment which included OHP, age, vertigo, and the initial averaged five-frequency hearing level. We conclude that OHP should be performed within 14 days from onset, and that OHP was able to achieve hearing improvement in many cases unresponsive to the initial therapy if it was performed very early.

Endothelium-dependent relaxation by angiotensin-converting enzyme inhibitors in canine femoral arteries.

The effects of angiotensin-converting enzyme (ACE) inhibitors on vascular reactivity were investigated using isolated canine femoral arteries with and without endothelium. N-N-(S)-1-carboxy-3-phenylpropyl-L-alanyl-N-(indan-2-yl)glycine (M-1; an active metabolite of delapril, a nonsulfhydryl ACE inhibitor) and captopril (a sulfhydryl ACE inhibitor, 10(-8) to 10(-5) M) relaxed in a dose-dependent manner canine femoral arterial rings precontracted with prostaglandin F2 alpha in the presence of endothelium only. The endothelium-dependent relaxations by M-1 and captopril were completely blocked by methylene blue, an inhibitor of soluble guanylate cyclase; NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis; and oxyhemoglobin, an inactivator of nitric oxide; they were partially blocked by aspirin, an inhibitor of cyclooxygenase and were enhanced by superoxide dismutase, a radical scavenger. The inhibitory effect of L-NMMA on the relaxations by M-1 and captopril were reversed by a high dose of L-arginine. Moreover, a bradykinin antagonist partially inhibited these relaxations. These results suggest that endothelium-dependent relaxations by M-1 and captopril in canine femoral arteries are mediated through the release of both prostanoids and endothelium-derived nitric oxide via endogenous bradykinin.