Ban Mihara

Inhibition of nitric oxide synthesis induces a significant reduction in local cerebral blood flow in the rat

The effect of intravenous administration of NG-monomethyl-L-arginine (L-NMMA, 30 mg/kg), a specific inhibitor of nitric oxide synthesis, on local cerebral blood flow (lCBF) was examined in the rat using the [14C]iodoantipyrine autoradiographic method. L-NMMA induced a statistically significant reduction in lCBF in the cerebral cortices as well as in various deep structures of the brain. This reduction in lCBF was accompanied by a clear increase in mean arterial blood pressure, suggesting that the cerebral resistance vessels constricted significantly beyond the autoregulatory response following L-NMMA administration. These findings indicate that the basal cerebral circulation may be closely related to nitric oxide production.

Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis

An ubiquitin-binding protein, p62, is one of the components of the ubiquitin-containing inclusions in several human neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of skein-like inclusions, Lewy body-like inclusions, and basophilic inclusions in the remaining anterior horn cells, in which these inclusions contain ubiquitin, while the other characteristic inclusions of Bunina type are ubiquitin-negative. We examined the spinal cord from 28 ALS cases including two ALS with dementia and two ALS with basophilic inclusions, using antibody to p62. The results demonstrated that p62 localized in skein-like inclusions, Lewy body-like inclusions and basophilic inclusions. The number of p62-positive inclusions observed in the remaining anterior horn cells of each section was variable among the ALS cases. In contrast, Bunina bodies, that do not contain ubiquitin, were negative for p62. As far as we examined, the 11 non-ALS cases did not show any p62 immunoreactivities in the anterior horn cells. Our results suggested that p62 plays important roles in forming the inclusions and may be associated with the protection of the neurons from degenerative processes involving ubiquitin.

Inhibition of nitric oxide synthesis impairs autoregulation of local cerebral blood flow in the rat.

The effect of intravenous administration of NG-monomethyl-L-arginine (L-NMMA, 30 mg kg-1), a specific inhibitor of nitric oxide (NO) synthesis, on the autoregulation of local cerebral blood flow (LCBF) was examined in the rat using the [14C]iodoantipyrine autoradiographic method. LCBF was significantly lower in various superficial regions such as the cerebral cortices and cerebellar cortex and in several deep brain regions in animals with haemorrhagic hypotension induced after L-NMMA infusion (the L-NMMA + HEM group) compared with animals without haemorrhagic hypotension after L-NMMA infusion (the L-NMMA group). The present findings suggest that NO synthesis may play a crucial role in the autoregulation of LCBF in response to a reduction in blood pressure in the cerebral cortices, cerebellar cortex and several deep brain regions.

Diffusion-weighted imaging demonstrates transient cytotoxic edema involving the corpus callosum in a patient with diffuse brain injury

Reversible T2 hyperintense signal abnormality in the corpus callosum, although frequently seen after diffuse brain injury, has not been well clarified. With some accumulated evidence, we report a case of diffuse brain injury in a 24-year-old man. Magnetic resonance imaging (MRI) demonstrated T2 hyperintense signals in the trunk and the splenium of the corpus callosum 12 days postinjury. Echo-planar diffusion-weighted imaging was also performed on the same day, which revealed decreased diffusion (hyperintense signals) in the same site and almost the same size as T2 hyperintense signals. T1-weighted images were normal. Neuropsychological examination of the patient did not show callosal syndrome, namely hemialexia, unilateral agraphia and unilateral apraxia. Repeat MRI on day 20 demonstrated a signal decrease of both T2-weighted images and diffusion-weighted images (DWI) in the lesion. Follow-up MRI at 6 months showed complete resolution of the T2 signal abnormalities and of the corresponding decreased diffusion. Considering that diffusion-weighted imaging showed transient decreased diffusion, the lesion in the corpus callosum indicated the existence of cytotoxic edema. Also, transient DWI hyperintensity, namely cytotoxic edema, in the trunk and the splenium of the corpus callosum does not necessarily reveal callosal deficits.

Enhanced erythrocyte aggregability in occlusive cerebrovascular disease.

We measured the rate of erythrocyte aggregation using our whole-blood aggregometer in 80 patients with occlusive cerebrovascular disease during the acute and chronic phases. We compared the data with values for 38 age-matched healthy controls. Mean +/- SD erythrocyte aggregability of the patients during both the acute phase (0.145 +/- 0.21/sec, n = 35) and the chronic phase (0.139 +/- 0.21/sec, n = 45) was higher than that in the controls (0.123 +/- 0.21/sec, n = 38; p less than 0.01). Erythrocyte aggregability was positively correlated with the plasma concentration of globulin and fibrinogen and inversely correlated with the albumin:globulin ratio. However, these correlations did not necessarily exclude the possibility that some unknown substance(s) released from ischemic tissue might enhance erythrocyte aggregability.

Reduction rate of body mass index predicts prognosis for survival in amyotrophic lateral sclerosis: A multicenter study in Japan

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3–3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis

Transferrin, an iron-binding protein, plays an important role in the transport and delivery of circulating ferric iron to the tissues. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of Bunina bodies, skein-like inclusions, Lewy body-like inclusions/round inclusions, and basophilic inclusions in the remaining anterior horn cells in the spinal cord. We examined transverse paraffin sections of lumbar spinal cords from 12 ALS cases including two ALS with dementia and two ALS with basophilic inclusions, using antibodies to human transferrin. The results demonstrated that transferrin localized in Bunina bodies and some of the basophilic inclusions. In contrast, skein-like inclusions and Lewy body-like inclusions or round inclusions did not show obviously detectable transferrin immunoreactivities. Our findings suggest that although the mechanisms underlying transferrin accumulation in Bunina bodies and basophilic inclusions are unknown, transferrin could be involved in forming these inclusions. Furthermore, following cystatin C, transferrin is the second protein that localizes in the Bunina bodies.

Risk factor profiles of stroke, myocardial infarction, and atrial fibrillation: a Japanese Multicenter Cooperative Registry.

OBJECTIVE We sought to clarify risk factor profiles and current treatment of Japanese patients with stroke, myocardial infarction (MI), and nonvalvular atrial fibrillation (NVAF) using the database of the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE). METHODS J-TRACE is a nationwide multicenter cooperative cohort of Japanese patients with MI, stroke, and NVAF. Baseline characteristics of 8087 Japanese patients (5804 male, average age 68.7 years) with history of stroke (n=3554), MI (n=2291), or NVAF (n=2242) were analyzed. RESULTS History of stroke (14.7%) was more frequent than history of MI (2.6%) in patients with stroke, whereas history of stroke (6.6%) was less frequent than history of MI (7.6%) in patients with MI. In patients with NVAF, history of stroke (14.3%) was far more frequent than history of MI (3.4%). Hypertension was more frequent in stroke (74.4%) than MI (62.0%) or NVAF (57.7%), whereas hypercholesterolemia, diabetes mellitus, and cigarette smoking were more prevalent in patients with MI (56.1%, 35.1%, and 33.3%, respectively) than in those with stroke (35.7%, 22.4%, and 19.7%, respectively) or NVAF (26.9%, 17.2%, and 16.1%, respectively). Alcohol consumption (34.9%) and obesity (body mass index>25) (32.8%) were most common in patients with NVAF. In all patients, nonmedication rates were higher in patients with hypercholesterolemia (29.8%) or diabetes (36.9%) than in those with hypertension (9.5%). Warfarin was used in 58.9% of patients with low-risk and 75.4% with high-risk NVAF. CONCLUSION Risk factor profiles and their modification were not similar among patients in Japan with MI, stroke, and NVAF, although they share a high risk of thrombotic events.

Bilateral hemispheric reduction of cerebral blood volume and blood flow immediately after experimental cerebral hemorrhage in cats.

Acute cerebral circulatory changes following experimental cerebral hemorrhage were investigated in eight cats. The cerebral hemorrhage was produced in the right basal ganglia by introducing arterial blood via a thin catheter, using the systemic arterial blood pressure of the cat as a driving force. Local cerebral blood volume was measured continuously in the bilateral parietotemporal cortexes employing photoelectric apparatuses. Carbon black dilution curves were recorded from the regions, and the mean transit time of blood was calculated. Local cerebral blood flow was estimated from mean transit time and cerebral blood volume. Intracranial pressure was monitored continuously in the right parietal epidural space. Five minutes after cerebral hemorrhage, intracranial pressure increased by 24.0 +/- 6.1 mm Hg, while mean arterial blood pressure increased by only 2.9 +/- 2.0 mm Hg. Cerebral blood volume decreased by 1.60 +/- 0.24 vol% in the hemorrhagic and 1.14 +/- 0.30 vol% in the nonhemorrhagic hemisphere. Cerebral blood flow decreased by 30.0 +/- 4.5 ml/100 g brain/min in the hemorrhagic (initially 64.5 +/- 13.6) and by 30.3 +/- 7.5 ml/100 g brain/min in the nonhemorrhagic (initially 60.9 +/- 6.9) hemisphere. Increased intracranial pressure appeared to be the main cause of the observed cerebral blood volume/flow reduction shortly after experimental hemorrhage in the basal ganglia. Several other factors and mechanisms involved are discussed.

Autoradiographic analysis of second-messenger systems in the gerbil brain

Quantitative in-vitro autoradiographic study was performed to localize two prominent second-messenger systems (the adenylate cyclase and phosphoinositide systems) in the normal gerbil brain. [3H] Forskolin and [3H] phorbol 12, 13-dibutyrate (PDBu) were used to identify the regional distribution of adenylate cyclase and protein kinase C, respectively. The localization of the forskolin binding was not uniform, being particularly concentrated in the striatum, the accumbens nucleus, the olfactory tubercle, the substantia nigra, the CA3 region of the hippocampus and the molecular layer of the cerebellum. On the other hand, the PDBu binding was rather uniform, although the superficial layer of the cerebral neocortices, the strata oriens of the CA1 region of the hippocampus and the molecular layer of the cerebellum showed relatively dense binding. Quantitative autoradiography of the second-messenger systems in the brain is expected to provide important information concerning the role of neurotransmitters in the pathophysiology of various conditions.