Biomedical subjects

H Miyajima

Publications and source records attributed to H Miyajima.

At least 19 recordsLinked to original sources

PubMed2006

Early onset insulin-dependent diabetes mellitus as an initial manifestation of aceruloplasminaemia.

BACKGROUND: Aceruloplasminaemia is an autosomal recessive disorder caused by specific mutations in the ceruloplasmin gene. Aceruloplasminaemia is clinically characterized by diabetes mellitus, pigment degeneration of the retina, and neurological abnormalities, such as cerebellar ataxia, extrapyramidal signs, and dementia. We present a patient with aceruloplasminaemia who, until progressive neurological abnormalities were noticed, had been treated for more than 30 years as having Type 1 diabetes mellitus requiring multiple insulin injection therapy. CASE REPORT: The patient was a 58-year-old man. At the age of 23 years, he developed diabetes that required multiple insulin injection therapy. At the age of 39 years, he was commenced on continuous subcutaneous insulin infusion (CSII) therapy. Despite CSII therapy, the patient's blood glucose levels were poorly controlled (HbA(1c), approximately 9.5%). He was diagnosed as having aceruloplasminaemia at 58 years of age when he presented with progressive cerebellar ataxia, extrapyramidal signs of recent onset and pigment degeneration of the retina. CONCLUSIONS: It is possible that some diabetic patients with aceruloplasminaemia are mistakenly diagnosed as having Type 1 diabetes mellitus, as they have reduced insulin secretion and develop diabetes at a younger age, before neurological abnormalities associated with aceruloplasminaemia are apparent. Therefore, aceruloplasminaemia should be considered in patients with insulin-dependent diabetes mellitus who develop progressive neurological abnormalities of unknown aetiology along with a microcytic hypochromic anaemia and retinal degeneration.

Blood Protein Disorders↗

PubMed2005

Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism.

The authors performed PINK1 mutation analysis of 51 families with autosomal recessive Parkinson disease (ARPD). They found two novel PINK1 mutations: one was a homozygous deletion (13516-18118del) and the other a homozygous missense mutation (C388R). Clinically, the patients with the deletion had dementia. Thus, early-onset PD with dementia may be considered PINK1-linked parkinsonism. Furthermore, patients with PINK1 mutations form 8.9% of parkin- and DJ-1-negative ARPD families.

Adolescent↗

PubMed2002

A case of aceruloplasminaemia: abnormal serum ceruloplasmin protein without ferroxidase activity.

A 34 year old diabetic man with a complete deficiency of serum ferroxidase activity, regardless of the presence of serum ceruloplasmin (Cp), a multicopper ferroxidase protein, is described. The patient had had diabetes mellitus for 13 years, and was also found to have retinal degeneration accompanied by the development of a hearing disturbance of unknown aetiology. Laboratory examination showed markedly increased serum ferritin and low serum iron. Magnetic resonance imaging showed a pronounced hypointensity in the putamen, caudate, cerebellar dentate, and thalamus on T2 weighted images, and also disclosed a low level signal in the liver, suggesting the accumulation of some magnetic substances in the brain and liver. Liver biopsies histochemically identified iron deposition in the hepatocytes. Most of these findings were consistent with the newly established autosomal recessive disease "aceruloplasminaemia", except for the presence of serum Cp and the lack of apparent neurological symptoms. Interestingly, no ferroxidase activity was detected in the patient's serum, whereas suppressed ferroxidase activity was found in his mother's serum. A nucleotide sequence analysis of the Cp gene showed two mutations; a C to T substitution at nucleotide 2701 in exon 16, resulting in a nonsense mutation at amino acid 882 (Arg882ter), and a T to G substitution at nucleotide 2991 in exon 17, resulting in an amino acid alternation at amino acid 978 (His978Gln). The second mutation was also found in the patient's mother. The absence of serum ferroxidase activity despite the presence of serum Cp protein in this compound heterozygote was considered to be due to the production of a non-functional Cp harbouring no ferroxidase activity.

Adult↗

PubMed2002

Functional analysis of the effect of the posterior stabilising cam in two total knee replacements. A comparison of the Insall/Burstein and Bisurface prostheses.

The Bisurface knee prosthesis (BP) has a posterior stabilising cam (ball-and-socket joint) in the mid-posterior region of the femorotibial joint in an attempt to improve the range of movement. Based on an in vitro weight-bearing study contact areas of the Insall/Burstein 2 (IB2) and the BP knee were compared using pressure-sensitive films. The stability afforded by the cam was evaluated by means of dislocation distances in the vertical and horizontal planes. Significant adverse anterior translation in mid-flexion was not observed with the BP knee since the cam was effective above 60 degrees of flexion. At flexion of 60 degrees or more, the total contact areas were larger, as the cam represented a weight-bearing surface. The dislocation distances for the BP knee compared favourably with those for the IB2 knee. We conclude that the cam of the BP knee allows good movement, stability and wear.

Arthroplasty, Replacement, Knee↗

PubMed2001

Cerebellar ataxia associated with heteroallelic ceruloplasmin gene mutation.

BACKGROUND: Aceruloplasminemia, an autosomal recessive disorder that affects human iron metabolism, is caused by mutation of the ceruloplasmin gene. Heterozygous individuals with a partial ceruloplasmin deficiency may have normal iron metabolism and no clinical symptoms. METHODS: The authors clinically characterized three Japanese patients from two families who had cerebellar ataxia with hypoceruloplasminemia from the fourth decade of life. Genetic analysis, restriction fragment length polymorphism analysis, and a pathologic study were performed. RESULTS: All three patients presented with cerebellar dysfunction that included relatively nondisabling gait ataxia and dysarthria, as well as hyperreflexia. Brain and abdomen MRI showed cerebellar atrophy and no low-signal intensities in the basal ganglia, thalamus, and liver. Direct mutational analysis excluded SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, SCA-12, and DRPLA. The patients partially lacked serum ceruloplasmin, and the protein concentrations and ferroxidase activities ranged from 36% to 41% of the control values; moreover, they were heterozygous for a nonsense mutation of the ceruloplasmin gene (Trp858ter). Serum iron concentration and transferrin saturation were normal. At autopsy, pathologic and biochemical examinations showed marked loss of Purkinje cells, a large iron deposition in the cerebellum, and small depositions in the basal ganglia, thalamus, and liver. CONCLUSION: Cerebellar ataxia reflects the site of iron deposition. Being heterozygous for mutation of the ceruloplasmin gene may result in cerebellar ataxia.

Aged↗

PubMed2001

Preferential blockade of CD8(+) T cell responses by administration of anti-CD137 ligand monoclonal antibody results in differential effect on development of murine acute and chronic graft-versus-host diseases.

We investigated the effect of CD137 costimulatory blockade in the development of murine acute and chronic graft-vs-host diseases (GVHD). The administration of anti-CD137 ligand (anti-CD137L) mAb at the time of GVHD induction ameliorated the lethality of acute GVHD, but enhanced IgE and anti-dsDNA IgG autoantibody production in chronic GVHD. The anti-CD137L mAb treatment efficiently inhibited donor CD8(+) T cell expansion and IFN-gamma expression by CD8(+) T cells in both GVHD models and CD8(+) T cell-mediated cytotoxicity against host-alloantigen in acute GVHD. However, a clear inhibition of donor CD4(+) T cell expansion and activation has not been observed. On the contrary, in chronic GVHD, the number of CD4(+) T cells producing IL-4 was enhanced by anti-CD137L mAb treatment. This suggests that the reduction of CD8(+) T cells producing IFN-gamma promotes Th2 cell differentiation and may result in exacerbation of chronic GVHD. Our results highlight the effective inactivation of CD8(+) T cells and the lesser effect on CD4(+) T cell inactivation by CD137 blockade. Intervention of the CD137 costimulatory pathway may be beneficial for some selected diseases in which CD8(+) T cells are major effector or pathogenic cells. Otherwise, a combinatorial approach will be required for intervention of CD4(+) T cell function.

Acute Disease↗

PubMed2001

Impaired retention of technetium-99m tetrofosmin in hypertrophic cardiomyopathy.

The purpose of this study was to determine whether myocardial imaging using technetium-99m tetrofosmin can noninvasively identify myocardial damage in hypertrophic cardiomyopathy (HC). The study consisted of 10 patients with apical HC, 10 with asymmetric septal HC (ASH) group, 5 with dilated cardiomyopathy (DC)-like group, and 20 healthy subjects. With use of a bull's-eye map of single-photon emission computed tomographic imaging, the total defect score of tetrofosmin and the washout rate were assessed in 5 segments (septum, and anterior, lateral, and inferior walls, and apex) of the left ventricle. A localized increase in defect score and washout rate was observed in the hypertrophied region in the group with apical HC. An increased washout rate was observed in the ASH group regardless of hypertrophy, suggesting that tetrofosmin retention by the mitochondria was impaired in the entire left ventricular wall. The washout rate was further increased at all segments in the DC-like group versus the ASH group. Tetrofosmin retention by mitochondria was impaired in the entire left ventricular wall in the ASH group and was increased further in the DC-like group. The dysfunction of myocardial cells was limited to the hypertrophied region in the apical HC group.

Cardiomyopathy, Dilated↗

PubMed2001

Increased anaerobic glycolysis in mitochondrial trifunctional protein-deficient brain.

Deficiency of mitochondrial trifunctional protein (TP), beta-oxidation enzyme, is characterized by recurrent rhabdomyolysis in adult patients. Positron emission tomography was used to measure brain oxygen (CMRO(2)) and glucose (CMRGlc) metabolisms in an adult patient with TP deficiency who had a homozygous G1331A transition of the beta-subunit gene. The molar ratio of oxygen to glucose consumption showed diffuse reduction; CMRO(2) was markedly decreased, whereas CMRGlc increased. Oxidative metabolism may be impaired and anaerobic glycolysis stimulated in the brain of this patient with TP deficiency.

Adult↗

PubMed2001

Relationship among gastric motility, autonomic activity, and portal hemodynamics in patients with liver cirrhosis.

BACKGROUND AND AIMS: We examined the effects of the autonomic nervous function and the volume of portal blood flow to clarify the mechanism of the abnormal gastric motility in patients with liver cirrhosis. METHODS: Heart rate variability, electrogastrogram (EGG), and volume of portal blood flow were measured before and after a meal in 27 patients with liver cirrhosis (LC group) and in 20 normal subjects (N group). Autonomic nervous function was evaluated by using spectral analysis of heart rate variability. We used the cine phase-contrast (PC) method, using magnetic resonance imaging (MRI) to measure the portal flow, while the peak frequency and spectral power of the EGG were measured at pre- and postprandial change. RESULTS: The ratio of low frequency power to high frequency power (LF/HF) was significantly higher, and the HF power was significantly lower in the LC group than in the N group both before and after a meal. In both groups, the electrogastrographic peak power ratio before and after a meal showed a positive correlation with the HF ratio, and an inverse correlation with the LF/HF ratio. In addition, portal blood flow volume was significantly decreased in the LC group than in the N group. However, the increased rate of portal blood flow after a meal correlated positively with the increased rate of electrogastrographic peak power. Moreover, gastric motility was positively correlated with esophageal varices and coma scale with the use of multivariate analysis. CONCLUSIONS: Parasympathetic hypofunction, sympathetic hyperfunction and portal hemodynamics were closely related with gastric motility in cirrhotic patients. In addition, gastric motility was decreased, at least in part, by the ingestion of food in cirrhotic patients because of abnormalities in autonomic functions and portal blood flow following a meal.

Aged↗

PubMed2001

Voiding dysfunction in a patient with adolescent adrenoleukodystrophy.

The details are reported of bladder dysfunction in a Japanese boy with adrenoleukodystrophy. He developed gait disturbance at the age of 15 years. Spastic paraparesis progressed from the legs to the hands and brain magnetic resonance imaging showed characteristic degenerative change. Detrusor hyperreflexia was found by a urodynamic study and detrusor-sphincter dyssynergia was also suspected.

Adolescent↗

PubMed2001

A neural network to predict melting temperature (Tm) of RNA duplex.

A straightforward method to predict RNA duplex stability by neural network is described. The best network consists of three layers in which the input layer units are 12 (frequencies of 10 nearest-neighbors and 2 terminals), the hidden layer units are 3 and the output layer unit is 1 (measured Tm). This method to predict Tm has the advantage that the determinations of thermodynamic parameters is not needed.

Base Sequence↗

PubMed2001

Increased oxysterols associated with iron accumulation in the brains and visceral organs of acaeruloplasminaemia patients.

Acaeruloplasminaemia is characterized by excessive neurovisceral iron accumulation due to mutation of the caeruloplasmin gene. Excess iron functions as a potent catalyst of biological oxidation, and increased iron concentration is associated with the products of lipid peroxidation in the serum and cerebrospinal fluid. We investigated whether the amount of iron accumulated paralleled lipid peroxidation levels in acaeruloplasminaemia tissues, examining brains and visceral organs of two affected patients at autopsy for iron and copper content, and oxysterols, including 7-hydroxycholesterol and 7-ketocholesterol, which are directly produced from cholesterol by active oxygen species. The amount of iron accumulated in various tissues was correlated with the levels of the oxysterols. These findings suggest that lipid peroxidation produced by the intracellular accumulation of iron is involved in the pathogenesis of acaeruloplasminaemia.

Aged↗

PubMed2001

Iron accumulation in the liver of male patients with Wilson's disease.

OBJECTIVES: There is accumulating evidence that ceruloplasmin, a copper protein with ferroxidase activity, plays an important role in iron metabolism. The genetic disorder, aceruloplasminemia, can lead to tissue storage of iron as in hemochromatosis. Because most patients with Wilson's disease, a genetic copper toxicosis, have hypoceruloplasminemia, some could be affected by iron overload. METHODS: Four male patients with Wilson's disease were enrolled in this study of pre- and post-treatment iron metabolism. RESULTS: Pretreatment copper contents of the liver were high in all four male patients studied as diagnostic of Wilson's disease. Genetic analysis supported their clinical diagnosis of Wilson's disease without a background of hemochromatosis. Pretreatment serum ceruloplasmin levels were <20 mg/dl in all four patients. A standard penicillamine treatment for 3-8.5 yr further decreased their serum ceruloplasmin levels. Post-treatment serum ferroxidase activity was low as was the serum ceruloplasmin protein. Copper contents in the liver decreased after treatment in all subjects. In contrast, nonheme iron in the liver increased during treatment. Pretreatment liver specimens were positive for histochemical iron in two patients, and post-treatment specimens were positive in all four patients. In two patients, serum aminotransferase levels rebounded with elevation of serum ferritin concentration during the treatment period. Subsequent iron reduction by phlebotomy ameliorated their biochemical liver damage. CONCLUSION: Iron overload related to hypoceruloplasminemia may be clinically important, particularly in male patients with Wilson's disease.

Adolescent↗

PubMed2001

Stiff-person syndrome associated with cerebellar ataxia and high glutamic acid decarboxylase antibody titer.

Glutamic acid decarboxylase (GAD) is the main target of humoral autoimmunity in patients with insulin-dependent diabetes mellitus (IDDM) and stiff-person syndrome. We reviewed the case of a 46-year-old woman who had cerebellar ataxia before getting stiff-person syndrome and IDDM with high anti-GAD autoantibody titers. This was a rare case in which there were both the clinical symptoms of stiff-person syndrome and cerebellar ataxia. In western blot analysis her serum reacted with 65-kDa proteins from rat cerebellum, cerebral cortex, and spinal cord. Autoantibodies to GAD may cause functional impairment of gamma-aminobutyric acid (GABA) neurons in the spinal cord as well as in the cerebellum.

Autoantibodies↗

PubMed2001

[Genotoxicity studies of cefmatilen hydrochloride hydrate (S-1090)].

Cefmatilen hydrochloride hydrate (S-1090), a new non-ester type of orally active cephem antibiotic synthesized in Shionogi Research Laboratories, was evaluated for its genotoxic potential using three assay systems. In a reverse mutation test with bacteria of Salmonella typhimurium TA100, TA1535, TA98, and TA1537, and Escherichia coli WP2uvrA using the preincubation method, the number of revertant colonies in the S-1090 treated plates was almost equal to that in the negative control plates in all strains with and without metabolic activation system with S9 mix (maximum dose, 100 micrograms/plate in TA98). In a chromosomal aberration test with cultured Chinese hamster lung cells (CHL/IU), S-1090 did not induce structural chromosome aberrations or polyploid cells either in the absence or presence of S9 mix up to the 50% growth inhibition doses. The potential of inducing clastogenicity and/or disruption of mitotic apparatus in vivo by S-1090 was evaluated by a micronucleus test with bone marrow cells of male Jc1:ICR mice. S-1090 suspended in 0.5% aqueous methylcellulose was administered by oral gavage up to 2000 mg/kg/day in single and double dosing groups. No induction of micronucleated polychromatic erythrocytes was observed 24 hr after the last dosing in each group. As all three genotoxicity tests showed negative responses, S-1090 is thought to have no genotoxic potential.

Administration, Oral↗

PubMed2000

Defective electron transfer in complexes I and IV in patients with aceruloplasminemia.

Aceruloplasminemia is a disorder of iron metabolism caused by mutations in the ceruloplasmin gene. It is characterized by progressive neurodegeneration of the retina, basal ganglia, dentate nucleus and cerebral cortex in association with iron accumulation in these tissues. Enzyme activities in the mitochondrial respiratory chain of the cerebral cortices of two patients were reduced to 62% and 71% for complexes I and IV. Malondialdehyde, a marker of lipid peroxidation, was three times higher than the control value and was accompanied by increased expression of superoxide dismutase 2 (Mn SOD). These findings suggest that iron-mediated free radicals contribute to the impairment of mitochondrial energy metabolism in aceruloplasminemia

Aged↗

PubMed2000

Increased lipid peroxidation in the brains of aceruloplasminemia patients.

Aceruloplasminemia is characterized by excessive neurovisceral accumulation of iron due to mutations in the ceruloplasmin gene. We report that the levels of malonaldehyde (MDA) and 4-hydroxynonenals (4-HNE) were elevated both in the frontal cortex and putamen in two patients with aceruloplasminemia compared with those in controls. Immunohistochemical analysis with an antibody raised against HNE-modified protein showed a large number of immunoreactive neurons and glias in the brain of a patient. MDA and 4-HNE are good indicators of lipid peroxidation because they are generated in the process of oxidation of polyunsaturated fatty acids. The data strongly suggest that the increase of oxygen free radicals associated with excessive iron accumulation plays an important pathogenic role in the process of neuronal cell death in the brains of patients with aceruloplasminemia.

Aged↗

PubMed2000

Blockade of CTLA-4 signals inhibits Th2-mediated murine chronic graft-versus-host disease by an enhanced expansion of regulatory CD8+ T cells.

CTLA-4 (CD152) is thought to be a negative regulator of T cell activation. Little is known about the function of CTLA-4 in Th2-type immune responses. We have investigated the effect of initial treatment with anti-CTLA-4 mAb on murine chronic graft-vs-host disease. Transfer of parental BALB/c splenocytes into C57BL/6 x BALB/c F1 mice induced serum IgE production, IL-4 expression by donor CD4+ T cells, and host allo-Ag-specific IgG1 production at 6-9 wk after transfer. Treatment with anti-CTLA-4 mAb for the initial 2 wk significantly reduced IgE and IgG1 production and IL-4 expression. Analysis of the splenic phenotype revealed the enhancement of donor T cell expansion, especially within the CD8 subset, and the elimination of host cells early after anti-CTLA-4 mAb treatment. This treatment did not affect early IFN-gamma expression by CD4+ and CD8+ T cells and anti-host cytolytic activity. Thus, blockade of CTLA-4 greatly enhanced CD8+ T cell expansion, and this may result in the regulation of consequent Th2-mediated humoral immune responses. These findings suggest a new approach for regulating IgE-mediated allergic immune responses by blockade of CTLA-4 during a critical period of Ag sensitization.

Abatacept↗