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M Wakakura

Publications and source records attributed to M Wakakura.

At least 19 recordsLinked to original sources
PubMed1998

Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy.

PURPOSE: To investigate the incidence and clinical significance of primary or proposed secondary mitochondrial DNA (mtDNA) mutations in Japanese patients with Leber's hereditary optic neuropathy (LHON). METHODS: Blood samples from the 80 unrelated Japanese patients with bilateral optic atrophy were screened for primary LHON mutations. Patients found to have a primary LHON mutation were then tested for 9 proposed secondary LHON mutations. We investigated the association between these mutations and clinical characteristics. RESULTS: Primary mtDNA mutations were identified in 68 patients: at np 3460 in 3 (4%) of 68 patients, at np 11,778 in 59 patients (87%), and at np 14,484 in 6 patients (9%). We identified 5 secondary mtDNA mutations (at np 3394, 4216, 7444, 9438 or 13,708) in 10 (15%) of 68 LHON patients and 3 mutations (at np 3394, 4216 or 3708) in 6 (7%) of 90 healthy Japanese individuals. No patient was positive for more than one secondary mutation. The frequency of secondary mutations was similar in the 68 LHON patients and 90 controls. The clinical features of the Japanese patients with any of the 3 primary LHON mutations were similar to those of Caucasian patients, despite different mtDNA backgrounds in these populations. The percentage of patients with familial LHON harboring the 3460 or 14,484 mutations was lower in the Japanese population. CONCLUSIONS: Japanese patients with LHON exhibited a very high incidence (87%) of the 11,778 primary mutation. Most of the proposed secondary LHON mutations were rare in the Japanese population and they, except the 7444 mutation, may not influence the clinical features of LHON.

Adolescent↗
PubMed1998

[Orbital and stomach metastasis from invasive lobular breast carcinoma].

Orbital or ocular metastatic tumors may originate from breast cancer. Few studies have been made regarding their histopathological classification. A 71-year-old female noted a tumor in the right orbital region. She had had bilateral breast cancer 2 years before and gastric cancer 5 months before. Histopathology had shown stage II invasive ductal cancer (scirrhus) in the right breast and stage III invasive lobular cancer in the left. Signet-ring cells were present in the breast and gastric cancers. Biopsy of the right lower eyelid showed poorly differentiated adenocarcinoma with signet-ring cells. Indian file pattern, which is specific for invasive lobular cancer, was also present, suggesting that the orbital tumor had metastatized from the left breast cancer. Genetic analysis of the gastric cancer using polymerase chain reaction showed a mutation at exon 8 of the p53 tumor suppressor gene, indicating the cancer to be metastatic. These results led to the conclusion that invasive lobular cancer of the left breast was the primary lesion for the gastric and orbital metastases. This case also illustrates that signet-ring cells, which are usually seen in gastric cancer, may be present in invasive lobular breast cancer and in orbital metastasis.

Aged↗
PubMed1997

[Central serous chorioretinopathy induced by corticosteroids].

Five patients were diagnosed as having central serous chorioretinopathy (CSC) during systemic corticosteroid treatment based on medical records and fluorescein angiography. Twenty-eight previously reported corticosteroid-induced CSC cases in addition to these 5 were examined to clarify clinical differences between idiopathic CSC and corticosteroid-induced CSC. Nine previously reported cases of corticosteroid-induced multifocal posterior pigment epitheliopathy (MPPE) were also reviewed. The corticosteroid-induced CSC patients were older and less male-dominant. In MPPE, bilateral involvement was noted in most cases and females were dominant. We found two patient groups; in the short latency group, the onset of CSC occurred within 70 days of corticosteroid administration and in the prolonged latency group, more than 6 months after. The daily dose of prednisolone for the former usually exceeded 20 mg/day, in contrast to the latter, at less than 20 mg/day. Immunosuppressive drugs such as cyclophosphamide made it possible to diminish the onset daily dose.

Adrenal Cortex Hormones↗
PubMed1997

High incidence of visual recovery among four Japanese patients with Leber's hereditary optic neuropathy with the 14484 mutation.

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA) is a genetic mutation associated with Leber's hereditary optic neuropathy (LHON) in Caucasian patients who show a high incidence of visual recovery. We evaluated four Japanese patients with LHON associated with the 14484 mutation who were negative for eight proposed secondary mutations. There was no family history of optic atrophy in three of the four patients. All four patients were initially diagnosed as having optic neuritis, either anterior (Cases 1 and 3) or retrobulbar (Cases 2 and 4), based upon their fundus findings and clinical history. Molecular genetic testing of mtDNA confirmed the diagnosis of LHON in all four patients. The three patients who experienced recovery had their vision return to 20/50 or better in both eyes. The patient who did not was a heavy consumer of alcohol and tobacco. These findings indicate that Japanese patients with the 14484 mutation have a visual prognosis similar to that of Caucasians with this mutation.

Adolescent↗
PubMed1996

[Application of oculokinetic perimetry in examination of the eye].

Oculokinetic perimetry was performed using the same protocol at four health screening facilities to determine its usefulness for identifying visual field abnormalities including glaucoma during complete physical screenings in Japan. Ophthalmoscopy of the optic disc, 26-point oculokinetic perimetry (OKP), and applanation tonometry were performed in 2,768 eyes. If any one of the tests yielded an abnormal result, the eye was then examined with a Humphrey visual field analyzer (HVFA, program 30-2). After the tests were completed, the results were evaluated by ophthalmologists for evidence of primary open-angle glaucoma and normal tension glaucoma and were classified into one of 3 groups: confirmed glaucoma, suspected glaucoma, and no glaucoma. OKP detected abnormalities in the visual field in 96 eyes (3.5%). Of these 96 eyes, 29 eyes had confirmed glaucoma, 52 eyes were suspected of having glaucoma and 15 eyes had no glaucoma. The remaining 15 eyes had no glaucoma, but in 7 of them other ophthalmological disease was diagnosed. The sensitivity, specificity, positive predictive value, and negative predictive value of OKP for detecting glaucomatous visual field defect were 0.46, 0.99, 0.84 and 0.96, respectively. The high specificity and negative predictive value show that OKP is unlikely to produce false positive results, but its low sensitivity suggests that it is not suitable for the early detection of glaucoma. However, OKP identified advanced glaucoma and other ophthalmological diseases associated with visual field abnormalities, suggesting that it is a useful screening test.

Adult↗
PubMed1996

[Analysis of mutations and heteroplasmy at mitochondrial DNA 11778 using non-RI single strand conformation polymorphisms in Leber's hereditary optic neuropathy].

Leber's hereditary optic neuropathy(LHON) is a maternally inherited mitochondrial disease of an acute or subacute bilateral loss of central vision. G to A substitutions at nucleotide position 11778 in mitochondrial DNA(mt DNA) have been identified in approximately 40% to 90% of patients. In this study, regions containing mt DNA 11778 mutations were analyzed by polymerase chain reaction(PCR), non-RI single strand conformation polymorphisms(SSCP) and direct sequencing. In 26 visually affected patients, mt DNA 11778 mutations were detected in 9 patients (36.4%). In one pedigree of a LHON patient(L-6), four unaffected family members had heteroplasmy of the 11778 mutation using non-RI SSCP. Ratios of the heteroplasmy between wild type and mutant mt DNAs can be detected in non-RI SSCP and accurately quantified by video densitometric analyzer. Two types of novel polymorphisms, 11696 G to A and 11719 A to G, in the mt DNA region were also found in this non-RI SSCP analysis. Non-RI SSCP is an efficient and accurate method for diagnosis of mt DNA 11778 mutations and quantifying heteroplasmy in patients with LHON and pedigrees.

Base Sequence↗
PubMed1996

Possible roles of AMPA/KA receptor in cultured Müller cells.

In order to identify the function of the AMPA/KA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate) receptor in cultured Müller cells, we studied the difference in the affinity of this receptor for cultured Müller cells and retinal neurons (neurons), comparing these to the characteristics of cultured Müller cells exposed to kainate (KA), a neurotoxic amino acid. The difference in the cellular responses of Müller cells and neurons to AMPA was evaluated by measuring the rapid change in intracellular calcium ions. Results showed that neurons were more sensitive to AMPA than Müller cells; the percentage of cells responding to AMPA was always higher for neurons. When Müller cells were exposed to 0.5 mM KA, the morphology of the cells was not affected and the concentration of lactate dehydrogenase in the culture solution did not increase. However, the percentage of cells responding to a high concentration of AMPA was higher in the Müller cells exposed to KA than in those not exposed. These findings indicated that the affinity of the AMPA receptor was lower in Müller cells than in neurons, and that Müller cells were resistant to neurotoxic amino acids. It was also suggested that when an extremely large amount of neurotoxic amino acid was released into the retina as a result of ischemia, Müller cells actively protected the neurons.

Animals↗
PubMed1995

Leber's hereditary optic neuropathy among Japanese.

This article reviews the literature on point mutation of mitochondrial DNA (mtDNA) among Japanese and the authors' research data on pupil reaction in patients with Leber's hereditary optic neuropathy (LHON). Among Japanese, a higher frequency (80-90%) of point mutation at nucleotide position 11778 of mtDNA was found; other point mutations found were at nucleotide positions 3460, 14484, 13708, 7444, and 3394. Although pupil reaction to light stimulus is usually defective in all types of optic neuropathy, in patients with LHON the reaction was well maintained even when vision was reduced. W cells in the retina may be preserved or less damaged, even when the degenerative process progresses in both X and Y cells. Possible treatment is also described.

Adult↗
PubMed1995

Evidence for preserved direct pupillary light response in Leber's hereditary optic neuropathy.

AIMS/BACKGROUND: Pupillary light response is usually defective in all types of optic neuropathy. However, the authors have observed in patients with Leber's hereditary optic neuropathy (LHON) relatively normal light response, with consequent misdiagnosis psychogenic visual loss in some cases. To confirm this clinical impression, afferent pupillary defect was assessed by measurement of adjusted constriction amplitude (CA) and escape rate (ER) by infrared videopupillography (Iriscorder-C 2515). METHODS: Thirteen consecutive patients (26 eyes) with LHON (average age 27.2 years) were examined; 12 had the mitochondrial DNA 11778 mutation and one the 14484 mutation. Seven of these patients had a positive family history. For comparison, the above rates were determined in 19 patients (23 eyes) with idiopathic optic neuritis (ON; average age 35.1 years), 18 patients (19 eyes) with anterior ischaemic optic neuropathy (AION; average age 58.1 years), and 25 volunteers (50 eyes) with healthy eyes (average age 39.6 years). RESULTS: The distribution of visual acuity was essentially the same in all optic neuropathy groups. Reduction in CA and increase in ER were significant in patients with ON and AION, but not in those with LHON. Only slight afferent pupillary defect was evident even 2 years after the onset of LHON. CA in AION and ER in ON were correlated statistically with visual acuity and Humphrey mean threshold deviation, while CA and ER in LHON were not. CONCLUSION: Pupillary light response in patients with LHON obviously differs from that in patients with other types of optic neuropathy. LHON appears to be pathophysiologically characterised by well preserved afferent fibres for pupillary light response (probably from W cells). Besides being of pathogenetic interest, the detection of clinical features should facilitate the diagnosis of LHON particularly when family history provides no indication.

Adult↗
PubMed1995

Quantitative determination of heteroplasmy in Leber's hereditary optic neuropathy by single-strand conformation polymorphism.

PURPOSE: The maternal inheritance of Leber's hereditary optic neuropathy (LHON) is caused by defects in the genes of mitochondrial DNA (mtDNA). The most prevalent mtDNA mutation, present in 40% to 90% of families with this disease, is a G to A substitution at nucleotide position 11778. The rapid and accurate quantification of heteroplasmy of this mutation will help determine the relative risk for disease expression. METHODS: The authors conducted screening tests for heteroplasmy in 44 visually affected patients with the 11778 mutation and 34 unaffected members of 36 Japanese families with LHON using the single-strand conformation polymorphism analysis. This method can detect even a single base difference between the sequences of wild type and mutant DNA strands. The percentage of mutant mtDNA was calculated using an image analyzer. RESULTS: Single-strand conformation polymorphism analysis allowed the detection of heteroplasmy ranging from 5% to 95%. Five (14%) of the 36 families showed heteroplasmy, and 14 (18%) of the 78 persons tested had heteroplasmy ranging from 10% to 94%. Seven patients with heteroplasmy with visual loss had mutant mtDNA ranging from 62% to 94%. CONCLUSIONS: Single-strand conformation polymorphism analysis is rapid, efficient, and accurate for detecting point mutations and quantifying heteroplasmy in mtDNA. Individuals with heteroplasmy with less than 60% of mutant mtDNA in circulating leukocytes are probably at lesser risk for developing optic atrophy.

Adult↗
PubMed1995

[Incidence of acute idiopathic optic neuritis and its therapy in Japan. Optic Neuritis Treatment Trial Multicenter Cooperative Research Group (ONMRG)].

Data on the incidence of and treatment for acute idiopathic optic neuritis were obtained by questionnaire sent to departments of ophthalmology, university hospitals, and general hospitals throughout Japan. Inquiry was made as to the number of cases which developed idiopathic optic neuritis from April 1992 to March 1993 along with their clinical features. The response rate was 53.6%. There were a total of 550 cases, and the male to female ratio was 1:1.22. Patients 14 to 55 years old were 65.9%; bilateral involvement: 28.2%; recurrence: 18.6%; positive past history of the other eye; 7.5%. Assuming the answering rate to be 100% and two thirds of the patients to be included, annual incidence of this disease (the annual number of patients) was determined to be 1.62 for an adult population of 100,000 (1.03 cases/100,000 people). Tochigi, Tokyo, Kanagawa, Hyogo, Wakayama, Okayama, Yamaguchi, Tottori, Shimane, Ehime, and Fukuoka showed an annual incidence exceeding 2.0/100,000 adults. At more than 95% of all medical institutions questioned, patients with optic neuritis were usually treated with systemic corticosteroids. Oral corticosteroid therapy, which was shown in a recent study in USA to be contraindicated, was still being used at 15% of the institutions.

Acute Disease↗
PubMed1995

[Possible role of the AMPA/KA receptors in cultured Müller cells].

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)/KA (kainate) receptors have been demonstrated in cultured Müller cells in a study on cytosolic free calcium ions ([Ca2+]i). The action of these receptors may be expressed under pathological rather than physiological conditions. 1. Critical concentration in response to AMPA was determined in retinal neurons and Müller cells. At 0.05mM AMPA, in all neurons and in only a limited number of Müller cells (20%) cytosolic calcium transients occurred. 2. The level of lactate dehydrogenase (LDH) and the change in [Ca2+]i following AMPA administration were measured before and after exposure to 0.5mM KA. Neither morphological change nor leakage of LDH could be detected after 24 hours. When AMPA was administered, the responsive cell number was higher for KA-exposed cells than for control cells. Müller cells may be concluded to resist neurotoxic agents and may possibly be involved in the survival mechanism of retinal neurons.

Animals↗
PubMed1994

Cytosolic calcium transient increase through the AMPA/kainate receptor in cultured Müller cells.

The intracellular concentration of free calcium ions ([Ca2+]i) following administration of glutamate agonist was monitored for retinal Müller cells cultured from adult rabbits using a fluorescence microscope equipped with a video camera system. The calcium concentration was imaged with fura-2. The transient increase of [Ca2+]i was observed following the administration of L-glutamate (3 mM), kainate (0.07-7 mM) and L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 0.07-7 mM), but not N-methyl-L-aspartate (NMDA, 0.7-7 mM) in Mg(2+)-free medium. The AMPA/kainate-induced increase of [Ca2+]i was blocked by the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or low concentrations of external calcium. High K+ solution induced a slight but definite increase in [Ca2+]i which was blocked by nifedipine, a voltage-dependent calcium channel blocker, at 100 microM, suggesting that L-type calcium channels are present in cultured Müller cells. The AMPA-induced transient increase of [Ca2+]i was not blocked at the same concentration of nifedipine. There must be an influx of calcium ions through non-NMDA AMPA-kainate receptors in Müller cells. In the retina, glutamate receptor-linked events are no longer considered as specific to neurons.

Animals↗
PubMed1993

Heat shock response and thermal resistance in cultured human retinal pigment epithelium.

The heat shock response was examined in cultured human retinal pigment epithelium (RPE) using indirect immunofluorescence. Mild head shock (39.5-40 degrees C for 1 hr) caused no changes in cell morphology and cells continued to produce the intermediate filament proteins, cytokeratin (keratin) and vimentin. In addition, cells subjected to mild heat shock demonstrated the presence of a heat shock protein (HSP-90). After severe heat shock (45.5-46 degrees C for 1 hr) most cells showed marked morphological changes and, in addition, HSP-90 and/or stress-induced 40 kDa protein production was significantly enhanced. The expression of vimentin was relatively well preserved whereas that of keratin was markedly reduced. When the more severe grade of heat shock was preceded by mild heat shock 20-24 hr earlier, the subsequent severe heat shock resulted in less marked morphological change than in cells not preconditioned and, in addition, the expression of both vimentin and keratin was relatively well preserved. Mildly heat shocked cells appeared to gain thermal resistance supporting the theory that the concomitant synthetic capacity for HSP and normal cellular proteins contributes to thermal resistance. In doubly heat shocked cells, however, HSP-90 expression was not enhanced. The discrepancy between the expression of HSP and thermal resistance is discussed.

Aged↗
PubMed1993

Critical flicker frequency in acute and recovered optic neuritis.

Multiple occasional changes in critical flicker frequency (CFF) were studied in patients who recovered from optic neuritis. Twenty-five patients (31 affected eyes) with onset visual acuity less than 0.5 and who showed recovered visual acuity exceeding 1.0 were included in this study. Recovery stages were determined individually as follows: T1, initial onset stage; T2, intermediate stage; T3, recovered stage when visual acuity was 1.0 or better; and T4, final follow-up stage. CFF was determined using red, yellow and green illuminated targets in a compact CFF measuring device recently developed at our department. The rates of abnormality were 100% at stage T1 for all colors, and gradually decreased as the stage advanced from T2 to T4. However, the rates of abnormality continued to be high at 67% in stage T3 for the red target and 37% in stage T4 for the red target. The rates of abnormal interocular difference in CFF in 15 unilateral optic neuritis patients were 100% for all colors at stage T1 and decreased gradually with recovery. Slight but definite abnormality of CFF was also noted in the silent eyes of clinically unilateral optic neuritis patients. The rates of abnormal CFF more than 7% in all colors could be detected in T1, T3 and T4. These results indicate that CFF abnormality can be detected even at the stage of recovery in the pathologic eyes and the fellow eyes of optic neuritis patients. CFF was also shown to be a sensitive indicator for detecting visual dysfunction in patients with optic neuritis.

Acute Disease↗
PubMed1993

Cerebello-oculo-hepato-renal syndrome with possible mitochondrial dysfunction.

Bilateral retinal dysfunction with optic atrophy was evident in a 26-year-old man along with renal, hepatic and cardiac dysfunction. MRI showed undersized cerebellar vermis. Blood lactate and pyruvate were high, indicating possible mitochondrial dysfunction. In biopsied biceps muscle, some ragged red fibers were identified. In five usually congenital or inherited syndromes, Dandy-Walker, Joubert, Arima, Dekaban and COACH, the symptoms such as hypoplasia or aplasia of the cerebellar vermis with multiple ocular and systemic disorders serve as the basis for differential diagnosis. The present case showed numerous symptomatic similarities and a few specific differences with Arima, Dekaban and COACH syndromes. These three syndromes and the present case were thus given a single designation, cerebello-oculo-hepato-renal syndrome, although the present case was an adult patient with sporadic onset. Some systemic disorders not included in cerebello-oculo-hepato-renal syndrome were also noted in our case and may possibly be explained by mitochondrial dysfunction, as indicated by blood pyruvate and lactate levels and the presence of ragged red fibers in biopsied biceps muscle. The relationship between cerebello-oculo-hepato-renal syndromes and mitochondrial dysfunction is discussed.

Abnormalities, Multiple↗
PubMed1992

Rapid increase of intracellular Ca2+ concentration caused by aminoadipic acid enantiomers in retinal Müller cells and neurons in vitro.

The ability of the gliotoxic compounds D,L-, D- or L-2-aminoadipic acid (AAA) to increase selectively the intracellular concentration of free calcium ion ([Ca2+]i) was examined in Müller cells cultured with or without retinal neurons. The monitoring of [Ca2+]i following exposure to 0.06 to 6 mM AAA was performed by a microfluorometry using a fluorescent Ca2+ indicator, Fura-2 acetoxymethyl ester. A rapid increase of [Ca2+]i occurred in the Müller cells following exposure to a relatively low concentration of the L-isomer. This is compatible with the known strong gliotoxicity of this isomer. The D,L- and D-forms of AAA activated neurons at low concentrations and activated the Müller cells at higher concentrations. The D-isomer appears to act selectively on retinal neurons and may be an agonist of an excitatory amino acid receptor. These results indicate that the ability of AAA to elevate cytosolic [Ca2+]i depends on the stereospecificity of the AAA and on cell type.

2-Aminoadipic Acid↗