Upward gaze-evoked nystagmus with organoarsenic poisoning.

The authors report assessment of abnormal ocular movements in three patients after organoarsenic poisoning from diphenylarsinic acid. The characteristic and principal sign is upward gaze-evoked nystagmus. Moreover, vertical gaze holding impairment was shown by electronystagmography on direct current recording.

Beta-site APP cleaving enzyme 1 (BACE1) is increased in remaining neurons in Alzheimer's disease brains.

Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid beta protein (Abeta) in the brain cortex. Abeta is produced from beta-amyloid precursor protein (APP) by beta-secretase and gamma-secretase. beta-Secretase has been identified as beta-site APP cleaving enzyme1 (BACE1). We produced rabbit polyclonal antibodies against the amino and the carboxyl terminals of BACE1. Using these antibodies, BACE1 was characterized in temporal lobe cortices by Western blotting and immunohistochemistry. Immunohistochemical studies employing anti-GFAP and anti-MAP2 antibodies as well as anti-BACE1 antibodies showed that BACE1 was expressed exclusively in neurons but not in glial cells. Brain samples were directly extracted by 0.5% SDS and analyzed by Western blotting and densitometer. Although the mean level of BACE1/mg protein in AD brains was not increased, the ratio of BACE1 to MAP2 or to NSE was significantly increased compared with that in control brains. Taken together, these findings suggest that those neurons that survive in AD brains might generate more BACE1 than normal neurons in control brains, indicating that increased BACE1 activity could be one of the causes of AD. This could justify the development of anti-BACE1 drugs for AD treatment.

Bladder and bowel dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy.

We present a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who developed severe bladder and bowel dysfunction (BBD) as evidenced by constipation, voiding difficulty, and urinary urgency. These symptoms appeared 10 years after onset of CIDP. Cystometry showed disturbance of bladder sensation and detrusor areflexia. Magnetic resonance imaging (MRI) showed greatly enlarged nerve roots filling the lumbosacral spinal canal; this appeared to be the likely cause of BBD. A 3-day course of intravenous methylprednisolone (1 g/day), followed by 30 mg/day of oral prednisolone, ameliorated the sensory disturbance and muscle weakness, but not BBD.

The model and moral justification for organ procurement in Japan.

Organ replacement therapy is a part of medical practice in today's world and many countries have adopted the required guidelines and regulations. Establishing the basis on which organs can be removed, is still one of the most controversial issues of health policy making in the debate. The critical disparity between supply and demand in organ replacement therapy, even with the existence of social acceptance and organ transplantation law, turns attention towards the importance of an appropriate model of organ procurement. This model should be able to expand the donor pool and increase the organ retrieval rate by converting potential donors to actual ones. In Japan the organ transplantation law which was enacted in 1997 allows organ procurement from brain death as well as non-heart beating cadavers according to restricted conditions. One such condition includes the necessity of both the donor's and the family's written consent. Under current organ procurement policy, organs from only 29 brain death cases have been so far procured. In this paper after examining the current organ procurement system in Japan and the moral justifications behind different organ procurement models we conclude that the Japanese system does not clearly fall into one of the popular organ procurement models.

Diphenylarsinic acid poisoning from chemical weapons in Kamisu, Japan.

We noted a new clinical syndrome with prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The well that provided drinking water contained diphenylarsinic acid, a degradation product of diphenylcyanoarsine or diphenylchloroarsine, which were developed for use as chemical weapons, inducing severe vomiting and sneezing. Characteristics of diphenylarsinic acid poisoning include brainstem-cerebellar and cerebral symptoms. Mental retardation associated with brain atrophy in magnetic resonance images was evident in some infants. We must be vigilant to prevent or minimize the effects of further diphenylarsinic acid poisoning in Japan or elsewhere.

A clinical and genetic study in a large cohort of patients with spinocerebellar ataxia type 6.

In order to clarify the clinical and genetic features of SCA6, we retrospectively analyzed 140 patients. We observed an inverse correlation between the age of onset and the length of the expanded allele, and also between the age of onset and the sum of CAG repeats in the normal and the expanded alleles. The ages of onset of four homozygous patients correlated better with the sum of CAG repeats in both alleles rather than with the expanded allele calculated from heterozygous SCA6 subjects. Clinically, unsteadiness of gait was the main initial symptom, followed by vertigo and oscillopsia, and cerebellar signs were detected in nearly 100% of the patients. In contrast, extracerebellar signs were relatively mild and infrequent. The results of neuro-otological examination performed in 22 patients suggested the purely cerebellar abnormalities of ocular movements in nature. There was a close relationship between downbeat positioning nystagmus (DPN) and positioning vertigo, which became more common in the later stage. We conclude that total number of CAG repeat-units in both alleles is a good parameter for assessment of age of onset in SCA6 including homozygous patients. In addition, clinical and neuro-otological examinations suggested that SCA6 is a disease with predominantly cerebellar dysfunction.

[A case of hair loss induced by carbamazepine].

We report a 52 year-old man presenting with an acute considerable hair loss induced by carbamazepine (CBZ). The remarkable scalp hair loss started within a week after CBZ administration. There was no evidence of dermatitis or allergic reaction, or other cause for the hair loss. The serum concentration of CBZ was 8.6 microg/ml (therapeutic range 8-12 microg/ml). CBZ was discontinued, and the hair loss stopped within several days with new hair growth. Medication-induced hair loss is an occasional adverse effect of many drugs used for neuropsychological diseases. CBZ also induces hair loss and its frequency was reported below 2%. Only a limited number of detailed case reports describing CBZ-induced hair loss were available, and we found these cases could divide into two groups with regard to a delay in starting hair loss after administration of CBZ. In one group, the hair loss started within a week suggesting anagen effluvium and in another it started after two or three months suggesting telogen effluvium. This finding suggests the causative mechanism of CBZ-induced hair loss is not unitary.

Early vestibular dysfunction in Machado-Joseph disease detected by caloric test.

The selective vulnerability of distinct neuronal structures is a major feature of Machado-Joseph disease (MJD), also known as spinocerebellar ataxia 3 (SCA3). Vestibular dysfunction is known to be a symptom of MJD, but little is known about precisely when the vestibular system becomes impaired. Using a caloric test, we evaluated vestibular function in 2 MJD patients. One developed the initial symptom 1 year before evaluation, and the other 3 years before evaluation. Neither demonstrated a bilateral response in electronystagmography using ice-cold water irrigation, indicating severe vestibular disturbance. These results suggest that vestibular dysfunction is a symptom that develops very early in MJD and may contribute to unsteady gait as the initial symptom. The vestibular system thus appears to be one of the structures most vulnerable to MJD.

Frontotemporal dementia with ubiquitinated neuronal inclusions presenting with primary lateral sclerosis and parkinsonism: clinicopathological report of an autopsy case.

We report a case displaying upper motor sign, parkinsonism, and behavioral abnormality, with marked degeneration of the precentral cortex, neostriatum and frontotemporal lobes, as well as ubiquitinated neuronal inclusions. The patient was a 66-year-old male at the time of death. At age 57, he noticed progressive difficulties in speaking and swallowing. At age 60, he was severely anarthric and displayed emotional lability and incontinence. Neurologically, very poor movement of tongue was observed, but without atrophy or fasciculation. Deep tendon reflexes were hyperactive. Grasp reflex and snout reflex were also positive. Needle electromyography revealed no abnormalities. A diagnosis of primary lateral sclerosis and character change was made. At age 62, he developed bradykinesia and rigidity of the neck and all extremities. Treatment with carbidopa-levodopa was initiated, but resulted in minimal improvement. At age 65, he was bed-ridden, and had repeated occurrences of aspiration pneumonia; he died of pneumonia. Neuropathological examination revealed marked atrophy of the frontal and temporal lobes with Betz cells completely absent and moderate atrophy of the neostriatum. The spinal cord and nerve roots appeared normal. Immunohistochemically, ubiquitin-positive but tau-negative intraneuronal inclusions were found in the frontal and temporal cortices, including the precentral cortex and the hippocampal dentate gyrus, and the neostriatum. This case could be included with inclusion-associated disorders such as frontotemporal dementia or amyotrophic lateral sclerosis with dementia, and furthermore, predominant upper motor sign and parkinsonism could represent phenotypes of clinical manifestations with such inclusions.

Pravastatin at 10 mg/day does not decrease plasma levels of either amyloid-beta (Abeta) 40 or Abeta 42 in humans.

It has been assumed that statins work as a preventative drug for Alzheimer's disease (AD). Although some epidemiological observations raise doubts to the effectiveness of statins for AD, many in vitro and clinical studies insist on the effectiveness of statins decreasing amyloid-beta (Abeta) levels in medium or blood. To explore the effect of pravastatin on Abeta production, we followed the longitudinal plasma levels of both Abeta 40 and Abeta 42 during the allocation of pravastatin in 46 patients with hyperlipidemia. We found no correlation between plasma cholesterol levels or the decreasing values of total cholesterol and those of Abeta 40 or Abeta 42. Patients having Apolipoprotein E4 (ApoE4) had higher low-density lipoprotein levels and lower Abeta 40 levels in plasma, suggesting ApoE4 seems to influence plasma Abeta levels via cholesterol metabolism.

Brain death and organ transplantation: knowledge, attitudes, and practice among Japanese students.

OBJECTIVE: To investigate the knowledge, attitudes and practice of Japanese students regarding brain death and organ transplantation. METHODS: A 22-item questionnaire was handed out among 383 Japanese students during the 2002 academic year. The data was finally analyzed using a statistical package for social sciences, SPSS. RESULTS: Most students knew that organ transplantation can save a life 97%, while only 38% of the students were aware that there is no treatment for brain dead patients. Overall, 60% of the respondents believed brain death is equal to human death and 63% believed that organ removal from brain dead donors is mutilation of the body. There was a negative association between the students who reported positive attitudes toward the idea that removing an organ is mutilation of the body with their willingness to be a donor. Of the students 27% were opposed to the necessity of family agreement for organ donation. Although 66% expressed their wish to be a donor, less than half of them, 31% had a donor card; and 40% did not even know how to get a donor card. CONCLUSION: Granting a veto power to the family as well as the mistaken idea that there is recovery from brain death, can be considered as obstacles to organ procurement from the brain dead in Japan. The high value of life among Japanese society and the willingness to be a donor, bring hope that giving correct medical information and proper public education can increase social acceptance of organ transplantation from the brain dead in Japan.

Association of Lewy bodies and glial cytoplasmic inclusions in the brain of Parkinson's disease.

We report the histopathological and immunohistochemical findings from the brain of an elderly patient diagnosed with Parkinson's disease (PD). Neuropathological examination revealed moderate neuronal cell loss and astrocytosis in the substantia nigra. Lewy bodies were found in many sites characteristic for PD, including the substantia nigra, locus coeruleus, hypothalamus, substantia innominata, pontine raphe nucleus, and dorsal motor vagal nucleus, cingulate and insular cortices. Furthermore, argyrophilic glial intracytoplasmic inclusions were found predominantly in the ventral pons, cerebellar white matter, precentral and frontal white matter, internal and external capsule, claustrum, and putamen. Inclusions were triangular in shape, and immunopositive for ubiquitin and alpha-synuclein. In view of these histopathological and immunohistochemical findings and patterns of distribution, the inclusions were suggested to be glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA). These findings suggested that our case might have experienced two pathological processes; PD and the early stage of MSA (striatonigral degeneration) that had not progressed to striatal involvement. Alternatively a common pathological background including abnormal processing of alpha-synuclein could contribute to widespread accumulation of Lewy bodies and GCIs in a single condition accompanied by nigral degeneration.

Chrysamine G and its derivative reduce amyloid beta-induced neurotoxicity in mice.

The neurotoxicity of amyloid beta (Abeta) is widely believed to play a seminal role in neurodegeneration in Alzheimer's disease. We examined the effect of Chrysamine G (CG) on such neurotoxicity using the specific measurement of surviving neurons. CG was found to reduce the neurodegeneration induced by both the active short fragment of Abeta(25-35) and full-sized Abeta(1-40). In this study, we synthesized a new chemical compound from a monovalent structure of CG (hCG), with a lower affinity for Abeta, and compared its activity with that of CG. Both CG and hCG were found to be equally efficacious in reducing Abeta-induced neuronal death at a concentration of 0.1-1 microM, indicating that the mechanism of action for CG was not due to its chelating activity, but rather due to its anti-oxidant activity.