Biomedical subjects
Publications and source records attributed to N Yamada.
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AIMS: The negative electroretinogram (ERG) is observed in many hereditary retinal disorders. However, no reports have described a negative ERG in a family with autosomal dominant cone-rod dystrophy. A Japanese family with autosomal dominant cone-rod dystrophy with negative ERG is described. METHOD: Members of a Japanese family with autosomal dominant cone-rod dystrophy were examined and evaluated with Goldmann and Humphrey perimetry, bright flash ERG with an intense white stimulus, rod, cone, and flicker ERGs, and fluorescein angiography. Molecular analysis of the rhodopsin and peripherin/RDS genes in the patients was also performed. RESULTS: A 45-year-old Japanese man (proband) presented with decreased visual acuity. His fundi revealed bull's eye maculopathy and his single flash bright ERG showed a negative configuration. Negative ERG responses also were found in his father, who had macular degeneration, and one of the proband's three children who showed no fundus changes. No irregularities were found in their rhodopsin or peripherin/RDS genes. CONCLUSION: The condition of this family is believed to represent a previously undescribed autosomal dominant cone-rod dystrophy.
A survey was conducted on 110 normal Japanese adults (55 men and 55 women) to determine their caloric intake, dietary fat content and its origin (animal, plant, or marine). In addition, their blood lipid levels and fatty acid compositions were examined. Men in their 30s-50s consumed 2,600-2,800 calories and 60 g of fats, while women in the same age range consumed 2,000-2,200 calories and 52-58 g of fats. In both sexes, caloric, fat, and cholesterol intakes were lower for those in their 60s but protein and crude fiber consumption remained generally unchanged. When the dietary fats were classified according to origin, men and women in their 30s were found to consume less oil of marine origin. This appeared to be the result of a western style diet for Japanese adults in their 30s. Compared with men, women exhibited lower blood lipid levels. As age increased, the total cholesterol level of the blood rose in women. Thus the blood lipid level was generally equal in the two groups in their 60s. There was a positive correlation between the blood eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels and dietary consumption of fish oil. The marine/plant lipid ratio was positively correlated with the blood EPA/arachidonic acid ratio. Therefore, it was believed that the origin of the dietary fats consumed is a factor in determining the blood fatty acid profile. The linoleic acid (18:2), arachidonic acid (20:4), and 18:2 + 20:4 contents were negatively correlated to the total cholesterol level in the blood but positively correlated to the HDL-cholesterol level. Polyunsaturated fatty acids (18:2 + 20:4 + 20:5 + 22:6) were negatively correlated with the blood triglyceride level. From the findings presented above, we concluded that dietary fats not derived from animal sources should be classified into fish and vegetable oils to evaluate their dietary significance. We also noted that Japanese in their 30s consume less fish oil, indicating the western trend in their dietary lipid consumption.
A 47-year-old man complained of poor near vision. He had chronic polyneuropathy, bilateral shortening of the proximal phalanges, and ichthyosis. His serum phytanic acid level was merkedly elevated. The fundus and fluorescein angiograms showed diffuse fine granular changes throughout the retina. However, no pigmentary retinal degeneration, vessel attenuation, or disk atrophy was found. The visual field and dark adaptation results were normal. The electroretinogram demonstrated mildly subnormal rod responses with normal implicit times and cone responses within the normal range. The S-cone electroretinogram showed decreased amplitude and normal implicit time. These ophthalmological findings were not consistent with classical retinitis pigmentosa. We believe that this patient may have an uncommon type of adult Refsum's disease.
Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)-BB on the synthesis of LPL by human monocyte-derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte-derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.
A ternary copolymer composed of m-acrylamidophenylboronic acid, N,N-dimethylaminopropylmethacrylamide and N-isopropylacrylamide was synthesized. Long-term culture of bovine aortic endothelial cells on this copolymer substrate demonstrated adhesion and proliferation of the cells. After 26 days in culture, endothelial cells spontaneously developed into capillary networks. The interactions between phenylboronic acid groups in copolymer and glycoconjugates on endothelial cell plasma membranes are proposed to regulate the induction of tissue formation, since phenylboronic acid groups are known to specifically form reversible complexes with cis-diol compounds such as glucose. This copolymer is a novel material capable of mediating specific signals analogous to extracellular matrix to promote proliferation of endothelial cells, inducing capillary structures and prompt angiogenesis.
Apolipoprotein E (apoE) plays a crucial role in lipoprotein metabolism both in plasma and in peripheral tissues. To test whether apoE in the vascular wall has a direct and local effect on atherogenesis, we established transgenic mice expressing human apoE under control of H2 Ld promoter. Studies on mRNA levels and immunohistochemistry demonstrated that this line was characterized by high expression of human apoE in the arterial wall while its expression was relatively low in other tissues as compared with the respective endogenous expression of mouse apoE. They showed no difference in plasma cholesterol levels and lipoprotein profile from controls when fed both normal and atherogenic diets. However, after 24 wk of an atherogenic diet, the formation of fatty streak lesions in proximal aorta was markedly inhibited in transgenic mice as compared with controls. Both lesion area and esterified cholesterol content were < 30% of those in controls. In a tissue cholesterol labeling study with 3H-cholesterol, the specific activity of aorta cholesterol was much less in transgenic mice, suggesting that apoE enhances cholesterol efflux from the aortic wall into plasma. Thus, apoE has anti-atherogenic action which is mediated via enhancing reverse cholesterol transport from arterial wall.
Vascular medial smooth muscle cells migrate, proliferate and transform to foam cells in the process of atherosclerosis. We have reported that the intimal smooth muscle cells express proto-oncogene c-fms, a characteristic gene of monocyte-macrophages, which is not normally expressed in medial smooth muscle cells. In the present study, we demonstrated that combinations of platelet-derived growth factor (PDGF)-BB and either epidermal growth factor (EGF) or fibroblast growth factor (FGF) induced high expression of c-fms in normal human medial smooth muscle cells to the level of intimal smooth muscle cells or monocyte-derived macrophages, whereas c-fms expression by PDGF-BB alone was 1/10 and both EGF and FGF had no independent effect on c-fms expression. By contrast, interferon (IFN)-gamma and macrophage colony-stimulating factor (M-CSF) suppressed the induction of c-fms expression. These results indicate that multiple growth factors and cytokines may play a role in the phenotypic transformation of medial smooth muscle cells to intimal smooth muscle cells in atherosclerotic lesions by altering c-fms expression.
To determine the role of apolipoprotein E (apoE) in diabetic hyperlipidemia, we induced diabetes in transgenic mice overexpressing apoE by intravenous injection of streptozotocin (STZ) and examined plasma lipoprotein metabolism in these mice. In STZ-induced diabetic mice, blood glucose levels were > 19 mmol/l (350 mg/dl) and plasma insulin levels were reduced to < 5 pmol/l (1 microU/ml). The diabetic nontransgenic mice developed hypercholesterolemia (plasma total cholesterol level: 4.55 +/- 1.32 vs. 1.97 +/- 0.13 mmol/l [176 +/- 51 vs. 76 +/- 5 mg/dl]) and hypertriglyceridemia (plasma triglyceride level: 0.82 +/- 0.29 vx. 0.42 +/- 0.11 mmol/l [73 +/- 26 vs. 37 +/- 10 mg/dl]) compared with values before induction of diabetes. In the diabetic nontransgenic mice, enhanced intestinal acylCoA:cholesterol acyltransferase activity was demonstrated, a factor that may contribute to the development of diabetic hyperlipidemia. Induction of apoE remarkably reduced the development of hyperlipidemia in diabetic transgenic mice compared with diabetic nontransgenic mice (plasma cholesterol level: 4.55 +/- 1.32 vs. 3.31 +/- 0.47 mmol/l [176 +/- 51 vs. 128 +/- 18 mg/dl], P < 0.01, and plasma triglyceride level: 0.82 +/- 0.29 vs. 0.17 +/- 0.11 mmol/l [73 +/- 26 vs. 15 +/- 10 mg/dl], P < 0.01). Plasma lipoprotein analysis by gel filtration chromatography showed that the reduction of plasma cholesterol and triglyceride levels was due to the disappearance of lipoproteins containing apoB. In these studies, we demonstrated the usefulness of STZ-induced diabetes in mice as an animal model for diabetic hyperlipidemia and demonstrated that endogenous induction of apoE in transgenic mice improved diabetic hyperlipidemia.
The purpose of this study was to examine whether epithelialisation is promoted when an allogeneic cultured dermal substitute is used as a biological wound dressing. The dermal substitute was prepared by plating fibroblasts on to a spongy collagen matrix, and then culturing them for 7 to 10 days. A new animal wound model was designed to measure re-epithelialisation quantitatively. A full thickness skin defect was made on the dorsum of each of 33 rats; the skin was excised, leaving a layer of pannicular carnosus with an island of intact skin in the central portion of the skin defect. In the first group of rats (n = 13), a piece of cultured dermal substitute was applied to the wound, and a medicated covering material was placed over it. Re-epithelialisation from the island of intact skin was monitored over a period of 7 days. In the second group of rats (n = 10), the wound was covered with an acellular collagen matrix in conjunction with the medicated covering material, and in the third group of rats (n = 10), the wound was covered with the medicated covering material alone. Both the macroscopic and histological findings indicated that the epithelial migration of the first group of rats was far more rapid than that in the other two groups. It comes to the conclusion that the application of this new fibroblastic cultured dermal substitute provided a good environment for the promotion of wound healing.
The clinical features of acute pulmonary embolism were evaluated and compared between Group A with 38 cases > 65 years old and Group B with 73 cases < 65 years old. The mortality rate was 58% (22/38) in Group A and 23% (17/73) in Group B (p < 0.01). However the size of the obstructive pulmonary vascular bed showed no significant difference in both groups. In group A dyspnea was the most common symptom in 27 of 31 (87%), in comparison with group B [45 of 66 (68%), p < 0.05]. In group B, dyspnea and other symptoms appeared abruptly in 44 of 57 (77%), compared with 19 of 36 (53%) in group A (p < 0.02). ECG abnormalities including tachycardia, right bundle branch block and clockwise rotation as well as hypoxemia were present more predominantly in group A. The presentation of pulmonary embolism is variable in the elderly, as in any age group. Many autopsy studies showed a significant rise in incidence of pulmonary embolism in higher age groups. We must keep in mind the characteristics of clinical features in pulmonary embolism in the elderly.
A 67-year-old patient has had exanthema in the lower right limb since 51 years ago (16 years old at onset), which underwent repeated remission and recurrence. At present, he has bilateral symmetrical widespread infiltrating exanthema and asymmetrical marked neuralhypertrophy, and has been diagnosed typical LLs (His father had the same disease). The exanthema recurred several years ago, and the patient is being treated for Hansen's disease. He had a dark brown flat elevation with a rough surface and the size of a small finger tip in his right abdominal skin for approximately 20 years. A biopsy was performed, and the specimen was fixed in 10% formalin and paraffin sections were prepared for histopathologic examination. A part of the specimen was processed forscanning electron microscopic examination. Seborrheic keratosis was diagnosed by H & E staining. Acid-fast (FITE) staining, immunohistochemical staining (keratin, S-100 protein, anti-PGL antibody and anti-BCG antibody) and scanning electron microscopy revealed the presence of bacteria (M. leprae) in the dermal foam cells, the matrix with a banded structure and the squamous epithelial cells which normally lack phagocytosis function. Compared to the basal cells of normal epidermis, the basal cells located adjacent to the dermis affected with seborrheic keratosis showed increased proliferation and more marked characteristics of a germinative cell. The degree of differentiation of the basal cells appeared regressed, and they probably possessed augmented phagocytic activity. The phagocytosed bacteria were probably carried by the epidermal cell cycle toward the surface layer. However, bacteria could not be found in the stratum corneum, probably due to an association with the lysosome.
Apolipoprotein E (apoE) plays an important role in plasma lipoprotein metabolism through its high affinity binding to cell surface low density lipoprotein (LDL) receptor. To determine the role of apoE in plasma lipoprotein metabolism, transgenic mouse lines with integrated rat apoE gene under control of metallothionein promotor were established. The plasma level of rat apoE in homozygotes for the transgene was 17.4 mg/dl after zinc induction. In this group, plasma cholesterol and triglycerides levels were 43%, 68% reduced as compared with controls, respectively. Gel filtration chromatography showed that lipid reduction was mainly due to decreased both very low density lipoproteins (VLDL) and LDL. Furthermore, we studied the effects of apoE on the atherogenic process in Watanabe heritable hyperlipidemic (WHHL) rabbits. We administered 10 mg of purified apoE intravenously into five WHHL rabbits three times a week from their age of 2.5 months to 11 months for 8.5 months. After sustained administration of apoE, we found a significant reduction in the accumulation of cholesterol ester in aortae (1.55 +/- 0.07 mg/g tissue) as compared to control rabbits (4.32 +/- 0.61 mg/g tissue). Thus, apoE plays an important role not only in plasma lipoprotein metabolism but also in atherosclerotic process.
In contrast to Alzheimer's disease, it is unclear whether the MMS (Mini-Mental State) or the RCPM (Raven's Coloured Progressive Matrices) is clinically useful as a mental test battery in patients with Pick's disease, and it has not been fully evaluated whether intelligence of these patients really deteriorate along with the staging of dementia. The present study aimed to make these problems clear. We administered the MMS and the RCPM to 17 cases of Pick's disease, including 7 cases with predominantly frontal lobe atrophy and 10 cases with predominantly temporal lobe atrophy, which were all classified into 3 groups according to the staging of dementia by using the NM scale (New Clinical Scale for Rating of Mental States). We also investigated whether these patients had "Denkfaulheit" (laziness of thinking) and/or "gogi" aphasia (word meaning aphasia), which may affect performances on the mental test batteries. Two cases with predominantly frontal lobe atrophy and 5 cases with predominantly temporal lobe atrophy were assessed by the same examinations several years later. In cases with predominantly frontal lobe atrophy, all the patients presented with "Denkfaulheit". However, the mean RCPM score was normal in the mildly damaged patients, suggesting that their intelligence were relatively preserved. In the moderately and severely damaged groups, their intelligence could not be assessed owing to their severe "Denkfaulheit". In cases with predominantly temporal lobe atrophy, all the patients had "gogi" aphasia and 3 cases of the severely damaged groups presented with "Denkfaulheit".(ABSTRACT TRUNCATED AT 250 WORDS)
We used naming and pointing tests and a proverb completion task to compare two cases of aphasia that exhibited a selective disturbance of word processing. One patient had anomia with word comprehension difficulty due to partial ablation of the left temporal lobe and the other patient had Gogi aphasia due to lobar atrophy with left temporal predominance. We presented 90 pictures of common objects divided into 9 categories in the naming and pointing tests, and used 10 well-known Japanese proverbs as stimuli in the proverb completion task. Performance of the naming and pointing tests was severely impaired in both patients. In the patient with anomia, words the patient could not name or point to varied from session to session and phonemic cue effects were frequently observed. The proverb completion phenomenon was positive. These findings indicate that the patient had an obstruction of the access route to the intact word store or a partial rarefaction of the word store itself. In the patient with Gogi aphasia, the words the patient could not name or point to were consistent from one occasion to another, and no phonemic cue effects or signs of familiarity were observed at all. The proverb completion phenomenon was totally negative. These findings indicate that the patient has lost the word store itself. MR images in the case of anomia revealed a lesion extending from the anterior to the central portion of the inferior part of the left temporal lobe. In the case of Gogi aphasia, the MR images displayed knife-edged focal atrophy in the anterior aspect of both temporal lobes, more prominently on the left.(ABSTRACT TRUNCATED AT 250 WORDS)
We assessed the anatomical findings and auditory comprehension of six patients with transcortical motor aphasia due to medical lesions of the left frontal lobe. All patients were right-handed and were initially mute for several hours after the onset, and they exhibited mild paresis of the right lower extremity. Their spontaneous speech was sparse and not fluent, and sometimes accompanied by echolalia, but their articulation was normal and repetition was excellent. They had difficulty in recalling words. A diagnosis of transcortical motor aphasia was made on the basis of their clinical symptoms. All patients were found to have an infarct in the left medial frontal region by MRI and/or CT. We administered the Western Aphasia Battery and 50 line drawing pointing task in order to evaluate auditory comprehension. Based on the results we concluded that there is no impairment of auditory comprehension of single words when lesions are limited to the superior frontal gyrus, but that lesions extending to the middle frontal gyrus interfere with auditory comprehension of single words. Our observations indicate that the middle frontal gyrus plays an important role in auditory comprehension of single words. All of the patients displayed impaired auditory comprehension of sentences even when their lesions were strictly limited to the medial frontal lobe. This suggests that the medial frontal lobe plays some role in the auditory comprehension of sentences.
MY-1250 (5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano [3,2-c]quinoline-2-carboxylic acid, CAS 63768-47-8), a major metabolite of the antiallergic drug repirinast (MY-5116, CAS 73080-51-0), inhibits antigen-induced histamine release from rat peritoneal mast cells. MY-1250 causes a rapid increase in cyclic adenosine monophosphate (AMP) levels in rat peritoneal mast cells. MY-1250 inhibited cyclic AMP phosphodiesterase activities from rat peritoneal cells and guinea pig lung tissue in a concentration dependent manner with IC50 values of 2000 mumol/l and 1670 mumol/l, respectively. However, MY-1250 showed no effect on adenylate cyclase activity from rat peritoneal cells. These results suggest that the inhibitory effect of MY-1250 on histamine release may be partly due to the inhibition of cyclic AMP phosphodiesterase activity.