[in Japanese]

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[in Japanese]

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Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a specific mitogen for vascular endothelial cells and causes neovascularization and capillary hyperpermeability. We previously found large amounts of VEGF peptide in areas with many macrophage-derived foam cells adjacent to the lipid core of human atherosclerotic plaques and in basal regions of plaque consisting predominantly of smooth muscle cells. In the present study, we examined the role of inflammatory cytokines and oxidative modified low density lipoprotein (OX-LDL) in the expression of macrophage VEGF. Interleukin 1β and tumor necrosis factor α upregulated the expression of VEGF mRNA in a macrophge cell line (RAW264). In addition, OX-LDL also upregulated the expression of VEGF mRNA in these cells in a time-dependent and a dose-dependent dependent manner, and there was an increase in the levels of VEGF protein in the conditioned medium. These results suggest that VEGF expression may be upregulated in atherosclerotic lesions and that VEGF may play a role in the development of atherosclerosis.

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Extracellular deposition of amyloid β protein (Aβ) as senile plaques and cerebral amyloid angiopathy (CAA) is one of the essential pathological characteristics of Alzheimer's disease (AD). Several Aβ species with different carboxyl termini, including Aβ42 (43) and Aβ40 ending at residue 42 (43) and 40, respectively, have been identified in CAA and in senile plaque cores. Because Aβ42 (43), the major component of diffuse plaque which is the earliest pathological change in AD brains, forms insoluble amyloid fibrils more rapidly than does Aβ40, it has been hypothesized that Aβ42 (43) plays a role in amyloid seeding and Aβ40, in the elongation of amyloid fibrils on a seed of Aβ42 (43).
We used enzyme-linked immunosorbent assay (ELISA) with site-specific monoclonal antibodies to differentiate Aβ42 (43) from Aβ40. First, we measured the amounts of different Aβ species in plasma from patients with sporadic probable AD, age-matched patients with neurologic diseases but without dementia, and age-matched normal controls. Concentrations of Aβ1-40 and Aβ1-42 (43) in plasma did not differ significantly among the three groups. Second, CSF levels of Aβ species (CSF-Aβ) with different carboxy termini, i.e., AβX-40 and AβX-42 (43) as well as Aβ1-40 and Aβ1-42 (43), were measured in patients with AD and in age-matched controls without dementia using ELISA. Levels of both CSF-AβX-42 (43) and Aβ1-42 (43) were significantly lower in the patients with AD that in the controls, but neither the levels of CSF-AβX-40 nor those of CSF-Aβ1-40 differed between the two groups, which suggest that increased adsorption of Aβ42 (43) to Aβ deposition in AD brains, decreased secretion of Aβ42 (43) in CSF, or increased clearance of Aβ42 (43) from CSF might explain the low levels of Aβ42 (43) in the CSF of patients with AD. Third, we measured the concentrations of various Aβ species post-mortem in the cerebral cortex of patients with PS-1 mutations and β amyloid precursor protein (APP) 717 mutation linked to familial AD or Down syndrome. The results indicate that one effect of PS-1 mutations, APP717 mutation and Down syndrome is to cause dramatic and accelerated accumulation of Aβ42 (43) in the brain as compared with sporadic AD. In particular, the increases in Aβ1-42 (43) showed a crude inverse correlation with the age of onset in each subtype of AD.
Thus, quantitative studies differentiating Aβ42 (43) from Aβ40 have established the fundamental importance of Aβ42 (43) in AD.

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Pneumonia is a major cause of death in the elderly. Swallowing disorders caused by cerebrovascular diseases can cause frequent aspiration during sleep, which can result in pneumonia. Patients with aspiration pneumonia may have abnormalities in systems involving dopamine-substance P in the central and peripheral nervous system. Activation of these systems may benefit elderly people with swallowing disorders.

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We report the clinical and neuropathologic phenotypes associated with two missence mutations in the presenilin I (PS I) gene in Japanese patients with early-onset familial Alzheimer's disease. The AM/JPN1 family showed a missense mutation (C→T) which is predicted to cause an Alanine to Valine missense substitution at codon 260 (A260V). The disease in the members of this family had a mean age-of-onset of 40.3 years old (the range of disease is 8-19 years). Neuropathologic studies of two members of AM/JPN1 pedigree showed wide-spread senile plaques, neurofibrillary tangles, and neuronal loss, as well abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree transmitting a C→T nucleotide substitution leading to the missense mutation of Alanine to Valine at colon 285 (A285V), the disease had a later age of onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PSI reveals no obvious clinical or pathological phenotype that uniquely distingguishes Alzheimer's disease associated with PS I mutations from other early-onset familial Alzheimer's disease. This implas that the variable phenotypes of familial Alzheimer's, disease might be aftribatable to factors other than the PS gene.

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Although studies of families and twin studies have demonstrated that non-insulin-dependent diabetes melllitus (NIDDM) has a strong genetic component, the genes responsible for the common forms of NIDDM are largely unknown, due to the complex and heterogenous nature of the disease. To study the genetics of NIDDM, we used an inbred animal model of NIDDM, the NSY mouse, in which NIDDM spontaneously develops in an age-dependent manner. The inheritance pattern of glucose tolerance, fasting insulin levels, insulin response to glucose, body mass index, and epididymal fat pad weight in F1 hybrids of NSY with control C3H/He mice suggested the different modes of inheritance in these phenotypes. Multipoint linkage analysis of glucose tolerance in F2 mice with microsatellite markers throughout the genome mapped at least three loci on different chromosomes. Positional cloning of susuceptibility genes for NIDDM in NSY mice may increase our understanding of the genetics and etiology of human NIDDM and may lead to more effective methods for prevention and intervention.

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We analyzed HLA class II genes of Okinawan centenarians using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to identify primary genetic factors in the major histo-compatibility complex (MHC) region associated with human longevity. Gene frequencies of centenarians were compared with those of normal adults of the same ethnicity who were selected in the same vicinity as the centenarians. The following differences were identified in the HLA-DQB1 and DQA1 genes: the frequencies of DQB1*0503, DQA1*0101 (04) and DQA1*05 were increased in the centenarians, whereas those of DQA1*0102, DQA1*0103 and DQB1*0604 were decreased. Similarly, for the DRB1 gene, the frequencies of DRB1*0101, DRB1*1201 and DRB1*1401 were increased in the centenarians, whereas those of DRB1*0403 and DRB1*1302 were decreased. These data suggest that several alleles of the HLA-DRB1 and/or HLA-DQ genes are involved in human longevity.

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The effects of warm bathing on short-term and circadian rhythms for blood pressure (BP), pulse rate (PR), and endocrine function were studied in 10 bedridden patients (5 men and 5 women; age 78.9±10.5 years old) hospitalized in Nomura Municipal Hospital. The results indicated a transient elevation of BP with bathing and its rapid fall after bathing. Compared with the days when patients did not take bath, systolic BP was significantly lower for 12 to 16 hours (p<0.005) after bathing and diastolic BP was also significantly lower during 8 to 12 hours (p<0.01), 12 to 16 hours (p<0.001) and 20 to 24 hours (p<0.001). The PR was significantly higher from 0 to 4 hours after bathing (p<0.01), but became significantly lower during 8 to 12 hours (p<0.001) and 12 to 16 hours (p<0.001). Plasma renin activity increased significantly after bathing (p<0.05). Thus, the effects of bathing in lowering BP of bedridden patients in stable condition may continue for several hours after bathing.

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To examine the relationship between disturbed upper airway reflexes and aspiration pneumonia, we administered a total volume of 20μl of Ad-CMV-lacZ (Ad vector) or 20μl of phosphate buffer solution (PBS) intranasal to C57 black mice. In nostrils, the lacZ gene expression was investigated in each mouse with or without anesthesia. Under anesthesia, the lacZ gene expression was detected by Xgal staining in the lungs of every mouse given the Ad vector. However, no gene expression was measured in the lungs of those given the Ad vector without anesthesia. In mice treated with PBS, there was no lacZ gene expression in the nostrils, trachea, or lungs, irrespective of anesthesia. These results suggest that unconsciousness or disturbed upper airway reflexes caused by anesthesia caused aspiration, resulting in an intranasal bolus that can reached the lower airways, This process can be analyzed in mice tracted with adenovirus vectors carrying the E. coli LacZ gene. Mice given Ad-CMV-lacZ transnasally can be used to study aspiration pneumonia in relation to unconsciousness.

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One hundred and ninety-nine elderly stroke patients, who received rehabilitation treatment, were examined, to clarify the relationship between cognitive function and discharge place. The patients who moved to long-term care facilities showed more severe disabilities of basic activities of daily living (ADL), more frequent incontinence, and lower functional impairments (Brunnstrom stage), compared with those discharged to their home. Multivariate regression analysis was done with discharge place as the dependent variable. Independent variables were age, sex, kind of stroke, rehabilitation period, level of ADL and IQ on Kohs test, or performance IQ on the Wechsler Adult Intelligence Scale. Older age, higher levels of ADLs, and higher scores on Kohs test IQ or Wechsler Adult Intelligence Scale Performance IQ were all significantly linked with home discharge. These results suggest that non-verbal cognitive dysfunction may affect discharge place in elderly stroke patients after rehabilitation therapy.

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