The adult life span in inbred strains of Drosophila melanogaster (Dm) has been found to be controlled by a few major genes (Hereditas 111: 207, 1989; Hereditas 117: 251, 1992). A 77kDa protein, which we named ju-myo (life-span) protein (JP) and is supposed to be the product of the gene on autosomal locus JmA on adult Dm was shown to have life-span prolonging effect when it was supplied in food. However, the knowledge of its structure and molecular mechanisms by which JP exerts its effects on cells is still unclear. Here we show that JP can exert neurotrophic activities on postmitotic fetal rat neurons isolated from cerebral cortical and dopaminergic neurons isolated from the midbrain: it enhanced survival of MAP2-positive cells and tyrosine hydroxylase immunoreactive neurons by approximately 2-fold over the control group. JP did not increase the density of astrocytes nor expression of glial fibrillary acidic protein (GFAP) in the mesencephalic neuron cultures. Aminoacid analysis of JP protein showed that JP is identical to the larval serum protein 2, of which sequence and structure were determined in 1997. Our work provides basis for defining the physiological role of JP at the molecular level and for exploring its potential utility as an alternative approach to study mechanisms of aging.
One recent strategy of gene therapy is to have cells express the lacking substances. Decline in dopamine D2 receptors (D2R) is observed in late-stage Parkinson's disease. We have constructed a replication-deficient adenovirus vector to transfer rat D2R cDNA (AdCMV. DopD2R) to the brain as a possible therapeutic strategy and a replication-deficient adenovirus vector to express nothing (AdCMV. Null) as a control. Using tissue culture cells infected with this vector, we detected D2R cDNA by Northern analysis and receptor protein in membrane preparations as specific binding of the D2R ligand, [3H] spiperone. In vivo demonstration involved autoradiographic analysis of [3H] spiperone binding in rat striatum, D2R expression was amplified above normal concentrations in the injection site. We investigated the expression and functionality of the adenoviral vector. Comparative analysis of the autoradiographic images from the striatum injected with AdCMV. DopD2R and the contralateral striatum injected with a control vector, AdCMV. Null, in male rats indicated that D2R binding was increased by 40-60% on days 3 and 5 after injection, but then declined to baseline levels by day 21. When injected with apomorphine on days 3 and 7 after vector injection, experimental groups that had received unilateral striatal injections of AdCMV. DopD2R exhibited a distinct and significant laterality in rotational behavior. These results provide the first demonstration of an adenovirally mediated, intracerebral delivery of a functional neurotransmitter receptor.
A total of 42 Japanese centenarians (9 males & 33 females) autopsied in Tokyo Metropolitan Geriatric Hospital during 22 years (1975-1996) were clinico-pathologically examined to determine details of the main cause of death. The main cause of death of the 42 cases were sepsis (16 cases), pneumonia (14 cases), suffocation (4 cases), heart failure (4 cases), cerebrovascular disorder (2 cases) and malnutrition (2 cases). Most pneumonias were caused aspiration of foreign bodies, and the origins of sepsis were pyelonephritis (7 cases), biliary tract infection (3 cases), necrotic lesions of the intestine due to ileus, ischemia and pseudomembranous colitis (3 cases) and indwelling vein catheter (3 cases). Malignant neoplasms were observed in 16 cases (38%), and 5 of them had 2 or 3 lesions. Thus, the total number of lesions of malignant neoplasms were 22, as follows; colonic cancer (36%), urinary bladder cancer (14%), lung adenocarcinoma (9%), gastric cancer (9%), malignant lymphoma (9%) and others. However, none of these malignant neoplasms were directly related with the cause of death. All 42 centenarians died not of simple “senile decay”, but due to diseases.
Daily blood glucose profiles were measured in 163 Type 2 elderly diabetic cases to evaluate whether a fasting (before breakfast) or a post-prandial (after breakfast) blood glucose concentration is able to predict blood glucose values throughout the day. In the diet-treated alone group (n=61), the percentage of daily blood glucose profiles having plasma glucose values less than the 08:00 hours (before breakfast) value were as follows: 59.0%, 32.8%, 59.0%, and 55.7% at 18.00 (before supper), 24.00, 03.00, 06.00 hours, respectively. In group treated by oral hypoglycemic agents (OHA) (n=102), these were as follows: 45.1%, 26.5%, 52.9%, and 67.6%, respectively. In the OHA group, the mean plasma glucose value at 08:00 hours was significantly higher in patients with the lowest plasma glucose levels between 60-79mg/dl than in patients with these levels between 80-99mg/dl (103.7±19.6 vs 118.7±16.9mg/dl, p<0.01), but that at 10:00 hours was similar in the two groups (218.8±43.9 vs 214.5±40.1mg/dl). In patients with lowest plasma glucose levels of between 60-99mg/dl, the 08:00 hours value correlated positively with that of 24:00 (r=0.40), 03.00 (r=0.53), and the 06.00 hours value (r=0.69), but no correlation was observed with the 18.00 hours value. On the other hand, the 10:00 hours value was not associated with these time-points values. Our results reveal that before breakfast plasma glucose values are more predictive of low blood glucose values in the night during sleep than after-breakfast blood glucose values, but do not predict low blood glucose values before supper in patients on OHA.
To clarify the relationship between long-term prognosis of patients with stroke and their MRI findings, 103 patients with initial cerebral thrombosis, who survived more than three months after the ictus, were studied for five years. The mean age of 98 patients (T group), who were followed up completely, was 73.1 years-old and 65 were men. The age-matched controls consisted of two groups: 65 subjects, who had hypertension and/or diabetes without a history of stroke (R group), and 85 subjects, who had any hypertension, diabetes and stroke (N group). MRI findings were divided into six categories: 1) types of causative lesion, 2) grades of periventricular hyperintensity (none, rims/caps, patchy, diffuse PVH), 3) number of spotty lesions, 4) presence of silent infarction, 5) ventricular dilatation, and 6) extents of brain atrophy. Types of causative lesion were subdivided into 3 subtypes; infarction of the perforating artery territory (P type), infarction of the cortical artery territory (C type), and brainstem infarction (B type). The presence of vascular risks and dementia, and the extent of activity of daily living (ADL) were assessed. The P, C, and B types were identified by MRI in 46, 36, and 16 of the T group, respectively. Motor impairment, dementia, and an ADL status of complete dependence at discharge were also seen in 84, 44, and 22, respectively. In the T group, 33 patients died during five years, which resulted in a cumulative mortality rate of 33.7% and an annual mortality rate of 8.2%. Based on log-rank analysis, the survival rate of the T group revealed was significantly lower than those of the R and N groups. The recurrent rate in the T group (annual stroke recurrence rate was 4.0%) was higher than in the R and N groups, but stroke recurrence was not the cause of death and two thirds of deaths were due to aspiration pneumonia and/or asphyxia. Cox hazard regression analysis for death due to respiratory diseases showed that the hazard ratios of infarction, patchy PVH, and more than 4 spotty lesions were 8.87 (p<.001), 0.31 (p=.058), and 0.44 (p=.098), respectively. Compared to the survival group, rates of complete dependence in ADL, dementia, and brain atrophy were significantly higher in the death group with low incidences of the P type and patchy PVH, which indicated small vessel disease. These findings suggested that in patients with cerebral thrombosis, even in the chronic phase, care should be taken to prevent pneumonia and/or asphyxia due to bulbar palsy. Furthermore, no MRI findings were distinct predictors of long-term prognosis, although infarction based on the small vessel disease had rather good outcome in terms of respiratory disease.
An 88-year-old woman was admitted to our hospital because of palpitations, dyspnea, orthopnea and appetite loss. On admission, small crackles were heard on her lower back, and her liver was swollen. Chest rentogenogram showed cardiomegaly (cardio-thoracic ratio 65.5%) and bilateral pleural effusion. Electrocardiograms showed atrial fibrillation with an average heart rate of 95 per minute. Echocardiography revealed mitral stenosis. Because the patient was considered to be suffered from heart failure due to mitral stenosis with atrial fibrillation, furosemide (20mg per day) and digoxin (0.25mg per day) was started. After digoxin had been raised to a dose of 0.50mg per day because of sustained rapid ventricular response on the fourth hospital day, she complained of nausea and vomiting. Serum digoxin concentration was 2.55ng/ml on the next day, and 1.08ng/ml 96 hours after discontinuing digoxin. There was no complaint after digoxin was restarted with a dose of 0.05mg per day. She complained of nausea again on the third day when the digoxin was raised to a dose of 0.083mg in a blinded study. This observation indicates that digoxin intoxication could occur even in the smaller dose of digoxin than usual in the elderly.