Characteristic developmental expression of amyloid beta40, 42 and 43 in patients with Down syndrome

We immunohistochemically studied the expression of beta-amyloid precursor protein (APP), Abeta40, Abeta42, and Abeta43 in the frontal lobes of 20 Down syndrome (DS) patients and 13 controls. The immunoreactivity for each antibody was different in the degree of intensity and the chronological pattern of expression. APP and Abeta43 immunoreactivity was increased in neurons initially, and then Abeta43 and 42 immunoreactivity appeared in diffuse plaques from 32 years of age. APP and Abeta43 were characteristically observed in axons around senile plaques. Finally, Abeta40 immunoreactivity was detected in the cores of senile plaques. This time course of immunoreactive expression may be related to the pathogenetic process of Alzheimer-type dementia in DS, and the axonal damage in senile plaques may lead to the formation of neurofibrillary tangles (NFT) or neuronal death through axonal flow disturbance and accumulation of Abeta43 in cortical neurons.     

Mortality due to silico-tuberculosis and lung cancer among 200 whetstone cutters

The objective of the present study was to examine if the mortality due to tuberculosis and cancer in the lungs was elevated in a cohort of 200 male whetstone cutters. 1955-1995 death certificate-based mortality data on the cohort were available, and the data were reviewed in the present study for mortality due to the two diseases to calculate standardized mortality ratios (SMR) in reference to the health statistics of Kyoto prefecture, where the cohort lived. Among the 200 cohort members, 99 men deceased during the observation period, the deaths including 10 cases of lung tuberculosis (of which 9 cases had silicosis together), 20 cases of all malignancies, and 6 cases of lung cancer (5 cases with silicosis). There was a significant elevation in the mortality due to lung tuberculosis (SMR = 3.47) although SMR for all causes was not elevated (1.10). There was no significant change in SMR for all malignancies (0.78), whereas SMR for lung cancer (1.24) tended to be elevated although insignificantly. Lung tuberculosis was a significant complication of silicosis in 1955-1995. Possible elevation in lung cancer SMR among this cohort needs further studies.     

Evidence-based evaluation of preventive procedures for osteoporosis, osteoporotic fractures and other diseases

In the present special articles entitled "Evidence-based prevention of osteoporosis and osteoporotic fractures", several preventive procedures for these diseases were evaluated for their effectiveness according to the best available evidence of literature. These procedures included optimization of calcium intake and physical activity as the primary prevention, bone density measurement as the screening, and prevention of falls in the elderly people. The present article described a method for the evaluation of preventive procedures for osteoporosis based on systematic review of the evidence, which was applicable for other preventive services of diseases. The next step to the review of evidence is how to communicate the evidence established to practitioners in the fields of preventive medicine and community health. One of the effective tools for this purpose is evidence-based preventive practice guideline. The Japanese Society for Hygiene should play a leading role in compiling a series of guidelines for the preventive procedures of various kinds of health problems such as lifestyle-related diseases.     

Transient crossed aphasia and persistent amnesia after right thalamic haemorrhage

A 45-year-old right-handed woman suffered transient aphasia and persistent amnesia after a right thalamic haemorrhage. This patient appeared to have crossed aphasia, although it disappeared within 8 weeks. It is noteworthy that the patient had a unilateral right thalamic lesion but exhibited both verbal and non-verbal memory impairment. Computed tomography and magnetic resonance imaging revealed cerebral haemorrhage in the right thalamus involving the ventral anterior nucleus, medioventral nucleus, mamillothalamic tract, internal medullary lamina, and mediodorsal nucleus. An amytal test was performed and suggested that the right hemisphere was dominant for language functions and the left hemisphere was dominant for visuospatial functions. Single photon emission CT revealed a low perfusion area only in the right thalamus. These findings suggest that the right hemisphere might be dominant for both verbal and non-verbal memory function in this patient, although visuospatial function was lateralized in the left hemisphere.     

Replacement of the Canine Inferior Vena Cava with a Seeded Graft

The patency and microscopic findings of gelatin-coated Dacron grafts seeded with endothelial cells and implanted into the inferior vena cava of dogs was evaluated. A total of 25 mongrel dogs were divided into four experimental groups according to whether or not an antiplatelet agent was administered and a seeded or nonseeded graft was implanted. In the groups not given antiplatelet therapy that were implanted with a nonseeded graft, occlusion of the graft occurred soon after surgery. In contrast, in the majority of animals implanted with a seeded graft and given antiplatelet therapy, graft patency was evident for up to 4 weeks postoperatively. In the latter animals, scanning electron microscopy 4 weeks after surgery showed the formation of confluent endothelial-like cells within 5 mm from the anastomosis, as well as insular endothelial-like cells in the central part of the graft. The simple centrifugal seeding method enables endothelial-like cells to adhere to grafts, suggesting that it may be useful in venous replacement. Received: October 18, 1999 / Accepted: November 20, 2000     

Association of osteopontin with ischemic axonal death in periventricular leukomalacia

Osteopontin (OPN) is a bone matrix protein expressed my macrophages and related to the process of tissue calcification, and is also known to protect ischemic cells. To understand how OPN is involved in the process of ischemic axonal death in periventricular leukomalacia (PVL), we examined the immunoreactivity of OPN and ionized calcium binding adaptor molecule 1 (Iba1; microglia/ macrophage marker) at various stages of PVL. OPN immunoreactivity paralleled the number of Iba1-positive foam cells; a finding which suggests the production of OPN protein by foam cells. OPN immunoreactivity was not found in either normal white matter or acute PVL lesions, but was detected at the subacute and chronic stages in swollen and calcified axons bordering the ischemic zone. These findings suggest that OPN is closely associated with death of swollen axons at the periphery of the ischemic zone, regulating the presence or absence of calcification. Received: 20 January 1999 / Revised, accepted: 21 September 1999     

Mechanism of decrease in levels of hepatic P450 isozymes induced by intracerebral endotoxin: independence from sympathetic nervous and adrenocortical systems

We previously reported that lipopolysaccharide (LPS) injected intracerebroventricularly (i.c.v.) at an ineffective dose (0.1 μg/rat) decreased the drug metabolizing activities and related cytochrome P450 (CYP) isozymes in rat liver microsomes when injected intraperitoneally (i.p.). The dose study (doses <0.1 μg intracerebrally and >0.1 μg i.p.), which was carried out to examine how much more effective is i.c.v.-LPS than i.p.-LPS, showed that the pattern of alteration of expression of CYP isozymes induced by i.c.v.-LPS was different from that caused by i.p.-LPS at an effective dose (10 μg/rat). These results indicate that the decrease in hepatic CYP isozymes caused by i.c.v.-LPS could not be explained by the LPS leaked from the brain, suggesting that the decrease in hepatic CYP isozymes by i.c.v.-LPS may be caused by a central action of LPS. In this study, the possible involvement of sympathetic nervous and adrenocortical systems in the down-regulation of CYP isozymes by i.c.v.-LPS was investigated using surgical or chemical sympathetecomized or adrenalectomized rats. The norepinephrine (NE) content in the liver in rats with surgical hepatic sympathetectomy was reduced by 88% compared with that of sham-operated rats that received i.c.v.-saline and 85% compared with that of sham-operated rats that received i.c.v.-LPS, indicating that hepatic denervation was successful. The NE content in the liver in rats chemically sympathetectomized by two i.p. injections of 6-hydroxydopamine (40 mg/kg each time) 1 and 2 days before i.c.v. injection was reduced by 82% in i.c.v.-saline-treated and by 74% in i.c.v.-LPS-treated groups compared with that in rats pretreated with i.p.-saline. These results indicate that sympathetic NE terminals were effectively removed. Intracerebroventricular LPS decreased the total P450 content and the activities of CYP dependent drug metabolizing enzymes, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-depentylase (PROD), imipramine N-demethylase (IMND) and erythromycin N-demethylase (ERND) after 24 h in both sympathetectomized rats and non-denervated rats. Adrenalectomy (ADX) reduced the level of corticosterone in serum by 81% compared to sham-operated rats, indicating that adrenalectomy was successful. ADX did not inhibit the decrease in the total P450 content and the metabolism of drugs induced by i.c.v.-LPS, but more profoundly emphasized the inhibitory effect of i.c.v.-LPS than the sham-operation. These results suggest that the sympathetic nervous systems both directly and indirectly innervating the liver do not participate in the primary mechanism of the decrease in the activities of CYP isozymes in rat liver microsomes induced by i.c.v.-LPS. Also, the adrenal glands, especially the adrenocortical system, play a suppressive role in the decrease in CYP isozymes caused by i.c.v.-LPS. Received: 31 August 1998 / Accepted: 24 November 1998     

Microsatellite instability in patients with gastric remnant cancer

Background. About 2% of patients who undergo partial distal gastrectomy for gastroduodenal diseases develop gastric remnant cancer 10 to 30 years after the gastrectomy. It is important in clinical practice to determine a molecular marker to identify patients susceptible to gastric remnant cancer. Methods. We investigated nine gastric remnant cancers (from nine individuals who had gastrectomies for primary gastric cancer or gastroduodenal ulcer) for microsatellite instability (MSI) at six loci, using the polymerase chain reaction (PCR). A control group of ten patients with sporadic gastric cancers in the upper third of the stomach was also similarly analyzed. Results. MSI was demonstrated in eight of nine cancers from the individuals who had had primary gastric cancer or gastroduodenal ulcer (88.9%) compared with two of ten cancers from the individuals with sporadic gastric cancer in the upper third of the stomach (20%). Conclusion. These results suggest that one or more MSI is associated with remnant gastric cancer after gastrectomy. Received on Sept. 6, 1999; accepted on Dec. 20, 1999     

Reduction of the Side Effects of an Antitumor Agent, KRN5500, by Incorporation of the Drug into Polymeric Micelles

For intravenous (i.v.) injection of a water-insoluble antitumor drug, KRN5500, we have successfully incorporated KRN5500 into polymeric micelles. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines and toxicity in mice of polymeric micelles incorporating KRN5500 (KRN/m) were evaluated in comparison with those of the prototype KRN5500. KRN/m was found to express similar antitumor activity to KRN5500 in the in vitro and in vivo systems. However, the vascular damage and liver focal necrosis observed with KRN5500 i.v. injection were not seen when KRN/m was administered i.v. Therefore, we expect that KRN/m will be superior to KRN5500 for clinical use and that the methodology of polymeric micelle drug carrier systems can be applied to other water-insoluble drugs.