Structure and function of myelin protein genes.
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Biomedical subjects
Publications and source records attributed to H Okano.
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Biopsies of 18 patients with lung cancer and cellular specimens of 21 lung cancer patients were analyzed with human monoclonal antibody HB4C5-clone 3 using avidin-biotin-peroxidase techniques. Analyses with the biopsies showed that HB4C5-clone 3 reacted with 16 of 18 biopsy specimens at a high rate of about 90% and reacted with all specimens of five adenocarcinoma tissues, five of six squamous cell carcinomas, two of three large cell carcinomas, both specimens of small cell carcinomas, and both of the other types of carcinomas. In all the reactive cases, the monoclonal antibody was reactive with greater than 50% of cancer cells. With cellular specimens of lung cancer patients, HB4C5-clone 3 reacted with 7 of 13 adenocarcinoma specimens, two of six squamous cell carcinomas, and one of two small cell carcinomas. The immunoreaction with HB4C5-clone 3 was observed in sites of the cytoplasm of cancer cells. From these data, HB4C5-clone 3 is considered to be of potential use in diagnoses of tissues and cellular specimens of lung cancer.
1. Myelin is an important structure for facilitating the conduction of impulses along the axons both in the central nervous system (CNS) and peripheral nervous system (PNS). 2. Myelin basic protein (MBP) is a major protein in CNS myelin. 3. MBP is expressed specifically in the nervous system. 4. The MBP gene has been cloned and characterized. 5. Two mutant mice, Shiverer (shi) and myelin-deficient (mld. shimid), are autosomal recessive mutants that show severe symptoms such as intentional tremor. They have been found to have a mutation in the MBP gene that results in poor myelination in the central nervous system. 6. It was found that rearrangement within the MBP gene results in low expression of the gene. 7. In Shiverer, the MBP gene is partially deleted (from exons 3 to 7), and in mld, the gene is duplicated tandemly and a large portion of the duplication is inverted upstream of the intact copy. 8. In mld, anti-sense RNA complementary to exons 3-7, which correspond to the inverted segment, was detected by RNase protection studies, and presumed to be responsible for the reduced expressions of MBP. 9. The mechanism of gene rearrangement in MBP was also characterized. 10. This article reviews the recent progress in the study of the MBP gene, especially the rearrangement of the gene and its expression in mutant mice.
Thirty-seven patients with advanced non-small cell lung cancer were enrolled to evaluate a combination chemotherapy of cisplatin (80 mg/m2), doxorubicin (30 mg/m2) and vindesine (2 mg/m2 x 3). The overall response rate was 27% with ten partial remission. The median survival of whole patients was 11.4 months. The calculation of median survival of the patients with partial remission has not been completed: nine of ten patients have been still alive during the follow-up period of 4 to 16 months. The survival of the patients with PR was significantly different from those of the patients with NC or PD. The major toxicity was myelosuppression. These results indicate that a combination chemotherapy with cisplatin, doxorubicin and vindesine is a moderately effective regimen against non-small cell lung cancer compared to others.
The purpose of this study was to analyze the risk factors of unexpected occurrence of mitral regurgitation (MR) following percutaneous transvenous mitral valve commissurotomy (PTMC) in patients with mitral stenosis. The analyzed factors were clinical pictures, hemodynamic findings, echocardiographic findings and balloon inflation techniques during PTMC. Among 24 patients undergoing successful PTMC using an Inoue's balloon, severe MR developed in five patients (21%). No significant correlation in the occurrence of MR was observed in clinical findings, hemodynamic data and balloon inflation techniques including the times and size of ballooning. Echocardiographic findings of the mitral valve including the pliability of the mitral leaflet and localized calcification of the mitral orifice were the most contributory factors to the occurrence of severe MR. The localized alternation of valve stiffness produced localized tear or excessive dilatation of the mitral leaflet during PTMC, resulting in severe MR. Hemodynamic results and calculated mitral valve areas after PTMC showed significant improvement in both groups with and without MR. However, symptomatic improvement in patients with severe MR was less prominent when compared to the patients without MR. Thus, the complete echocardiographic evaluation of the mitral valve apparatus before PTMC is important to prevent severe MR.
The shiverer and myelin-deficient (mld) mutants are two allelic mutations. Both are characterized by hypomyelination in the CNS and deficient expression of the MBP gene. Chimeric analysis of the pathogenesis of shiverer showed that shiverer mutation acts intrinsic to the oligodendrocyte, which is the only cell type expressing the MBP gene in the CNS. Molecular genetic studies by several groups demonstrated that shiverer is a deletion mutation in the MBP gene. Consequently, no MBP is produced in the shiverer mutant. In mld, however, partial expression of the MBP gene was observed. Interestingly, MBP was expressed in a mosaic fashion in the CNS of mld mice. Molecular genetic studies revealed that the mld mutant has duplicated MBP genes in tandem on a distal part (E2-4) of chromosome 18q. The reduced expression was based on the level of mRNA. A large portion is inverted in the upstream copy, and an intact copy is located downstream. We showed in mld mutants that antisense RNA corresponding to the inverted segment is transcribed, and it forms RNA duplex, with the RNA transcribed from the normal gene located downstream.
We investigated the effects of nifedipine on left ventricular diastolic function in 17 asymptomatic or minimally symptomatic patients with hypertrophic cardiomyopathy by simultaneously measuring left ventricular pressure and volume with a catheter-tipped manometer and biplane cineangiography. Studies were performed before and 20 minutes after sublingual administration of nifedipine (20 mg). Heart rates were held constant (79 +/- 12 beats/min, mean +/- SD) by right atrial pacing. Left ventricular volumes and instantaneous rates of left ventricular volume were derived from frame-by-frame (20-msec) analyses of left ventricular biplane angiograms. Left ventricular peak systolic pressure (from 122 +/- 21 to 108 +/- 13 mm Hg, p less than 0.01 vs. control) and mean aortic pressure (from 96 +/- 15 to 87 +/- 11 mm Hg, p less than 0.01) decreased significantly with nifedipine. With afterload reduction, left ventricular ejection fraction (from 0.69 +/- 0.12 to 0.74 +/- 0.08, p less than 0.01) and cardiac output (from 6.4 +/- 2.0 to 7.2 +/- 2.2 l/mm, p less than 0.05) increased significantly. However, there was a slight but significant increase in left ventricular end-diastolic pressure (from 15 +/- 8 to 18 +/- 8 mm Hg, p less than 0.05). Nifedipine did not improve left ventricular relaxation as assessed by the time constants of isovolumic pressure decay (t1/2, from 39.8 +/- 6.6 to 39.4 +/- 7.7 msec, NS; t1/e, from 53.8 +/- 9.0 to 54.4 +/- 10.7 msec, NS).(ABSTRACT TRUNCATED AT 250 WORDS)
The blood flow in esophageal varices was measured by endoscopic laser Doppler velocimetry (LDV) in 27 patients histologically or clinically diagnosed as having liver cirrhosis. The effect of endoscopic injection sclerotherapy (EIS), and of intravenous oral administration of propranolol, on the output signal of LDV was evaluated. EIS was performed intravariceally after the measurement, with a 50% glucose solution, human thrombin (1000 U), and Aethoxysclerol as sclerosants.
A case of bleeding duodenal varix which was treated successfully with endoscopic injection sclerotherapy (EIS) is reported. The patient developed a hemorrhage from a varix in the descending portion of the duodenum two months after EIS for esophageal varices, and hemostasis was achieved using EIS with an intravericeal injection of 1% polidocanol. The duodenal varix decreased in size after EIS. Two months after EIS, a splenectomy was performed. During a 14-month follow up period after the EIS for the duodenal varix, there was no recurrent bleeding.
The mouse myelin basic protein promoter was transcribed in brain nuclear extracts. The distal promoter region from -253 to -54 directed preferential transcription in brain extracts, whereas the same region repressed transcription activity in liver extracts. Stimulation of transcription was observed when the distal region was located only in a native orientation. The proximal region downstream from -53 alone still directed preferential transcription. It is suggested that cooperative function by the two promoter regions may be required for higher specificity.
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The goal in treating intraoral cancer is to obtain tumor control with preservation of shape and function of oral cavity. For T1, T2 lesions of the tongue, the floor of the mouth and the cheek mucosa, interstitial radiation therapy provides a control rate of 80-90% with excellent preservation of function. With surgical salvage for persistent or recurrent tumor, the ultimate control rate is 90-95%. Unfortunately, for more advanced lesions surgery is frequently required to obtain local control. The use of bleomycin or peplomycin in simultaneous combination with external radiation therapy provides a good chance of local control without surgery. For T1, T2 lesions of the lower gum and the cheek mucosa complete response rate is approximately 65% and 70% of these are cured without surgery. With surgical salvage for persistent or recurrent tumor the ultimate control rate is 90%. For most of the poor responders surgery or interstitial irradiation is required to control the tumor.
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Fungus ball type pulmonary aspergilloma is easily recognizable on chest X-ray. This is a report on "productive aspergilloma on the inner wall of a cavity" (PAIC), named from our clinical experience in 1980, which grew to form aspergillus strata on partial or overall inner walls of the cavity. Our 5 cases with this type supported the existence of this type and revealed an 18% incidence in patients with pulmonary aspergilloma, characteristic clinical features and immunological reactions, thus pointing to the necessity of early diagnosis and treatment for this type of aspergilloma. The species of aspergillus cultured from the patients with this type of disease was Aspergillus fumigatus.
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The first hybrid mice ('shiverer*mld' mice) produced by intercrossing the homozygotes of the shiverer (BALB/c strain) and mld (MDB/Dt strain) were used for investigating the fine structure of the myelin lamellae, immunoreactive pattern for myelin basic proteins (MBP) and Golgi impregnated images of oligodendrocytes, with special reference to the influence of aging. All of the hybrid mice had an intermediate coat color between the white of the shiverer and black-brown of the mld, and revealed the same neurological symptoms, intention tremor, ataxic behavior, etc., as those of the shiverer and mld. The central myelin lamellae of the 'shiverer*mld' mouse exhibited the similar characteristics to the shiverer type rather than the mld type from the standpoint of the infrequent occurrence of major dense lines, although they did display a tendency to increase major dense lines with aging like the mld. Observation of the immunohistochemical preparations for MBP showed that immunopositive myelin sheaths were present in the white matter, although they were far more infrequent than those of the mld mutant, probably reflecting the amount of major dense lines. Thus, in the CNS of the 'shiverer*mld' mouse, the MBP-synthesis was possibly much more disturbed than in the mld mutant, or at least, revealed an intermediate pattern between the mld and shiverer.
The mouse proteolipid protein (PLP) gene was cloned into the lambda bacteriophage Charon 4A. The organization and the nucleotide sequence of the exons of the mouse PLP gene were quite similar to those of their human counterparts, consisting of seven exons. The transcription of the PLP gene started from multiple sites. There was a unique sequence tandemly repeated four times, sharing homology with the herpes simplex virus DR2 sequence, upstream from the transcribed region. Expression of the myelin basic protein (MBP) is also restricted to the oligodendrocytes in the central nervous system as is the PLP expression. Homology search against the mouse MBP gene revealed that several boxes in the 5'-flanking region of PLP show a high degree of homology with the sequence present in the MBP 5'-flanking region, possibly of importance in the concomitant expression of both genes in the central nervous system. PLP-mRNA in jimpy mutant mice does not contain exon 5 and its content is greatly reduced. We analyzed the jimpy PLP-mRNA and showed that the transcription initiated from the same sites as those in normal mice. Cloning and sequencing of the 5'-flanking region of the jimpy PLP gene revealed that there were no mutations in the promoter region of the jimpy PLP gene. Therefore, it is likely that a mutation, presumably existing within the jimpy PLP gene, caused the skipping of exon 5 and directly affected the mRNA level.