Kunio Shimazu

Modification of striatal arginine and citrulline metabolism by nitric oxide synthase inhibitors.

The effects of NG-substituted L-arginine (ARG) analogues on striatal ARG and citrulline (CIT) levels were investigated using in vivo microdialysis technique. A microdialysis probe was implanted into the striatum of anaesthesized Sprague-Dawley rats. Direct intrastriatal perfusion with 1 mM NG-nitro-L-arginine methyl ester (n = 8) increased striatal ARG release and decreased CIT release, suggesting suppressed NO synthase activity in the tissue. On the other hand, 1 mM NG-monomethyl-L-arginine (L-NMMA) (n = 6) evoked a persistent increase in both ARG and CIT. Considering that 4-320 microM L-ARG (n = 8) failed to increase CIT formation, CIT seems to be synthesized in the striatal tissue from L-NMMA by the enzyme that has been demonstrated in the kidney and aortic endothelium (NG,NG-dimethylarginine dimethyl-aminohydrolase).

Idiopathic pure sudomotor failure: Anhidrosis due to deficits in cholinergic transmission

Background: Acquired idiopathic generalized anhidrosis (AIGA) represents a heterogeneous clinical syndrome including sudomotor neuropathy and failure of the sweat glands. However, most AIGA cases comprise idiopathic pure sudomotor failure (IPSF), a distinct subgroup without sudomotor neuropathy or sweat gland failure. Methods: Eight patients with IPSF (mean ± SD age 20 ± 5 years) were assessed by thermoregulatory and pilocarpine-induced sweating tests, as well as emotional sweating using sudorometer (4 cases), microneurography of skin sympathetic nerve activity (2 cases), and skin biopsies from the forearm or axilla (3 cases). Results: Clinical features of IPSF comprise early onset; acute or sudden onset; concomitant sharp pain or cholinergic urticaria over the entire body; lack of autonomic dysfunction other than generalized anhidrosis; elevated serum IgE levels; and marked response to steroid. Sudomotor function testing revealed complete absence of thermoregulatory sweating, but well-preserved emotional sweating; pilocarpine did not induce sweating, and microneurography revealed that bursts of skin sympathetic nerve activity were not decreased; and skin biopsy displayed no morphologic abnormalities in sweat glands. The first two findings suggest lesions on the postsynaptic side of the nerve–sweat gland junction. Conclusion: The lesions in IPSF may be in the muscarinic cholinergic receptors of sweat glands. Allergic mechanisms are probably involved in its pathophysiology.

Clinical and genetic analysis of lipid storage myopathies

Causative genes have been identified only in four types of lipid storage myopathies (LSMs): SLC22A5 for primary carnitine deficiency (PCD); ETFA, ETFB, and ETFDH for multiple acyl‐coenzyme A dehydrogenation deficiency (MADD); PNPLA2 for neutral lipid storage disease with myopathy (NLSDM); and ABHD5 for neutral lipid storage disease with ichthyosis. However, the frequency of these LSMs has not been determined. We found mutations in only 9 of 37 LSM patients (24%): 3 in SLC22A5; 4 in MADD‐associated genes; and 2 in PNPLA2. This low frequency suggests the existence of other causative genes. Muscle coenzyme Q10 levels were normal or only mildly reduced in two MADD patients, indicating that ETFDH mutations may not always be associated with CoQ10 deficiency. The 2 patients with PNPLA2 mutations had progressive, non‐episodic muscle disease with rimmed vacuoles. This suggests there is a different pathomechanism from other LSMs. Muscle Nerve 39: 333–342, 2009

Nitric oxide regulates NMDA-induced dopamine release in rat striatum.

We investigated the effect of nitric oxide (NO) on N-methyl-D-aspartate (NMDA)-induced changes in levels of dopamine (DA) and its metabolite in the striatum using in vivo microdialysis. Local administration of 1 mM NMDA into the striatum significantly augmented DA release in the striatum. Simultaneous administration of 5 mM NG-nitro-L-arginine methyl ester (-NAME), a NO synthase inhibitor, into the striatum significantly potentiated NMDA-induced DA release. This effect of L-NAME was completely reversed in the presence of 50 mM L-arginine (L-Arg). Administration of 1 mM NMDA significantly decreased the levels of dihydrox-yphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect of NMDA was not affected by concurrent administration of L-NAME. This study provides in vivo evidence for the involvement of NO in NMDA-induced DA release.

Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Sträussler-Scheinker syndrome P102L mutation complicated with dementia

Abstract. Hyperphosphorylated tau (p-tau) deposition has been documented in a limited population of patients with Gerstmann-Sträussler-Scheinker syndrome (GSS) with particular point mutations of the prion protein (PrP) gene. Although its pathogenesis is only poorly understood, p-tau in GSS is known to be identical to that in Alzheimers disease (AD). We conducted immunohistochemical and quantitative image studies on the brain from a 44-year-old man with a 7-year history of dementia, diagnosed as having GSS with a point mutation of the PrP gene at codon 102 (GSS102), the commonest mutation in GSS. Severe spongiform degeneration and numerous PrP plaques were disclosed in the cerebral cortices and hippocampus, consistent with the diagnosis. However, rarely described in GSS102, prominent p-tau deposits as pretangles, neurofibrillary tangles and degenerating neurites were demonstrated adjacent to or around PrP plaques. β-Amyloid protein (Aβ) plaques were generally sparse and appeared invariably to be of a diffuse type. Double-labeling immunohistochemistry yielded co-localization of p-tau with PrP but not with Aβ. Most PrP plaques did not contain Aβ. These results excluded a diagnosis of concomitant AD. Quantitative analysis on a fractional area density of immunoreactive pixels demonstrated that burdens of PrP and p-tau but not Aβ were significantly correlated. These results suggest that p-tau deposition in this GSS102 is secondarily induced by PrP but not by Aβ (secondary tauopathy). Our study also suggests that p-tau deposition might be a more common phenomenon in long-standing GSS.

Regional cerebral blood flow measured by intracarotid injection of hydrogen Comparison of regional vasomotor capacitance from cerebral infarction versus compression

Following the description of Brawley et al.’ of reduction of blood flow in the ischemic area in 5 of 7 dogs following occlusion of the middle cerebral artery (MCA), much controversy arose concerning the use of COz inhalation versus hyperventilation in treating patients with acute cerebral infarction (stroke). This phenomenon, termed the “intracerebral steal,” though rare, has been described in numerous clinical and experimental investigations. Various methods, including external monitoring from the head with diffusible isotopes following intracarotid injection,’ > 3 heat clearance methods, and oxygen electrode^,^ were employed to estimate regional cerebral blood flow (rCBF). The underlying factors responsible for such paradoxical reactions of rCBF to changes in the partial pressure of arterial COz (PaCO,) have never been determined, but vasomotor response or capacitance to COz was assumed to be lost. Brock et were the first to postulate that changes in intracranial pressure (ICP) induced by COz inhalation or hyperventilation might influence regional tissue perfusion pressure (PP) in zones with impaired autoregulation. They proposed that inhalation of COz may decrease rCBF by increasing intracranial pressure and that hyperventilation increases rCBF by decreasing intracranial pressure. Meyer et a1.6 demonstrated that if massive experimental cerebral infarction is accompanied by progressive cerebral edema and greatly increased intracranial pressure, inhalation of 5% COz does indeed reduce rCBF. They proposed the term “intracerebral squeeze” to describe this phenomenon. In the present series of experiments rCBF was measured in 18 monkeys ( 6 baboons and 12 Macacus monkeys) by inserting hydrogen electrodes into the brain. These electrodes are similar to those described by Aukland et al.’ who measured regional blood flow in the kidney. Fieschi et al.’ attempted to use such electrodes in their acute preparations; however, it is known that the responses of acutely implanted platinum electrodes to hydrogen inhalation are unreliable and, furthermore, that accurate rCBF values cannot be calculated unless the arterial hydrogen desaturation curve is also recorded. Both of these drawbacks were overcome in our experiments by chronically implanting the electrodes from four to twenty-five days until their response to hydrogen was consistent and by injecting the hydrogen gas as a bolus, saturated in saline, via the carotid artery.

Effect of l-DOPA on nitric oxide production in striatum of freely mobile mice

In Parkinsons disease, nitric oxide (NO) and other free radicals are thought to be involved in neuronal degeneration. Furthermore, L-DOPA is suggested to have a cytotoxic action on dopaminergic neurons. We studied 24-h NO production and the effect of L-DOPA on this in freely mobile mice using in vivo microdialysis. A microdialysis probe was implanted into the right striatum 12 h before the experiment. This dialysis probe was perfused with Ringer solution for 100 min, then with 20, 50, or 100 nM L-DOPA for 20 min, and finally with Ringer solution. Dialysate fractions were collected every 20 min for 4 h. Production of nitrite and total NO were significantly higher during daytime than during nighttime. Nitrate production was increased significantly by L-DOPA. NO production in the striatum appears to exhibit a diurnal rhythm and to increase with exposure to L-DOPA.

Secondary SUNCT syndrome caused by viral meningitis

A 49-year-old male had been complaining of general fatigue since July 31, 2007. On August 3, he developed a headache in the forehead bilaterally, and he had a slight fever on the next day. At 3:00 a.m. on August 3, a stabbing pain lasting less than 3 seconds suddenly occurred on the right side of the forehead, cheek, and jaw. He felt pain while he was awake. The pain attacks occurred at least once every two or three minutes, and at most once every 10 seconds; attacks occurred with a frequency from 100 to 200 times per day. During the attacks, he showed dacryorrhea, swelling of the eyelids of the right eye, and rhinorrhea. The patient was not able to keep still because of his severe, stabbing headache. During the daytime of August 6, the pain moved to the right occipital and right upper auricular regions. The symptoms persisted, and he was admitted on August 7. His past history and family history were not contributory. The patient reported a stabbing headache in the right side of the forehead, cheek, and jaw, as well as in the upper auricular and occipital regions. On physical examination, Yasuo Ito Toshimasa Yamamoto Mikiko Ninomiya Yoshikazu Mizoi Kaori Itokawa Naotoshi Tamura Nobuo Araki Kunio Shimazu

Effect of hexobendine on cerebral hemispheric blood flow and metabolism. Preliminary clinical observations concerning its use in ischemic cerebrovascular disease.

APPROPRIATE AND EFFECTIVE TREATMENT of patients with cerebral infarction is one of the most vexing problems in contemporary medicine. Most therapeutic efforts have been directed toward improving the collateral circulation and increasing the oxygen delivery to ischemic areas surrounding an infar~t . l -~ Studies in which vasodilators were employed have indicated that these agents may be effective in increasing overall cerebral blood flow (CBF) not only in areas of acute regional cerebral infarction but also in remote areas with diffusely reduced CBF as a result of diaschisis.5 For example, inhalation of 5% COP in oxygen in patients with cerebral infarction was found to increase oxygen deliveiy to ischemic and anoxic brain.2 Intravenous injection of papaverine hydrochloride3 or acetazolamide4 was also shown to increase average CBF and oxygen supply. McHenry and colleagues,E in a recent study based on clinical and arteriographic findings, demonstrated that intravenous injection of papaverine increases regional CBF in zones of infarction and ischemia as well as in bordering zones. The purpose of the present investigation was to measure the effect of hexobendine (supplied by the Wm. S. Merrell Co., Cincinnati, Ohio), a new and experimental drug, on cerebral hemispheric blood flow (HBF) and metabolism in patients with ischemic cerebrovascular disease. In experiments with animals, hexobendine has been reported to be a potent cerebral vasodilator.7vs Results of intravenous and oral adniinistration of the drug will be presented, together with preliminary findings from a pilot study carried out in 25 patients with cerebral infarction in the majority of whom a doubleblind crossover method was used to establish whether the drug is well tolerated and without serious side effects. A list of terms and their abbreviations used in this report are as follows: CBF = cerebral

An adult case of cyclic vomiting syndrome successfully responding to valproic acid

Sirs: The pathophysiology of cyclic vomiting syndrome (CVS) has not yet been established, and treatment for CVS remains unsatisfactory [1, 2]. We herein report an adult case of CVS associated with vascular headache and consciousness disturbance. Valproic acid had a completely protective effect against the vomiting attacks in this patient. The efficacy of an anticonvulsant for CVS thus supported the existence of a nosological link between CVS, migraine, and epilepsy. A 48-year-old woman, with several attacks of vomiting during one hour, was admitted to our hospital seeking treatment for this symptom on December 10, 2005. Nausea and vomiting developed suddenly on the evening of December 9. Her symptoms included fever, headache and palpitations, but no vertigo or abdominal pain. The attack did not subside until the next day, and she visited to her family doctor and then was transferred to our hospital. Her first attack had appeared in August LETTER TO THE EDITORS