Biomedical subjects
Publications and source records attributed to S Murayama.
We report on a Japanese family affected by Emery-Dreifuss muscular dystrophy carrying a novel mutation of the emerin (STA) gene. The cardinal clinical feature of the family was cardiac conduction block and mild myopathy. A deletion of 11 bp with a frameshift was identified in exon 6, causing truncation of the predicted protein. The relationship between mutation and phenotype is discussed.
The demonstration of a genetic linkage between the copper-zinc superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis has aroused interest in the role of SOD1 in motoneuronal death. We investigated the expression of the human SOD1 gene at a cellular level in the motoneurons of patients with sporadic amyotrophic lateral sclerosis, patients with familial amyotrophic lateral sclerosis, and normal control subjects, using a quantitative in situ hybridization technique. There were no significant differences between the amounts of SOD1 messenger RNA observed in patients with sporadic disease, patients with familial disease, and normal control subjects. However, many of the atrophic motoneurons from patients with sporadic or familial disease had significantly lower levels of SOD1 messenger RNA, compared to morphologically intact motoneurons. Moreover, motoneurons in the normal spinal ventral horn and precentral motor cortex exhibited significantly higher levels of SOD1 messenger RNA than did other neurons. Our study indicated that vulnerable neurons in amyotrophic lateral sclerosis exhibit high levels of SOD1 messenger RNA, suggesting a close relationship between the SOD1 gene and the pathogenesis of amyotrophic lateral sclerosis.
AIM: Treatment of carcinoma of the uterine cervix by remote afterloading brachytherapy has been accompanied with new isotopes having dose rates different from the classical low-dose rate (LDR) radium source. The dose rate conversion factor from LDR to high-dose rate (HDR) found to be around 0.54 in most studies. As regards medium-dose rate (MDR) brachytherapy, the published data are very few and the experience is still short. In this study the experience of Osaka University Hospital with micro-HDR-Selectron and Selectron-MDR, as a preliminary report of the clinical trial, is presented. PATIENTS AND METHOD: From August 1991 through April 1993, a total of 45 patients with carcinoma of the uterine cervix were randomly allocated to either microSelectron-HDR or Selectron-MDR at the Osaka University Hospital. As regards HDR, dose to point A was adjusted to 32 Gy (for stages I and II). 30 Gy/4 fractions, and 22.5 Gy/3 fractions, for stages III, and IV, respectively. The corresponding values in case of MDR were 35.6, 34 Gy/4 fractions, and 25.5 Gy/3 fractions. External irradiation, according to the stage, was the same in the 2 groups. Nucletron Planning System (NPS) was used for pre-treatment dose calculation at point A, rectal and bladder wall. The dose rate at point A ranged from 24 to 75.6 cGy/min for the HDR group, while for the MDR group ranged among 174.8 to 229.6 cGy/h. RESULTS: The 3-year survival and loco-regional control rates for both modalities were nearly equivalent (62% and 67% for HDR and 68% and 74% for MDR). The cumulative rectal and bladder complication rates were the same in both groups (29% at 3 years), with only 1 patient (MDR-group) developed grade 3 rectal and bladder complication. In this study, point A dose rate correction factor from LDR to HDR was 0.53 and 0.6 from LDR to MDR. CONCLUSIONS: From the previous reports from Osaka University Medical School, as well as others, HDR was proposed as an alternative to LDR brachytherapy for treatment of carcinoma of the uterine cervix. In this report, Selectron-MDR was nearly equivalent to the microSelectron-HDR as regards survival and loco-regional control rates as well as radiation-induced complication. This is a preliminary report, and the study still needs larger number of patients, and longer follow-up period.
We report the MR findings in two cases of acute suppurative perithyroiditis. MR has the advantages over other imaging modalities of being able to distinguish areas of inflammation from adjacent normal tissue and of allowing imaging in planes which more accurately demonstrate the extent of the lesion. MR imaging is one of the most useful methods to evaluate this entity.
Iron accumulation in the basal ganglia and spheroid formation are pathological hallmarks of Hallervorden-Spatz disease (HS). Since an overaccumulation of iron (iron thesaurosis) that exceeds the binding capacity of ferritin could cause oxidative damage, we studied the possible role of oxidative stress in the pathogenesis of HS. The basal ganglia and spinal cord from patients with HS were investigated at autopsy, using histochemistry for iron and immunohistochemistry for Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and ferritin. SOD1-like immunoreactivity (IR), SOD2-IR and ferritin-IR occurred frequently in spheroids observed in the basal ganglia, and associated iron accumulation indicated the possible existence of increased oxidative stress in HS patients. Spheroids in the spinal cord showed intense SOD1-IR and SOD2-IR in HS, in sharp contrast with the occasional weak SOD1-IR and SOD2-IR observed in spheroids from patients with amyotrophic lateral sclerosis (ALS). Neither increased ferritin-IR nor iron accumulation were observed in spinal spheroids from HS and ALS patients. These data may suggest that, at least in the spinal cord, SOD1-IR and SOD2-IR in spheroids in HS patients do not result from oxidative stress directly related to iron accumulation.
We present a long-surviving patient with Wiskott-Aldrich syndrome complicated by atypical progressive multifocal leukoencephalopathy (PML). MRI showed multiple tiny spots of Gd-DTPA-enhanced lesions on the T1-weighted image. Pathologic findings for brain biopsy were patchy demyelinated vascularized lesions infiltrated by a surprising number of eosinophils. The presence of polyomavirus JC was confirmed by in situ hybridization and polymerase chain reaction. PML should be included in the differential diagnosis when Gd-DTPA-enhanced spotty lesions are present in the white matter, especially in patients who have a mild immunologic defect.
More than 40,000 cases have been treated with gamma knife radiosurgery, but few neuropathological reports are available. This paper describes two autopsy cases in which the patients had been treated with gamma knife. As these patients died 67 and 24 days after therapy, early neuropathological changes are reported. The first case was a 58-year-old woman diagnosed with multiple brain metastases from breast cancer. One of these lesions, in the medullaoblongata, was irradiated with a gamma knife. Sixty-seven days later, she died from heart failure. The second case was a 69-year-old man diagnosed with multiple brain metastases from lung cancer. One of these lesions, in the pons, was irradiated with a gamma knife. Twenty-four days later, he died from acute renal failure caused by hepatorenal syndrome. In both cases, the irradiated lesions were well demarcated from the undamaged surrounding tissues on light microscopy. Histologically, the tumor cells showed a variety of degenerative changes, such as pyknosis, multinuclear cells, and vacuolar degeneration in the cytoplasm. Fibrosis, more prominent in the first case, was observed spreading in the irradiation field, adhering to the hyalinized and thickened vessel walls. Demyelination was also observed in the first case. As far as we know, this report is the first published description of fibrosis in the radiosurgical irradiation field.
We report a case of intrapulmonary hematoma in which magnetic resonance imaging was useful in establishing the diagnosis. A 53-year-old man had bronchial asthma that was well controlled with inhaled beclomethasone dipropionate and salbutamol, and with oral theophylline. A spherical mass was found in the right lower lung field on a chest radiograph taken during a regular physical examination. A CT scan showed a well circumscribed spherical mass, which was attached to an intrapulmonary bullae. Magnetic resonance imaging showed a well-circumscribed mass in the superior segment of the right lower lobe. On a T1-weighted image the mass was hyperintense and had a higher-intensity rim. On a T2-weighted image the mass was hyperintense and had some hypointense areas. We therefore diagnosed intrapulmonary hematoma. Chest radiography 6 months later revealed a substantial decrease in the size of the mass, which supported the diagnosis. As in this case, intrapulmonary hematoma can be difficult to diagnose because of the lack of a history of injury and because of the slow regression. In this case, magnetic resonance imaging was useful in making the diagnosis.
In radiotherapeutic management for pediatric tumors, we have to pay more attention to confinement of higher dose to the target volume than for adult tumors, in order that the risk of untoward normal tissue complications dose not increase, such as growth retardation. Two current approaches performing in our department to match this purpose are presented, namely, perioperative brachytherapy and fractionated stereotactic radiotherapy (F-SRT). In perioperative brachytherapy for bone and soft tissue sarcoma, plastic guide tubes for introducing radioactive sources are placed in the residual tumor bed or at the margins during the surgery, and patients are treated by high-dose-rate brachytherapy after surgery. Patients are not restricted in radioprotective area, and the overall treatment period is short enough. F-SRT is used either as the boost of conventional brain radiotherapy in primary brain neoplasms, or as hypofractionated F-SRT for control of metastatic brain tumors, with nearly perfect local control and maintenance of good quality of life. F-SRT is planned in 3-dimensional fashion from computed tomography images. Easily detachable, relocatable cast made for F-SRT is useful in pediatric patients.
We applied low dose external beam radiation (6 MV) to 17 eyes of 17 patients (Mean age 70.9 years, range 58 approximately 85) who had subfoveal choroidal neovascularization associated with age-related macular degeneration. None of the cases were suitable for photocoagulation according to the Macular Photocoagulation Study protocol, and no feeding vessels underlying choroidal neovascular membrane could be detected. Corrected visual acuity ranged from 0.02 to 0.6 before treatment. The patients were divided into two groups. One group of 11 eyes was treated with 10 Gy and the other group of 6 eyes with 21 Gy. Mean follow up period was 347 +/- 89 (mean +/- standard deviation) days in the 10 Gy group and 312 +/- 100 days in the 21 Gy group. We evaluated the outcome as "effective' if no progression in neovascular membrane was found by ophthalmoscopic and angiographic examination. Only 3 eyes (21%) of patients in the 10 Gy group and 2 eyes (33%) in 21 Gy group showed any effect. Although the rate of progression in choroidal neovascular membrane was significantly smaller in the 10 and 21 Gy group than in the controls, the corrected visual acuity in the treated group was not improved over that of the controls. No serious complications were seen. Only one case showed a stabilized neovascular membrane in the control group of 7 patients. Although the present results seem to be worse than those in previous reports, the efficacy of this treatment still needs to be evaluated because no beneficial strategies in the treatment of subfoveal neovascularization have been established.
PURPOSE: Oral tongue carcinomas are highly curable with radiotherapy. In the past, patients with tongue carcinoma have usually been treated with low dose rate (LDR) interstitial radiation. This Phase III study was designed to compare the treatment results obtained with LDR with those obtained with high dose rate (HDR) interstitial radiotherapy for tongue carcinoma. METHODS AND MATERIALS: The criteria for patient selection for the Phase III study were: (a) presence of a T1T2N0 tumor that could be treated with single-plane implantation, (b) localization of tumor at the lateral tongue border, (c) tumor thickness of 10 mm or less, (d) performance status between O and 3, and (e) absence of any severe concurrent disease. From April 1992 through December 1993, 15 patients in the LDR group (70 Gy/4 to 9 days) and 14 patients in the HDR group (60 Gy/10 fractions/6 days) were accrued. The time interval between two fractions of the HDR brachytherapy was more than 6 h. RESULTS: Local recurrence occurred in two patients treated with LDR brachytherapy but in none of the patients treated with HDR. One- and 2-year local control rates for patients in the LDR group were both 86%, compared with 100% in the HDR group (p = 0.157). There were four patients with nodal metastasis in the LDR group and three in the HDR group. Local recurrence occurred in two of the four patients with nodal metastases in the LDR group. One- and 2-year nodal control rates for patients in the LDR group are were 85%, compared with 79% in the HDR group. CONCLUSION: HDR fractionated interstitial brachytherapy can be an alternative to traditional LDR brachytherapy for early tongue cancer and eliminate the radiation exposure for medical staffs.
Presenilin 1 (PSNL1) is a novel causative gene for early-onset familial Alzheimer's disease (EOFAD). We have examined the regional and cellular distribution of PSLN1 gene expression in normal human and rat tissues. In situ hybridization and Northern blot analysis showed that PSNL1 mRNA was ubiquitously expressed in many different organs. We also demonstrated that PSNL1 mRNA was expressed predominantly in the neuronal cells of the central nervous system, but only at low-level in glial cells. Furthermore, the distribution of PSNL1 mRNA in human and rodent brains was similar.
Machado-Joseph disease (MJD) is an autosomal dominant disorder characterized pathologically by spinocerebellar degeneration. Recently, an expansion of CAG repeat in a gene located at the chromosome 14q32.1 was found to be responsible for the disease. Here, we investigated in situ the expression of the MJD gene (MJD1) in the central nervous systems of normal and affected individuals and in rat brains. This gene was expressed in all regions of rat and human normal brains with certain regional variations. MJD1 was transcribed preferentially in neurons, although low levels of MJD1 mRNA were also observed in glial cells. Neurons susceptible to degeneration in MJD expressed MJD1 but not selectively. In the affected brains, the MJD1 mRNA distribution and amount in all the areas examined were similar in patients and controls. In addition, the cellular MJD1 mRNA level correlated neither with clinical severity nor expanded length. Our study showed that the expression levels of trinucleotide repeats in MJD patients and normal controls did not differ, indicating that the pathogenesis of MJD may involve direct toxicity to vulnerable subsets and/or region-specific cofactors of MJD proteins.
To investigate the physiological significance of hepatocyte growth factor (HGF) after transcatheter arterial chemo-embolization (TACE), we measured serum HGF levels in 23 patients who underwent angiography (n = 3) or TACE (n = 20). HGF levels increased biphasically after TACE. It rapidly increased to 10-fold higher levels immediately after heparin-injection even before embolization. Serum HGF then decreased to below 1.0 ng/ml at 6 hours after the procedure. The second peak (a 2-fold increase) appeared 1-3 days after TACE. The first increase may be due to the injection of heparin which releases HGF from the cell-surface and extracellular matrix of the liver. Patients treated to a larger extent showed higher increase in serum HGF levels, and thus the impaired hepatic HGF clearance and size of regeneration may cause second elevation of serum HGF levels. Six out of eleven patients whose serum HGF levels before TACE were more than 0.5 ng/ml died in the follow-up period whereas no patients died with serum HGF under 0.5 ng/ml. Therefore, serum HGF levels before the procedure have the potential to be a good indicator of outcome.
Hepatocyte growth factor (HGF) has been shown to have a pleiotropic function to act as a potent organotropic factor in the regeneration of injury in various organs, including the liver, kidney and lung. To examine the involvement of HGF in radiation injury, the authors analysed the changes in HGF mRNA and HGF protein levels in the rat organs (liver, lung, kidney) and plasma following 6 Gy of total body irradiation. Expression of HGF mRNA in the liver and kidney increased 6-48 h after total body irradiation and returned to previous values 1 week later. HGF protein levels in lung and liver showed 1.3-2-fold elevations 1-2 weeks after irradiation (P < 0.05). HGF levels in plasma stayed at undetectable levels up to 1 month after total body irradiation. The labelling index determined 2 weeks and 1 month after total body irradiation indicated no enhancement of regeneration. Thus, total body irradiation induced transient HGF elevation in these organs without enhancement of regeneration.
We evaluated the usefulness of fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) in the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer and then compared the findings with the results of X-ray CT by region based on the histological diagnoses. We examined 29 patients with non-small cell lung cancer. One hundred and thirty-two mediastinal lymph nodes were surgically removed and the histological diagnoses were confirmed. FDG PET images, including 146 mediastinal regions, were visually analysed and the mediastinal lymph nodes were scored as positive when the FDG uptake was higher than that in the other mediastinal structures. On the X-ray CT scans, any mediastinal lymph nodes with a diameter of 10 mm or larger were scored as positive. All three examinations were successfully performed on 71 regions. For FDG PET, we found a sensitivity of 76%, a specificity of 98% and an accuracy of 93%. On the other hand, for X-ray CT a sensitivity of 65%, a specificity of 87% and an accuracy of 82% were observed. A significant difference was observed in respect of both specificity and accuracy (P<0.05). Based on the above findings, FDG PET is suggested to be superior to X-ray CT when used for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer.
The usefulness of FDG-PET in the detection of infectious foci and the assessment of lesion activity was evaluated. The study covered 24 patients with 25 FDG-PET studies, including lesions of bacterial, tuberculous and fungal origins. The FDG uptake was determined by the lesion to muscle ratio (LMR) on the static images. The time activity curves (TACs) were classified into four patterns based on both the existence of an initial peak and a slope thereafter. A high FDG uptake was observed in 23 of 25 lesions (92%). Two lesions, in which no abnormal uptake was noted, included one in the healing stage and the other consisting of a cavity with a thin wall. The acute active lesions showed higher LMRs than the chronic active or healing lesions (mean +/- SD: 9.8 +/- 3.6, 3.6 +/- 1.8 and 4.3 +/- 1.7, respectively, p < 0.05), and they could be approximately distinguished by an LMR of 6. The patterns of the TACs in acute or chronic active lesions were either an increase without an initial peak or a plateau, while those in the healing lesions demonstrated predominantly an increase with an initial sharp peak. Our results indicated that FDG-PET is clinically useful in the detection of the infection of miscellaneous microorganisms as well as in the assessment of lesion activity.
Missense mutations in presenilin 1 (PSNL1) are known to cause familial Alzheimer's disease which is a subtype of Alzheimer's disease (AD). Our investigation, using an in situ hybridization technique, indicated that the localization of PSNL1 mRNA is similar in sporadic AD affected and normal human brains. Furthermore, the amounts of PSNL1 mRNA in neurofibrillary tangle (NFT)-bearing neurons and those without NFTs did not differ, and the clinical severity of AD was not related to PSNL1 mRNA expression level.