Biomedical subjects
Publications and source records attributed to K Kosaka.
We report a rare polymorphism in the human proteolipid protein (PLP) gene. A synonymous mutation, 168 A-->G, was detected in exon 2 of the PLP gene. Mutations in this gene have been reported in some cases of Pelizaeus-Merzbacher disease.
Bleaching of melanin prior to Gallyas staining enabled us to detect an unexpectedly large number of neurofibrillary tangles (NFTs; 62 and 50 NFTs in the upper and the lower substantia nigra, respectively, mostly in the neuronal cytoplasm of the medial zona compacta) in brains of patients who had had Alzheimer's disease. Amyloid-like deposits were quite scarce. In Alzheimer's disease it has been commonly observed that other subcortical nuclei projecting widely to the cerebral cortex also contain a large number of NFTs, although they have few amyloid deposits. In these subcortical nuclei retrograde degeneration may initially affect intraneuronal processes, leading to the preferential development of NFTs in the neuronal cytoplasm.
To examine the relationship between non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM), we studied beta-cell function, HLA type, and serologic markers of IDDM and NIDDM in the parents of IDDM patients. Fifty-two parents of 33 IDDM patients were examined in terms of islet-cell antibody (ICA) status, haptoglobin phenotype, HLA type, and insulin responses during an oral glucose tolerance test (OGTT). Twenty-seven parents were prospectively evaluated for up to 113 months. They were divided into the following three groups based on pattern of ICA positivity during the follow-up period: group 1, persistently positive ICA (n = 4); group 2, fluctuating ICA (n = 7); and group 3, persistently negative ICA (n = 16). Twenty-three percent (12 of 52) of the parents of IDDM patients had NIDDM, and 12% (six of 52) of the matched controls did. The prevalence of ICA in the parents (11 of 52, 21%) was greater than in normal controls (one of 112, P < .01). Diabetic parents tended to show a higher prevalence of ICA (six of 12, 50%) than nondiabetic parents (six of 40, 15%; P = .06). ICA-positive parents showed higher glucose levels and lower insulin responses than ICA-negative parents. Three of four parents in group 1 slowly progressed to an insulin-dependent state during 25 +/- 3 months of follow-up evaluation. Parents in group 2 and group 3 did not show any changes in glucose levels or insulin responses during the study.(ABSTRACT TRUNCATED AT 250 WORDS)
A 31-year-old man suffered burns to the forehead, alar grooves and forearms. Vascular island skin flaps, with the infraorbital vessels as the pedicle, were used to reconstruct the burned nasal alae. The case is reported here and the relevant literature is reviewed.
We studied the effects of the protein synthesis inhibitor, cycloheximide (CH), on cell killing by doxorubicin (DOX) in vitro and in vivo. At the concentration of CH used (1 microgram/ml) the cytotoxicity of DOX was reduced in cultured P388 leukemia cells. An analysis of the DNA histogram obtained by flow cytometry showed that DOX exerts its growth-inhibitory effect by blocking the cell cycle at the G2/M phase in P388 cells. Treatment with CH diminished this blocking effect. When CH was added to the growth medium before DOX exposure, no change in intracellular DOX accumulation was observed. Treatment with CH (15 mg/kg) significantly diminished the lethality of DOX (20 mg/kg) in mice and it also reduced the antitumor activity of mice with P388 leukemia. Thus, CH inhibited cell death induced by DOX in vitro and in vivo. These results suggest that CH has an antagonistic effect on the pharmacological actions of DOX in cells and mice. The cytoprotective effect of CH may be due to protein synthesis inhibition.
To identify risk factors for diabetic retinopathy in insulin-dependent diabetes mellitus (IDDM), we studied the relationships among residual beta-cell function, human leukocyte antigen (HLA), long-term glycemic control, and development of diabetic retinopathy in 128 IDDM patients. Residual beta-cell function was assessed by serum C-peptide immunoreactivity (CPR) response to a 100-g oral glucose load (delta CPR). The patients were stratified into three groups: those with delta CPR of < 0.033 nmol/l (group 1, n = 50), those with delta CPR of 0.033-0.1 nmol/l (group 2, n = 38), and those with delta CPR of > 0.1 nmol/l (group 3, n = 40). The cumulative incidence rate of background retinopathy was higher in the order of groups 1, 2, and 3 (P = 0.032). Group 1 progressed to preproliferative retinopathy at an earlier stage than did groups 2 and 3 combined (P = 0.028). Further progression to proliferative retinopathy tended to be earlier in group 1 than in groups 2 and 3 combined (P = 0.083). The mean HbA1c value rose from 9.01 +/- 1.06% (mean +/- SD) in group 3 to 9.75 +/- 0.79% in group 2 to 10.48 +/- 1.12% in group 1 (P < 0.0001). In group 1, 89.6% of the patients had HLA-A24, whereas 50 and 43.6% of the patients had this antigen in groups 2 and 3 respectively (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
In order to identify the inner ear autoantibodies, sera of 195 patients with sensorineural hearing loss and/or vertigo were reached with bovine inner ear antigen by western blotting method. Positive reaction was seen at several molecular weights, in which 33-35 kD, 42 kD and 68 kD were highly reactive. In moderate to severe hearing loss patients, positive reactions with 33-35 kD, 42 kD, 68 kD and others were 25.8%, 26.8%, 26.8% and 71.5% respectively. On the other hand, a positive rate did not clearly correlate with diagnostic entities. Further study to purify inner ear antigen may evaluate inner ear autoimmune disease.
From 1988 to 1993 we treated 1,310 cases of fine needle aspiration cytology of breast lesions. The results were positive for malignancy in 218, suspicious in 134, negative in 857, and inadequate specimen in 101. Histological examinations were performed in 461 cases; 243 malignancies and 218 benign lesions. The cytological diagnosis of these cases was positive in 211, suspicious in 91, negative in 142 and inadequate specimen in 17. The cytologic diagnosis of the cases of histological malignancy was positive in 198, suspicious in 24, negative in 17 and inadequate specimen in 4. Therefore we have 17 false negative cases. The histological diagnoses in these cases were scirrhous carcinoma (7), papillotubular carcinoma (6), invasive lobular carcinoma (2), mucinous carcinoma (1) and angiosarcoma (1). There were 13 cases of cytologically false positive cases; the histological diagnoses were fibroadenoma (4), mastopathy (4), papilloma (3), adenosis (1) and xanthogranuloma (1). For over six years, we have used a computer system incorporating both cytologic and histologic records. This system is very useful in quickly review the correlations of cytologic-histologic diagnoses. In addition to this system, a close relationship between clinical to pathological department is necessary in the quality control of diagnostic cytology.
Chemically-defined neuron groups and their subpopulations in the glomerular layer of the rat main olfactory bulb were revealed immunocytochemically using antibodies against gamma-amino butyric acid (GABA), tyrosine hydroxylase (TH), methionin-enkephalin-Arg6-Gly7-Leu8 (ENK), calretinin (CR), calbindin-D28K (calbindin) and thyrotropin-releasing hormone (TRH). GABA-like immunoreactive (GABA-LIR) neurons and CR immunoreactive (CR-IR) neurons were most numerous; they were about 1.5-3 times more numerous than calbindin immunoreactive (calbindin-IR), TH immunoreactive (TH-IR), ENK-like immunoreactive (ENK-LIR) and THR-like immunoreactive (TRH-LIR) neurons. We identified at least three distinct chemically-defined neuron groups, GABA-LIR neurons, CR containing neurons and calbindin containing neurons, since these three neuron groups were almost separate from one another. On the other hand, TH-IR and ENK-LIR neurons were nearly included in and thus considered to be subpopulations of GABA-LIR and CR-IR neurons, respectively, for about 80% of these two neuron groups contained GABA-L and CR immunoreactivities, respectively. TRH-LIR neurons appeared to be divided into two subpopulations, one containing the GABA-L immunoreactivity and the other containing the CR immunoreactivity. Thus in the glomerular layer of the rat olfactory bulb, GABA-LIR, CR-IR and calbindin-IR cells could be considered to be three distinct chemically-defined neuron groups, whereas TH-IR, TRH-LIR and ENK-LIR neurons were regarded as their subpopulations. Furthermore, some neurons groups, whereas TH-IR, TRH-LIR and ENK-LIR neurons were regarded as their subpopulations. Furthermore, some neurons are supposed to contain three substances (e.g. GABA + TH + TRH, GABA + TRH + EnK, CR + TRH + ENK, GABA + TRH + CR) or a few might even contain four substances (e.g. GABA + TRH + CR + ENK). Preliminary quantitative analysis using the optical disector method showed percentages of these three main neuron groups to total cells in the glomerular layer; that is, neuron groups containing GABA, CR and calbindin were about 20%, 20% and 10%, respectively.
In the incubation of 3-acetylcoumarin in rat liver supernatant fraction (S-9), four metabolites were isolated, and two of which were inseparable diastereomeric mixture as a major product. However, when 3-acetylcoumarin was fermented with baker's yeast (Saccharomyces cerevisiae), only two compounds were obtained as the same as the above mixture. The structures of those metabolites were confirmed by NMR and Mass spectra. However, the above metabolites in rat 9000xg supernatant fraction were not induced by phenobarbital, nor inhibited with SKF-525A at all.
We describe two brothers with early onset cerebellar ataxia associated with hypoalbuminemia (EOCAH). Choreo-athetoid movements preceded the cerebellar ataxia, and serum pseudocholinesterase elevation preceded the hypoalbuminemia. The parents are first cousins. Patient 1, the 22-year-old elder brother, developed choreoathetoid movements of the neck and extremities at the age of eighteen months. He later developed slowly progressive cerebellar ataxia with decreased tendon reflexes. The choreoathetoid movements ceased at about 16 years of age. A recent examination revealed cerebellar ataxia, action myoclonus of the neck and upper limbs, diminished tendon reflexes, mild sensory disturbance in the lower extremities, and very slight amyotrophy of the feet. Patient 2, the 18-year-old younger brother, developed choreo-athetoid movements at the age of 6 years, followed by slowly progressive cerebellar ataxia with disminished tendon reflexes. No scoliosis, ECG abnormalities, or edema was detected. Serum biochemistry studies revealed elevated pseudocholinesterase (6,226 to 2,390 IU) in the patient's early teens. Serum albumin levels tended to be low (3.7 to 4.1 g/dl). Serum triglyceride and beta-lipoprotein levels were elevated in the patients' late teens. Genetic studies showed slight linkage of D9S15. The maximum lod score was 0.289 (recombination fraction rate was 0.14).
Regio- and stereo-selective oxidation of butylbenzene (1) has been examined in vitro by rat liver supernatant fraction(S-9). When phenylbutane (1 ) was incubated at 37 degrees C for 1 hr with S-9, asymmetric oxidation occurred regioselectively at benzylic and omega-1 positions to afford preferentially (R)- and (S)-alcohol (2, 4), respectively. This enzymatic propensity was the case for the production of 1, 3-diols. (1R, 3S)- or (1R, 3R)-Butanediols(3a, 3b) were also obtained at 87% and 27%, respectively. This oxidation was induced by phenobarbital (PB) or beta-napthoflavone(beta-NF), and significant sex-related differences in control and PB pre-treated rats have been observed. Since these oxidations were inhibited with SKF-525A and CO, it was inferred that cytochrome P-450 was responsible for the oxidation.
Diffuse Lewy body disease (DLBD), which we have proposed since 1976, has received great attention among both researchers and clinicians. Recently, it was reported by some English and American research groups that DLBD is the second most frequent dementing illness in the elderly, following Alzheimer-type dementia (ATD). Our recent research of 79 autopsied dementia cases in a hospital disclosed that DLBD (15.4%) was the second most common degenerative dementia, following ATD (43.6%). In 1980 we proposed Lewy body disease, and classified it into three types: brain stem type, transitional type, and diffuse type. Diffuse type of LBD is now called DLBD. In 1990 we divided DLBD into two forms: common form and pure form. The common form of DLBD has more or less Alzheimer pathology, and pure form has none. Very recently, we proposed the cerebral type of LBD, in which numerous Lewy bodies are found in the cerebral cortex and amygdala, but no PD pathology is present in the brain stem. Therefore, LBD is now classified as follows: [table: see text]
Burn death based on circulatory shock is often encountered after recovery from primary shock in patients with deep and extensive burns, i.e., late death. Several toxic substances have been proposed, however, the responsible substance remains obscure. Since we have found leukotoxin, a highly cytotoxic linoleate epoxide biosynthesized by neutrophils, in the burned skin, in the present study we determined plasma leukotoxin concentrations in various degree of 30 burn patients. C-reactive protein and circulatory white blood cells were also measured. A significantly high mortality rate of patients with extensive burns (burn surface area over 70%) was observed compared with that in patients with burn surface area under 70%, and significantly high leukotoxin concentrations were observed within a week, and 3 weeks after the thermal injury in patients with extensive burns compared with those in patients with burn surface area under 70%. There were two peaks of plasma leukotoxin concentrations, i.e., the early phase (within 1 week) and the late phase (over 1 week) in patients with extensive burns. Plasma leukotoxin concentrations significantly correlated with burn surface area in the early phase, and similar correlations were observed in the late phase. A significantly high mortality rate (61%) of patients with peak leukotoxin concentrations over 30 nmol/ml was observed compared with 8% for those below 30 nmol/ml. Plasma leukotoxin concentration correlated significantly to C-reactive protein concentration, log (leukotoxin nmol/ml) = 0.042 x C-reactive protein (mg/dl) + 0.74, (r = 0.83, P < 0.01) in the late phase. From these results, it is concluded that leukotoxin is produced in patients with burns particularly in the late phase of extensive burns, and leukotoxin might play an important role in the tissue destructive procedure associated with severe burns.
The genes for muscarinic acetylcholine receptors, m1 and m2, were studied in autopsied brains from nine Alzheimer's disease, six vascular dementia and three control. The genes were amplified by the polymerase chain reaction and sequenced by the dideoxy method. Although one DNA polymorphism was found in m1, the deduced amino acid sequences of the muscarinic acetylcholine receptor were unchanged. The amino acid sequences of m1 and m2 in Alzheimer's disease and vascular dementia were intact.
We studied a simple tandem repeat DNA polymorphism in the glycogen synthase gene and polymorphisms at codon 513 (Ala-->Pro) and 972 (Gly-->Arg) in the insulin receptor substrate-1 (IRS-1) gene in 197 non-insulin-dependent diabetes mellitus (NIDDM) and 178 control subjects in Japan. Eight alleles (-3G, -2G, -1G, 0G, 1G, 2G, 3G, and 4G) were identified in the tandem repeat polymorphism in the glycogen synthase gene. No difference in the frequencies of these alleles was found between diabetics and controls. The codon 972 polymorphism of IRS-1 gene was observed in 7 diabetics (3.6%) and 8 controls (4.5%), whereas the codon 513 polymorphism was not found in either of the two groups. We conclude that the tandem repeat polymorphism in the glycogen synthase gene and the polymorphisms at codons 513 and 972 of the IRS-1 gene are not associated with a higher risk for the development of NIDDM in Japanese subjects.
It has been believed so far that in the mammalian olfactory bulb, only granule cells form reciprocal synapses with mitral/tufted cells in the external plexiform layer (EPL). However, the present electron microscopic study demonstrated for the first time that another group of immunocytochemically defined interneurons different from granule cells, viz., neurons containing a specific calcium-binding protein parvalbumin, also made reciprocal synapses with mitral/tufted cells in the EPL.
The previous paper reported on the synthesis and pharmacological evaluation of N-(6-amino-3-pyridyl)-N'-bicycloalkyl-N"-cyanoguanidine derivatives, from among which three compounds were selected as potent potassium-channel openers. In the present study, selected compounds were tested for antagonism of potassium-induced contraction of rat aorta, hypotensive activity in normotensive rats, and diuretic activity in spontaneously hypertensive rats. This led to further evaluation of compound (+/-)-10 and selection of (+)-N-(6-amino-3-pyridyl)-N'- [(1S,2R,4R)-bicyclo- [2.2.1]hept-2-yl]-N"-cyanoguanidine ((+)-10) (AL0670) for development as an antihypertensive agent. Although AL0670 is regarded as a pinacidil-type K(+)-channel opener, it showed different pharmacological and conformational profiles from pinacidil.