[Etiology of stroke--with special reference to cerebral infarction].
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Cerebral Infarction↗
Biomedical subjects
S Konno
Publications and source records attributed to S Konno.
Ocular and extraocular inflammation induced by immunization of tyrosinase related protein 1 and 2 in Lewis rats.
Vogt-Koyanagi-Harada (VKH) disease is an ocular inflammatory disease and is considered to be a cell-mediated, autoimmune disease against melanocytes. To learn more about the mechanisms involved in VKH disease, the identification of the antigens specific to the disease and the development of an animal model are critically important. We have expressed and purified the melanocyte specific proteins, tyrosinase-related protein 1 (TRP1) and 2 (TRP2). Lewis rats developed an ocular and extraocular inflammatory disease 12 days after immunization with TRP1 or TRP2 that was characterized clinically by the infiltration of inflammatory cells and accumulation of massive fibrin in the anterior and posterior chambers of the eye. Histologically, inflammatory cells were found in the anterior and posterior chambers, iris, ciliary body, the choroid, subretinal space and vitreous body. In severe cases, a serous detachment of the retina was observed. In mild cases, focal inflammatory lesions surrounded by normal chorioretinal architecture were observed and the inflammation persisted for more than 42 days after the injection. Some eyes showed accumulation of epithelioid cells in the choroid or the retinal pigment epithelium which were similar to the Dalen-Fuchs nodules found in patients with VKH disease. The alterations of the photoreceptor outer segment and the outer nuclear layer were less severe than in experimental autoimmune uveitis induced by retinal antigens. Extraocular manifestations such as skin lesions and meningitis were also observed. The clinical course and histological findings in these rats resembled the changes in patients with VKH disease.
Animals↗
Methylglyoxal-induced apoptosis in human prostate carcinoma: potential modality for prostate cancer treatment.
OBJECTIVE: To examine the cellular effects of methylglyoxal (MG), a toxic physiological metabolite, on human prostatic cancer PC-3 cells. METHODS: The effects of MG on cell growth and viability were evaluated first, and then its effects on the cell cycle and the glycolytic process were analyzed by Western blots and specific assays. Possible MG-induced apoptosis was also assessed by DNA analysis using agarose gel electrophoresis. RESULTS: MG > or =3 mM caused severe growth inhibition, resulting in nearly 100% cell death by 24h. The time course study revealed that expression of cyclin D(1), cdk2, and cdk4 was significantly (>50%) downregulated in 3 h of MG (3 mM) exposure, followed by the dephosphorylation of retinoblastoma protein by 6 h. Both the glyceraldehyde-3-phosphate dehydrogenase activity and the cellular lactate level were also reduced by approximately 50 and 80%, respectively, following 6-hour MG exposure. Induction of apoptosis by MG was indicated by partial degradation of poly(ADP-ribose) polymerase and further confirmed by discrete DNA fragmentation detected on an agarose gel. CONCLUSION: MG is capable of inducing apoptosis in prostatic cancer PC-3 cells, due primarily to a blocking of the cell cycle progression (G(1) arrest) and glycolytic pathway. Therefore, MG could be a potent apoptosis inducer, which may have a potential for prostate cancer treatment.
Apoptosis↗
Chromium supplementation does not influence glucose metabolism or insulin action in response to cold exposure in mature sheep.
An isotope dilution method using [U-(13)C] glucose infusion and a glucose clamp approach were applied to determine the effects of supplemental Cr and cold exposure on blood glucose turnover rate and tissue responsiveness and sensitivity to insulin in eight sheep. The daily profiles of blood metabolites and hormones were also determined. The sheep consumed diets containing either 0 or 1 mg of Cr/kg from a high-Cr yeast and were exposed from a thermoneutral environment (20 degrees C) to a cold environment (0 to 4 degrees C) for 9 d. The experiment used a crossover design. Body weight was lost (P = 0.02) during cold exposure, regardless of Cr supplementation. Blood glucose turnover rate and the maximal glucose infusion rate did not differ between diets, but both were higher (P = 0.0004 and P = 0.0001, respectively) during cold exposure than in the thermoneutral environment. The plasma insulin concentration at half-maximal glucose infusion rate changed with neither diet nor environment. Plasma concentrations of glucose and NEFA increased (P < 0.05) during cold exposure for both diets. In sheep, Cr supplementation, 1 mg/kg of diet as high-Cr yeast, has little influence on blood glucose metabolism and insulin action, whereas cold exposure enhances both without further modification by Cr supplementation.
Animal Feed↗
Induction of apoptosis in human prostatic cancer cells with beta-glucan (Maitake mushroom polysaccharide).
PURPOSE: To explore more effective treatment for hormone-refractory prostate cancer, we investigated the potential antitumor effect of beta-glucan, a polysaccharide of the Maitake mushroom, on prostatic cancer cells in vitro. MATERIALS AND METHODS: Human prostate cancer PC-3 cells were treated with various concentrations of the highly purified beta-glucan preparation Grifron-D(R) (GD), and viability was determined at 24 h. Lipid peroxidation (LPO) assay and in situ hybridization (ISH) were performed to unravel the antitumor mechanism of GD. RESULTS: A dose-response study showed that almost complete (>95%) cell death was attained in 24 h with GD > or = 480 microg/mL. Combinations of GD in a concentration as low as 30 to 60 microg/mL with 200 microM vitamin C were as effective as GD alone at 480 microg/mL, inducing >90% cytotoxic cell death. Simultaneous use with various anticancer drugs showed little potentiation of their efficacy except for the carmustine/GD combination (approximately 90% reduction in cell viability). The significantly (twofold) elevated LPO level and positive ISH staining of GD-treated cells indicated oxidative membrane damage resulting in apoptotic cell death. CONCLUSION: A bioactive beta-glucan from the Maitake mushroom has a cytotoxic effect, presumably through oxidative stress, on prostatic cancer cells in vitro, leading to apoptosis. Potentiation of GD action by vitamin C and the chemosensitizing effect of GD on carmustine may also have clinical implications. Therefore, this unique mushroom polysaccharide may have great a potential as an alternative therapeutic modality for prostate cancer.
Agaricales↗
Adverse effects of oxidative stress on renal cells and its prevention by antioxidants.
BACKGROUND AND PURPOSE: Recent reports suggest that reactive oxygen species; e.g., hydrogen peroxide (H(2)O(2)), could be the primary cause of various drug-induced renal injuries. We investigated the effects of H(2)O(2) on renal cells to understand its mode of action and to explore cytoprotection from such a fatal injury. MATERIALS AND METHODS: Renal proximal tubular LLC-PK(1) cells were exposed to various concentrations of H(2)O(2), and cell viability was determined at specified times. Lipid peroxidation assay and Western blot analysis of heat shock proteins (Hsp70 and Hsp90) were performed to assess the cellular effects. RESULTS: The dose-response study showed that H(2)O(2) > or = 100 microM was severely cytotoxic. Even a 1-h exposure was sufficient to induce >95% cell death in 24 h. Lipid peroxidation was significantly (>50%) increased, while Hsp90, but not Hsp70, was partially degraded, to an approximately 85-kDa fragment, after a 3-h H(2)O(2) exposure. However, such cytotoxic cell death was remarkably ( approximately 90%) prevented by the antioxidants pyruvate or N-acetylcysteine (NAC), and Hsp90 remained intact. CONCLUSION: Hydrogen peroxide-induced renal cell death involves increased lipid peroxidation and partial degradation of Hsp90. Both pyruvate and NAC are capable of detoxifying H(2)O(2) to maintain cell viability and Hsp90 integrity. Acute renal injuries associated with oxidative stress might preventable by appropriate antioxidants.
Acetylcysteine↗
Presence and distribution of antigen-antibody complexes in the herniated nucleus pulposus.
STUDY DESIGN: Herniated tissue was studied by immunohistochemistry in eight patients with lumbar disc herniation. The results were compared with those of control subjects. OBJECTIVE: To assess the presence and distribution of possible antigen-antibody complexes in herniated disc tissue. SUMMARY OF BACKGROUND DATA: It has been suggested that the nucleus pulposus may be recognized as a foreign-body by the immune system and that this will lead to secondary nerve root disturbance. Such immunologic events should be initiated by binding of antibodies to a specific antigen in the disc tissue. However, the presence of antigen-antibody complexes in the herniated disc tissue has not been assessed. METHODS: Amplification of the peroxidase reaction produced in avidin-biotin-peroxidase complex immunostaining by diaminobenzidine was used to visualize antigen-antibody complexes in the herniated tissue. The authors used herniated tissue from eight patients with lumbar disc herniation and nucleus pulposus from five control subjects with nonlumbar disc herniation. Thin paraffin sections, prefixed in 4% paraformaldehyde, were incubated with anti-human IgG antibody to allow visualization of antigen-antibody complexes in the specimens. RESULTS: A brown deposit, indicating antigen-antibody complexes, could be observed in the pericellular capsule in herniated disc tissue but not in control discs or in the residual discs of the herniation patients. CONCLUSION: Antigen-antibody complexes seem to be commonly present in herniated disc tissue, but not in healthy discs. However, the pathophysiologic and clinical significance of this observation has to be elucidated further.
Adult↗
Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia.
OBJECTIVES: Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risk factors accelerating subtle cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions and cognitive testing among neurologically and cognitively normative ageing volunteers. METHODS: Two hundred and twenty-four normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59. 5+/-15.8 years. Mean follow-up is 4.3+/-3.1 years. At follow-up, 22 developed subtle cognitive decline (deltaCCSE>/=-3), 19 became demented, eight with vascular type (VAD) and 11 with Alzheimer's type (DAT) and 183 remain cognitively unchanged. Standardized questionnaires, medical, neuropsychological, neurological and blood work examinations were obtained. Cerebral atrophy, tissue densities and perfusions were measured by xenon-enhanced CT. RESULTS: After age 60, cerebral atrophy, ventricular enlargement, polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis and leuko-araiosis (thinning of grey-white matter densities) were: transient ischaemic attacks (TIAs), hypertension, smoking, hyperlipidemia, male gender. At age 71.5+/-11.9, subtle cognitive decline began, accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension and hyperlipidemia correlated with VAD. Excessive cortical perfusional decreases and cerebral atrophy correlated with cognitive decline. Family history of neurodegenerative disease correlated with DAT. CONCLUSION: TIAs, hypertension, hyperlipidemia, smoking and male gender accelerate cerebral degenerative changes, cognitive decline and dementia.
Adult↗
Ammonium-chloride-induced prostatic hypertrophy in vitro: urinary ammonia as a potential risk factor for benign prostatic hyperplasia.
To test the possibility that urinary ammonia could be a risk factor for benign prostatic hyperplasia (BPH), we explored the cellular effects of ammonium chloride (NH(4)Cl) on prostatic cancer cells used as an experimental model. Following treatment of human prostatic cancer DU-145 cells with the varying concentrations of NH(4)Cl for 3 days, cell growth was inhibited by approximately 50% at 5 mM NH(4)Cl and almost completely inhibited at 10 mM NH(4)Cl. However, the individual cell size in these treated cells became approximately 2-fold larger and cellular protein content was also up to 2.5-fold greater than in untreated cells. This protein increase appeared to result from the reduced protein degradation, verified by metabolic labeling with [(14)C]valine. Western blot analysis further suggested that such reduced protein turnover could in part be due to the inactivation of a lysosomal acid protease, cathepsin D. Taken together, these studies demonstrate NH(4)Cl-induced hypertrophy in prostatic cancer cells, as evidenced by the growth inhibition, cell enlargement, and cellular protein increase. Therefore, ammonia is not an inert metabolic product; instead, its chronic effects on the prostate may ultimately lead to significant cellular and biochemical alterations of the prostate such as BPH.
Ammonia↗
Retinal detachment associated with a macular hole in severely myopic eyes.
PURPOSE: To investigate factors associated with extensive retinal detachment in severely myopic eyes with a macular hole. METHOD: Fifty-two consecutive eyes with a macular hole and severe myopia were retrospectively studied. RESULTS: An extensive retinal detachment, defined as extending beyond the cuff of subretinal fluid, was observed in 37 eyes (71%). Extensive retinal detachment developed in 36 (95%) of 38 eyes with a posterior staphyloma and in one (7%) of 14 eyes without a posterior staphyloma (P<.0001). Extensive retinal detachment also developed in 32 (89%) of 36 eyes with complete posterior vitreous detachment and in five (31%) of 16 eyes without posterior vitreous detachment (P<.0001). CONCLUSION: Posterior staphyloma rather than anteroposterior vitreomacular traction may contribute to the development of retinal detachment associated with a macular hole in severely myopic eyes.
Adult↗
Brefeldin A-induced apoptosis in prostatic cancer DU-145 cells: a possible p53-independent death pathway.
OBJECTIVE: To investigate the growth inhibitory mechanism of brefeldin A (BFA), an antiviral antibiotic, in androgen-independent prostatic cancer DU-145 cells. MATERIALS AND METHODS: The inhibitory effects of BFA (30 ng/mL) on cell growth were monitored by cell counting and viability tests after specified exposures. Flow cytometry and western immunoblot analysis were performed to examine the effects of BFA on the cell cycle and on specific growth regulators. The possible induction of apoptosis by BFA was further assessed by in situ hybridization (ISH) assay and by qualitative DNA analysis using agarose-gel electrophoresis. RESULTS: Cell growth was completely inhibited with BFA (30 ng/mL), accompanied by 40-50% cell death. Cell cycle analysis revealed that this growth inhibition coincided with an 85% reduction in the S-phase cell population. Western blots showed that the expression of cell cycle-dependent kinases (cdk2 and cdk4), cyclin D1 and p53 was significantly reduced, while WAF1 was increased, after BFA treatment. Apoptosis was confirmed by both the ISH assay, which showed the characteristic brownish staining of BFA-treated cells, and by DNA analysis, which revealed the internucleosomal DNA ladder. CONCLUSION: BFA-induced growth inhibition in DU-145 cells is primarily due to the modulation of specific G1 cell-cycle regulators, blocking the G1-S phase progression. Such a growth arrest ultimately results in apoptosis, presumably through a p53-independent pathway.
Antiviral Agents↗
Transformed migraine is a cause of chronic daily headaches.
Chronic daily headaches (CDH) consist of episodes of head pain occurring daily; more than 15 days each month; often associated with a history of migraine, with or without aura; or with a history of tension-type headaches occurring alone or both occurring together. Chronic daily headaches are frequently associated with rebound headaches after ergotamine, barbiturate, caffeine, and analgesic abuse. We previously reported that migraineurs with typical intermittent headaches exhibited excessive cerebral cortical vasodilation after oral acetazolamide which usually precipitated and reproduced their typical headaches. In the present study, cerebral vasodilator responses were tested by measuring changes in local cerebral blood flow (Delta LCBF) utilizing xenon-contrasted CT scanning, before and after oral administration of 14.3 mg/kg of acetazolamide, in 11 patients with CDH. The results were compared with 12 age-matched typical migraineurs, with and without aura, who had a history of migraine attacks occurring at intervals of 1 month or longer. Global and subcortical gray and white matter Delta LCBFs were quantitated and compared between both groups. After acetazolamide, Delta LCBF increased in cortical gray matter by 11.8% among patients with CDH and by 16.7% among migraineurs, with no significant differences between groups. Typical migraine attacks were provoked by acetazolamide in 9 patients (82%) with CDH and in 11 (92%) migraineurs with intermittent headaches. These observations are taken as evidence that at least 82% of patients with CDH have transformed migraine as judged by the provocation by acetazolamide of typical migraine attacks associated with excessive Delta LCBF increases. Serotonin agonists should be considered in the treatment of CDH to avoid ergotamine, caffeine, barbiturate, and analgesic abuse.
Acetazolamide↗
Relapsing polychondritis diagnosed by Tc-99m MDP bone scintigraphy.
PURPOSE: Relapsing polychondritis is a generalized recurring disease of cartilage that involves joints, trachea, bronchi, laryngeal cartilages, costal cartilages, and cartilages of the ear and nose. It is associated with autoimmune diseases, including Hashimoto disease in some cases. METHODS: The authors evaluated a 29-year-old man with relapsing polychondritis who had symptoms and signs of a common cold for 2 months and anterior chest pain near the sternum for 1 month. RESULTS: After the diagnosis, the authors found that the patient had a history of thyroid therapy for hyperthyroidism 15 years before. Tc-99m MDP bone scintigraphy performed to evaluate anterior chest pain showed diffusely increased accumulation of radioactivity in all costocartilages and sternoclavicular joints. Based on that information, relapsing polychondritis was diagnosed. Ga-67 citrate scintigraphy was preformed to determine the optimum biopsy site of the cartilage. The diagnosis was histologically supported by the results of the open biopsy. CONCLUSIONS: In this case, Tc-99m MDP bone scintigraphy was useful for diagnosing relapsing polychondritis, and Ga-67 citrate scintigraphy was helpful in determining the biopsy site.
Adult↗
Nucleus pulposus-induced nerve root injury: relationship between blood flow and motor nerve conduction velocity.
OBJECTIVE: It is well known that nucleus pulposus induces nerve root injury. The aim of this study was to assess the relationship between intraneural blood flow and motor nerve conduction velocity (NCV) after incision of the adjacent disc. METHODS: A total of 65 dogs were used. A left hemilaminotomy was performed, the annulus fibrosus of the L6-L7 intervertebral disc was incised, and nucleus pulposus was gently pushed into the epidural space by saline solution injection. A left hemilaminotomy without disc incision was used as the sham operation. Seven dogs were used for incision and five dogs for sham treatment for each of the following time points: 1 day, 3 days, 1 week, 1 month, and 2 months of exposure. Five additional dogs were used to establish baseline data. Blood flow in the nerve root was measured in the left L7 nerve root with a tissue blood flowmeter, using an electrolytic hydrogen clearance method. Motor NCV over the exposed area of the nerve root was measured using a neurophysiological technique. RESULTS: There was a reduction in blood flow in the nerve root after disc incision that began after 1 day and was maximal after 1 week. This reduction had resolved by 1 month, however. The motor NCV showed a reduction pattern similar to that for blood flow in the nerve root, but reduction did not begin until 3 days after disc incision and was not fully resolved until 2 months. CONCLUSION: This study demonstrates that the reduction and recovery of motor NCV are related to, and preceded by, a reduction in blood flow in the nerve root. The data might provide important information regarding the basic pathophysiological mechanisms of nucleus pulposus-induced nerve root injury.
Animals↗
Diversity of response of optic nerve head circulation to timolol maleate in gel-forming solution.
PURPOSE: This randomized, double-masked, placebo-controlled, two-period crossover study was conducted to investigate the effects of 0.5% timolol maleate in gel-forming solution on intraocular pressure (IOP) and blood circulation in the optic nerve head in patients with untreated ocular hypertension. METHODS: The effects of 0.5% timolol in gel-forming solution on IOP and optic nerve head capillary blood speed were studied in 12 patients with untreated ocular hypertension. Optic nerve capillary blood speed was measured using the laser Doppler technique before and at the end of each treatment period. RESULTS: In each patient, IOP decreased after treatment with timolol (mean decrease 16.8% versus placebo). Systemic blood pressure and pulse rate did not differ significantly after treatment with topical timolol from values after placebo. The mean change from baseline in Doppler broadening was 10.6% greater after treatment with timolol than after placebo. There was no significant change in mean Doppler broadening from baseline after treatment with either timolol or placebo. However, optic nerve head capillary blood speed increased in six patients, and was within the range of placebo response in six patients after treatment with timolol. Spearman correlation analysis of the baseline with Doppler broadening measurements after treatment showed a correlation for placebo but not for timolol. The percent change in Doppler broadening after timolol treatment was correlated with iris color. CONCLUSION: These results indicate that administration of timolol for 4 weeks reduces IOP in patients with ocular hypertension and generally does not change the blood circulation in the optic nerve head. Individual patients, however, showed variable changes in optic nerve head circulation after topical administration of timolol. Although the sample size was small, these changes in optic nerve head circulation were correlated with iris color.
Adrenergic beta-Antagonists↗
[Effect of topical levobunolol on retinal, optic nerve head, and choroidal circulation in normal volunteers].
PURPOSE: Using three different techniques of ocular blood flow measurement, we evaluated the effects of topical levobunolol on retinal, optic nerve head, and choroidal circulation. METHODS: Twenty normal volunteers received one drop of levobunolol in one eye and one drop of placebo in the fellow eye. Retinal venous blood flow was measured using multiple scattering laser velocimetry. Retinal capillary blood flow and optic nerve head blood flow were measured by Heidelberg Retina Flowmeter. Pulsatile ocular blood flow was measured by ocular blood flow tonography. Changes in blood pressure, heart rate, retinal venous blood flow, retinal capillary blood flow, optic nerve head blood flow, intraocular pressure and pulsatile ocular blood flow were detected from measurements taken at baseline and at 90 to 120 minutes following the instillation. RESULTS: Intraocular pressure decreased significantly in both eyes. Retinal capillary blood flow increased significantly in both eyes. Optic nerve head blood flow increased significantly in treated eyes but remained unchanged in placebo eyes. There were no significant changes in retinal venous blood flow or pulsatile ocular blood flow in either eyes. CONCLUSION: Our results suggest that one administration of levobunolol may increase the retinal and optic nerve circulation but does not decrease the choroidal circulation.
Administration, Topical↗
Mechanism of Brefeldin A-Induced Growth Inhibition and Cell Death in Human Prostatic Carcinoma Cells.
The mechanism of growth inhibition and triggering of cell death by the antibiotic brefeldin A (BFA) was investigated in human prostatic cancer DU-145 cells. After cells were cultured with various concentrations of BFA, cell number and viability were determined at specified times. Compared with untreated cells, a drastic growth reduction (>80%) with approximately 50% cell death was observed in the cells cultured with BFA (30 ng/mL) for 72 h. Cell-cycle analysis using flow cytometry revealed that such growth inhibition was associated with approximately 85% reduction in the S-phase population, indicating the inhibition of the G(1)-S phase progression. Western blots further showed that cell-cycle-dependent kinases (cdk2 and cdk4), cyclin D(1), and p53 were all downregulated, whereas WAF1 (p21) was upregulated with BFA treatment. Possible induction of apoptosis by BFA was also assessed by TUNEL assay and by DNA analysis using agarose gel electrophoresis. The TUNEL assay demonstrated the positive staining of BFA-treated cells, and gel electrophoresis confirmed nucleosomal DNA ladder formation. Thus, these results suggest that growth inhibition of DU-145 cells by BFA is attributable mainly to a G1 cell-cycle arrest through the modulation of specific cell-cycle regulators. The accompanying cell death may follow a p53-independent apoptotic pathway.
Journal Article↗
Differential Glycosylation of Cellular Prostate Specific Antigen and the Regulatory Mechanism of Its Secretion.
Although serum prostate specific antigen (PSA), derived from cellular PSA through secretion, is widely used as a marker for prostate cancer (CAP), the exact regulatory mechanism of its secretion is not fully understood. To explore the regulation of serum PSA concentration, we examined whether the glycosylation state of cellular PSA might be associated with its secretion, thus determining its serum concentration. Blood and prostate tissue specimens were obtained from patients undergoing radical prostatectomy. Following preparation of cell extracts by tissue homogenization, the concentrations of serum and cellular PSA were determined using the Tandem-E PSA kit. The extent of cellular PSA glycosylation was then assessed by Western blot and affinoblott analyses. Neither serum nor cellular PSA concentrations correlated with the Gleason scores. Similarly, no direct relation between serum and cellular PSA levels was observed. However, the Western blots showed that the cellular PSA proteins were converted to the deglycosylated forms with glycosidase treatment, indicating differential glycosylation of cellular PSA. Affinoblotting further revealed that the various amounts of PSA glycosylation were associated wtih the serum PSA levels, with an inverse correlation between serum PSA and cellular PSA glycosylation: the greater the PSA glycosylation, the lower the serum PSA, and vice versa. The present study demonstrates that cellular PSAs in CAP specimens are differentially glycosylated and that such difference correlates well with the serum PSA concentration. Therefore, the concentrations of serum PSA appear to depend in part on a selective secretion of cellular PSA, which could be regulated primarily by its glycosylation state.
Journal Article↗