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.

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.

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.

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.

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.

Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype.

Little information is available on molecular defects involved in adult Sandhoff disease presenting as motor neuron disease phenotype. We studied enzyme activities of beta-hexosaminidase (Hex) and the HEXB gene encoding the beta-subunit of Hex in a family of the Japanese case. Enzyme assay with 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside revealed a reduction in Hex A and B activity in proband's leukocytes. Although the activity of both in the mother were intermediate between those of controls and the proband, only Hex B reduction determined with heat inactivation was found in the father. Analysis of HEXB gene demonstrated two novel point mutations. The first mutation, IVS2-1G>A, was located at the 3'-splice acceptor site of intron 2 derived from the mother, causing exon 3 skipping. The resultant mRNA encoded a shorter beta-chain, which may not form an active enzyme. The second mutation was a G-to-A transition in exon 13 (c.1598G>A) derived from the father and resulted in arginine-to-histidine substitution at amino acid position 533 (R533H). Expression of R533H mutation in COS-1 cells demonstrated a lack of normal Hex activity, indicating that this mutation is pathological. Compound heterozygosity of these two mutations may trigger the development of adult Sandhoff disease with a motor neuron disease phenotype.

The expression of dystrophin, alpha-sarcoglycan, and beta-dystroglycan during skeletal muscle regeneration: immunohistochemical and western blot studies.

We evaluated re-expression of dystrophin, alpha-sarcoglycan and beta-dystroglycan in regenerating skeletal muscles of rats after cardiotoxin-induced myonecrosis in order to understand the dynamic behaviour of these proteins during the regeneration process. Immunohistochemical staining of these proteins almost disappeared in the sarcolemma of necrotic fibers on the 1st day, and was obscured due to non-specific staining on the 3rd day. Dystrophin was labeled faintly at the sarcolemma of regenerating muscle fibers on the 5th day. From the 5th day to the 10th day, levels of immunostaining of dystrophin increased. After the 14th day, dystrophin was stained conspicuously. alpha-Sarcoglycan was labeled weakly at the sarcolemma of small regenerating muscle fibers on the 5th day and was labeled conspicuously after the 7th day. beta-Dystroglycan was labeled moderately at the sarcolemma of regenerating muscle fibers on the 5th day and was labeled conspicuously after the 7th day. In western blot analysis, beta-dystroglycan persisted throughout the entire cycle of myonecrosis and regeneration, and re-expression of alpha-sarcoglycan progressed faster than that of dystrophin. We speculate that regeneration advances from the basement membrane side to the subsarcolemmal side, and that proteins at the basement membrane side resist disruption and have a high capacity for regeneration.

[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.

[A case of sensory perineuritis with Bowen disease].

A 60-year-old man was admitted because of subacutely progressive sensory disturbance characterized by fluctuating dysesthesia and light pain on the skin of his hands and feet. He exhibited mononeuritis multiplex, and a plaque with sloughing was observed on the left side of his back. Sural nerve biopsy revealed marked thickening of the perineurium with vascularization, and no necrotizing vasculitis. The pathological features of the nerve biopsy were compatible with sensory perineuritis. A biopsy from his skin lesion revealed Bowen's disease. There have been several reported cases of sensory perineuritis accompanied by malignant tumors. In these cases, immune dysfunctions were considered a common underlying cause in both diseases. This is the first reported case of sensory perineuritis associated with Bowen's disease.

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.

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.

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.