Biomedical subjects
Publications and source records attributed to M Mizuguchi.
A 25-year-old woman complained of coughing for over 8 weeks. The coughing was not relieved by a bronchodilator (beta 2-adrenoceptor agonist; clenbuterol), and anti-allergic agent (azelastine), or an inhaled corticosteroid. The thromboxane synthetase inhibitor ozagrel completely abolished her cough. In this case, thromboxane A2 may have contributed to the coughing.
We demonstrate the distribution and development of endothelial nitric oxide synthase (eNOS) immunoreactivity in vessels of the human brain. eNOS-positive endothelial cells were recognized in small vessels in the parenchyma of the cerebrum, as well as in the large arteries and veins in the leptomeninges. By 10-13 weeks of gestation, eNOS-positive endothelial cells had already appeared in the vessels of the leptomeninges and deep white matter. Immunoreactivity for eNOS was noted in most vessels at 14-17 weeks in the intermediate white matter, at 18-21 weeks in the cortex, and at 23-26 weeks in the subcortical white matter. Such differences in regional development may be responsible in part for the topographical predilection for hemorrhagic or hypoxic-ischemic lesions in the developing brain.
We investigated the immunohistochemical localization of epidermal growth factor (EGF) in the developing human brain from 6 weeks of gestation to 3 months postpartum. EGF-like immunoreactivity varied in its localization and intensity according to the stage of development. At 10 - 20 weeks of gestation, EGF-like immunoreactivity appeared in proliferating and migrating cells in the cerebrum, disappeared thereafter, and appeared again in cortical neurons after 27 weeks of gestation. Astrocytes also showed EGF-like immunoreactivity from 27 weeks of gestation. These results suggest developmental regulation of EGF expression in the human brain, suggesting its physiological role in both neuronal and glial cells.
CD38 is a lymphocyte differentiation antigen which is involved in the cyclic ADP-ribose-mediated second messenger system. We provide immunochemical and immunohistochemical evidence for the expression of CD38 in the adult human brain. We used six polyclonal antibodies against synthetic CD38 polypeptides, in addition to four monoclonal antibodies already available. Brain CD38 was detectable by Western blotting after immunoaffinity purification of the brain extracts. Immunoperoxidase staining localized CD38 immunoreactivity to the perikarya and dendrites of many neurons, such as the cerebellar Purkinje cells, implying that CD38 is involved in the signal transduction within the central nervous system neurons.
The temporal profile of apolipoprotein-E (apo-E) expression was investigated immunohistochemically in the brains of Down syndrome patients and of normal controls. The number of apo-E immunoreactive astrocytes in the frontal cortex was larger in Down syndrome patients than in controls from 7 months to 24 years of age. It suggests that apo-E producing astrocytes in the early phase of pathological process lead to presenile dementia in Down syndrome patients. In contrast, the number in the white matter was smaller in Down syndrome patients from 28 gestational weeks to 5 years. Apo-E immunoreactive senile plaques were noted in Down syndrome brains from the age of 25 years, while APP immunoreactivity was first noted in senile plaques at the age of 32 years.
The expression of heat shock protein (HSP) 73, a constitutive form of HSP, was evaluated immunohistologically in human brains, from embryos to adults. HSP 73 immunoreactivity was first detected in the embryo at 6 weeks of gestational age (GW) in the ventral horn cells of the spinal cord and the dorsal root ganglion cells. During the fetal period, the reactivity extended cranially, becoming detectable in the cerebral pyramidal cells at 40 GW. Glial cells in the spinal cord also showed HSP 73 immunoreactivity, from 22 GW. The time course of the development of HSP 73 immunoreactivity was mostly consistent with the time courses of overall neuronal and glial maturation, suggesting an increasing role of HSP 73 during neural cell differentiation.
Pontosubicular neuronal necrosis is characterized by neuronal karyorrhexis, showing a peculiar distribution. In infants delivered at more than 29 gestational weeks (GW), neuronal karyorrhexis is restricted to the pons and subiculum, while in very premature infants (delivered at less than 28 GW), neurons in other brain regions, such as the inferior olivary nucleus, cerebellum, basal ganglia, thalamus and cerebral cortex, are also involved. Thus, karyorrhexis is more widely distributed in the more immature brain, implicating neuronal maturation as one of the pathogenetic factors relevant to this type of neuronal cell death.
Cystic necrosis in the cerebellar white matter was found in three premature infants. The necrosis was characteristically localized in the center of the white matter of the superficial cerebellar folia, sparing the overlying cortex. The patients were aged between 28 and 34 gestational weeks, and had a clinical history of severe systemic hypotension. Thus, cystic leukomalacia represents a characteristic brain lesion in premature infants which may be caused by cerebellar hypoperfusion.
Human beta-amyloid precursor protein immunoreactivity was demonstrated in axonal swellings (spheroids) around periventricular leukomalacia (PVL) of neonates. Immunoreactive axons were found at the early, but not late stage of PVL. beta-Amyloid precursor protein immunoreactivity was homogeneous in damaged axons at the early stage of PVL manifesting microglial activation, concentrated at the center of axonal swellings at the subsequent stage manifesting astrogliosis, and undetectable at the terminal stage of cavitation or neovasculation. Immunostaining for beta-amyloid precursor protein was useful in localizing PVL lesions at their early stages.
Salicylate hydroxylase from Pseudomonas putida S-1 was irreversibly inactivated by trinitrobenzenesulfonic acid (TNBS). The reaction was linearly dependent on TNBS concentration and the second-order rate constant was 120 M-1.min-1 for the holoprotein at pH 8.5. Modification of one mole of lysine residue per mole of enzyme caused a large loss of the activity, and the enzyme was no longer able to show NADH-dehydrogenase activity after uncoupling. The presence of NADH, NAD+, ATP, or AMP afforded protection against the inactivation. The enzyme modified at a single lysine residue was isolated by hydrophobic chromatography as an apoprotein form and characterized. It could bind FAD with the same Kd value for that of native apoprotein. The apparent Michaelis constant of the enzyme was increased 13-fold for NADH, but not for salicylate. Vmax for NADH oxidation was decreased to one-fifth of that of the native enzyme. A peptide containing one trinitrophenyl-lysine residue was isolated from the chymotryptic digest of the modified enzyme and its amino acid sequence was determined to be TADVAIAADGIKSSM, which is homologous to the sequence from R-154 to I-168 of salicylate hydroxylase from P. putida PpG7. The lysine in the peptide may represent a basic residue interacting with an anionic group of NADH in the binding site of the enzyme.
The clinicopathological features of a previously unrecognised type of acute encephalopathy prevalent among Japanese children is described by reviewing the records of 13 consecutive patients treated and 28 previously reported cases. The hallmark of this encephalopathy, proposed to be a novel entity termed acute necrotising encephalopathy of childhood, is multiple, necrotic brain lesions showing a symmetric distribution. The encephalopathy was noted in previously healthy children after respiratory tract infections, with presenting symptoms of coma, convulsions, vomiting, hyperpyrexia, and hepatomegaly. Laboratory examinations disclosed liver dysfunction, uraemia, and hypoproteinaemia. The histological appearance of the liver was variable and non-specific. Cerebrospinal fluid contained an increased amount of protein. Computed tomography and MRI showed the presence of symmetrically distributed brain lesions of the thalamus, cerebral white matter, brainstem, and cerebellum. Necropsy examination confirmed extensive fresh necrosis of these regions with evidence of local breakdown of the blood-brain barrier. Based on the characteristic combination of clinical and pathological findings, acute necrotising encephalopathy of childhood can be distinguished from previously known encephalopathies, including Reye's syndrome.
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The Miller-Dieker syndrome, a disorder of neuronal migration, is caused by deletions of chromosome 17p13.3. Recently, a gene on 17p13.3, named LIS-1, was identified as the causative gene for this cerebral anomaly. Here we immunochemically and immunohistochemically localized the gene product, LIS-1 protein, among control normal subjects and patients with Miller-Dieker syndrome, using specific antibodies raised against synthetic peptide fragments of LIS-1 protein. Western blot analyses identified LIS-1 protein as a 45-kd, heparin-binding protein abundant in the cytosolic fraction. The protein was restricted to the central nervous system and detectable in brains of controls of all ages, from the early fetal to adult period. Immunostaining demonstrated the widespread distribution of LIS-1 protein in the brain and spinal cord of controls and a loss of immunoreactivity in individuals with Miller-Dieker syndrome. These results are consistent with the notion that a deficiency of LIS-1 protein is the direct cause of the brain malformation and that the protein plays a critical role in neuronal migration.
Although gastro-esophageal reflux (GER) is one of the major causes of chronic persistent cough (CPC) in the USA and in Europe, it is a rare cause of CPC in Japan. We report a rare case of CPC caused by GER, in which treatment with an H2-blocker or with a proton pump inhibitor was successful. A 65-year-old woman had complained of coughing for over 25 years. Her coughing was not alleviated by treatment with a bronchodilator (beta 2-adrenoceptor agonist), an anti-allergic agent, a corticosteroid, or a sedative. GER was considered as a possible cause of her coughing because exacerbation of the coughing was associated with the development of gastrointestinal symptoms (heartburn). Fiberoptic esophagoscopy showed esophagitis and esophageal herniation of the sliding type. Twenty four-hour monitoring of distal esophageal pH showed that the coughing occurred when the pH dropped below 4, and that the pH was less than 4 for about 7% of the whole monitoring time. An H2-blocker or a proton pump inhibitor completely eliminated the symptoms. Therefore, CPC caused by GER was diagnosed. We found that coughing could be induced by instillation of 0.1 N hydrochloric acid at the distal esophagus, and that the coughing was partially inhibited by inhalation of an anti-muscarinic agent (ipratropium bromide) and by esophageal instillation of 4% xylocaine. These data support the "reflex theory". Although CPC caused by GER is rare in Japan, we should remember that GER can be a cause of CPC even in Japanese patients.
A 59-year-old man came to our hospital for further examination of multiple small nodular lesions in both lungs. Chest CT scan revealed multiple nodular lesions in rt-S6, It-S5, and It-S9 (two lesions). All of these nodules measured about 10 mm or less and those in It-S9 had spicula. Bronchoscopic examination did not yield a definitive diagnosis, so open lung biopsy was done. The open lung biopsy specimen revealed intra-pulmonary lymph nodes with anthracosis and pulmonary emphysema. Intrapulmonary lymph nodes are very difficult to distinguish from small lung tumors by radiographic examination alone, so the possibility that small nodules in the lungs may be intra-pulmonary lymph nodes should be kept in mind.
MR imaging was performed with the retrograde administration of ferro-magnetic contrast material and air in 10 patients with rectosigmoid colon cancer. The border of the lesions was well demonstrated in spin echo images, and MR imaging yielded additional diagnostic information to that provided by barium enemas and CT scans in all cases. In conclusion, this type of contrast material seemed promising in the MRI diagnosis of rectal lesions.
The effect of clarithromycin on symptoms and on mucociliary transport (as assessed by the saccharin test) were studied in 32 patients with sino-bronchial syndrome. Before treatment with clarithromycin, the nasal clearance time was significantly longer in these patients (70.3 +/- 64.7 min, mean +/- SD) than in control subjects (11.9 +/- 5.3 min, p < 0.001). By the end of 4 weeks of treatment with oral clarithromycin (400 mg/day), nasal clearance time in the patients had improved significantly (30.4 +/- 39.5 min, p < 0.001). Before clarithromycin therapy, bacteria were found in cultures of sputum from 15 patients. After clarithromycin therapy, bacteria were found in cultures of sputum from only 3 of those 15 patients. Cough frequency, volume of sputum, and dyspnea on exertion were significantly improved by clarithromycin therapy. These findings suggest that mucociliary transport is abnormal in patients with sino-bronchial syndrome, and that clarithromycin can be clinically useful in these patients.
We describe stereocontrolled synthesis of phosphorothioate oligonucleotides including stereospecific transesterification to form chiral phosphite triester backbone under basic conditions. Substrate phosphite triesters with phenoxy derivative substituents as leaving groups were separated into individual stereoisomers and reacted with hydroxyl-containing compounds to form chiral phosphite triester backbone. Subsequent stereoretentive sulfurization and deprotection gave desired stereocontrolled phosphorothioate linkages.