Takesaburo Ogata

Central nervous system changes in mitochondrial encephalomyopathy: light and electron microscopic study

SummaryAn autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is reported. It presented with generalized muscle atrophy, stroke-like episodes, schizophrenia-like mental disorder and progressive dementia. Serum lactate and pyruvate levels were high. In the biopsied muscles, ragged-red fibers were observed by light microscopy and aggregation of abnormal mitochondria with paracrystaline formation by electron microscopy. The most characteristic neuropathological findings were infarct-like lesions widespread in the cerebral cortex. In addition, this case showed some unusual pathological features: (1) diffuse moderate fibrillary gliosis in the whole cerebral and cerebellar white matter, which might have been due to metabolic disturbances; (2) several focal lesions with demyelination and numerous spheroids in the pontocerebellar fibers; and (3) marked degeneration of the posterior columns and spinocerebellar tracts. Electron microscopic examination revealed that abnormal mitochondria were markedly aggregated in smooth muscle cells and endothelium of the cerebral and cerebellar blood vessels. These fine structural findings suggest a “mitochondrial angiopathy”.

Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer.

Small cell lung cancer (SCLC) is characteristically not associated with tumour‐infiltrating lymphocytes. Since SCLC has been reported to show marked reduction of class I HLA, the reduced expression has been considered a means of escaping anti‐cancer immunity. However, HLA‐DR expressed in cancer cells is now known to contribute to anti‐cancer immunity. To clarify the difference in HLA‐DR expression between SCLC and non‐small cell lung cancer (NSCLC), and the mechanism, the expression and the cis‐ and trans‐acting factors involved were investigated. HLA‐DR was not immunohistochemically detected in any SCLC and could not be induced by interferon gamma (IFN‐γ) in any SCLC cell line, whereas HLA‐DR was expressed to varying degrees and was easily induced in NSCLC. SCLC cell lines lacked class II transactivator (CIITA) even after IFN‐γ induction, whereas NSCLC cell lines expressed CIITA. The other class II HLA‐specific transcription factors were expressed and genomic DNA of HLA‐DR, including the promoter, was conserved well both in SCLC and in NSCLC cell lines. CIITA transfection improved the expression of HLA‐DR in SCLC. In conclusion, the lack of CIITA results in severe deficiency of HLA‐DR expression in SCLC. Since CIITA has also been reported to induce class I HLA, CIITA transfection might make it possible to establish effective anti‐cancer immunotherapy against SCLC through the up‐regulation of class I and class II HLA. Copyright

Correlation between lipid peroxidation and morphological manifestation of paraquat-induced lung injury in rats.

Biochemical and morphological studies of rat lung were performed to determine the role of lipid peroxidation in the in vivo lung toxicity of paraquat. Two injections of 20 mg/kg paraquat were administered intraperitoneally every other day. While notable epithelial damage in the lungs was observed on the day after the second paraquat injection and progressed through the 5th day, the concentration of lipid peroxides in the rat lungs did not increase by the 3rd day after the injection. The lipid peroxide concentrations increased after the 5th day post-injection, and reached the maximum concentrations on the 7th day, when the damaged alveolar surface had been mostly repaired by regenerative pneumocytes. On the other hand, the delayed increase of lung lipid peroxides in paraquattreated rats paralleled the increased number of macrophages in the lung, which reached maximum numbers on the 7th day. Glutathione peroxidase activity in the lungs also increased with a similar time course. Macrophages from the lungs contained a large amount of engulfed degradation products and cellular debris, and immunohistochemical study showed high glutathione peroxidase content on the 5th and 7th days. These results suggest that lipid peroxidation is a relatively late event in the in vivo paraquat-treated lung and that the delayed increase of lipid peroxides in the lungs occurs from the phagocytic activities of macrophages rather than from toxic cell injury.

Lymphocytic infiltration in juvenile thyroid carcinoma.

In this study, the significance of lymphocytic infiltration in juvenile thyroid carcinoma is clarified. We examined nine patients younger than 20 years of age. Histopathologically, there was good correlation between lymphocytic infiltration and the development and spread of carcinoma. It is believed that lymphocytic infiltration around the tumor is an immunologic reaction induced by antigens from the carcinoma itself, and also that the reaction may progress according to tumor development. Immunocytochemically, we determined what type of inflammatory cells infiltrated the thyroid and demonstrated HLA‐DR expression in the cancer cells. These findings are similar to autoimmune thyroiditis in which antibody‐dependent cellular cytotoxicity (ADCC) works as a main immunomechanism.

Flow cytometric dna analysis of parathyroid tumors with special reference to its diagnostic and prognostic value in parathyroid carcinoma

The nuclear DNA content of paraffin‐embedded parathyroid tumors from 49 patients with proven primary hyperparathyroidism was determined by flow cytometric analysis. The lesions included 14 primary and 11 locally recurrent or metastatic lesions from 16 carcinoma patients, 28 single adenomas from 28 patients, and 15 hyperplastic glands from five patients with familial multiple endocrine neoplasia type 1. No abnormal DNA stemline was found in any of the hyperplastic glands. One (3.6%) of the adenomas was aneuploid. There was no difference in ploidy patterns between the primary and recurrent lesions of the carcinomas and five (31%) of the carcinomas expressed aneuploidy. Four of the five patients with aneuploid carcinoma had recurrences including pulmonary metastases. One of them died of this disease 12 years after the initial operation, and all except one of the others are hypercalcemic even after removal of the successive recurrent or metastatic tumors. Of the 11 patients with diploid carcinoma, four had either local recurrence or pulmonary metastasis. Two of them are living with normocalcemia 3 and 6 years, respectively, after removal of the recurrent tumors and the others are alive with mild hypercalcemia. The remaining seven patients with diploid carcinoma, however, have no recurrence 2 to 5 years after the initial operation. Thus aneuploid parathyroid carcinomas are likely to show more malignant behavior than those with a diploid DNA pattern. All of the patients with adenoma and hyperplasia have been normocalcemic after a mean follow‐up‐interval of 37 months. This study indicates that flow cytometric analysis of nuclear DNA content is a valuable adjunct to histologic examination in the diagnosis of parathyroid carcinoma and the prediction of the clinical outcome.

Preoperative radiotherapy and surgery for advanced thymoma with invasion to the great vessels

From 1983 to 1994, 12 advanced thymomas with invastion to the great vessels were initially treated by irradiation (mean dose, 18.3 Gy) and subsequent surgical resection. In nine patients, complete resection was possible by concomitant resection of the surrounding tissues, mainly pericardium and/or brachiocephalic vein. Histologically, all tumors showed prominent fibrosis. Ten patients also received postoperative radiotherapy (mean dose, 42.3 Gy). Tumor‐related deaths occurred in only two patients; one who did not receive postoperative irradiation 21 months and one who had viable cells at the surgical margin 10 months after operation. However, there were also 2 patients who died of respiratory failure due to operation and/or irradiation, one 45 days and the other 7 years after the treatment. Preoperative radiotherapy could facilitate complete resection of the advanced thymomas. The prognosis of the patients treated with preoperative radiotherapy seemed fair if followed by adequate resection and subsequent irradiation.

Myoclonus, cerebellar disorder, neuropathy, mitochondria1 myopathy, and ACTH deficiency

A 50-year-old Japanese woman with action myoclonus, cerebellar signs, neuropathy with axonal degeneration and onion-bulb formation, muscle atrophy with mitochondrial abnormalities, and isolated ACTH deficiency was reported. Her daughter had myoclonus epilepsy and cerebellar ataxia. Neuropathologic findings included atrophy of the dentate and inferior olivary nuclei, Purkinjes cell loss, and demyelination of the posterior columns and spinocerebellar and pyramidal tracts of the spinal cord, besides severe respirator changes. Laforas bodies were absent. The present case should be included in the entity “myoclonus epilepsy associated with mitochondrial myopathy.”

Calbindin-D 28k immunoreactivity in the cerebellum of spinocerebellar degeneration

We studied immunoreactivity for calbindin-D 28k (CaBP), an intracellular calcium-binding protein, in the cerebellum of control subjects and of patients with spinocerebellar degeneration (SCD) including sporadic olivopontocerebellar atrophy and familial cortical cerebellar atrophy. In the cerebellum, CaBP immunoreactivity was seen exclusively in the Purkinje cell in both SCD and control groups. However, the number of CaBP-immunoreactive Purkinje cells was significantly reduced in SCD. CaBP immunohistochemistry also disclosed abnormal morphological changes of Purkinje cells, which was not visualized on conventional strains or not clearly demonstrated on immunohistochemistry for neurofilaments. Moreover, reduced CaBP immunoreactivity was observed even in some remaining Purkinje cells of SCD suggesting that loss of CaBP precedes neuronal loss of Purkinje cell. We conclude that CaBP is a useful marker for Purkinje cell degeneration, and that reduced CaBP expression might have some association with the mechanism of the Purkinje cell degeneration in SCD.

Cerebral cortical pathology of sporadic olivopontocerebellar atrophy.

We examined the cerebral cortices of six brains from patients with sporadic olivopontocerebellar atrophy (s-OPCA), five control brains including four from patients who had died without neurological disease, and one from a patient with Holmes-type cerebellar cortical atrophy. Distinct laminar astrocytosis of the motor cortices in the fifth layer were demonstrated in 4 of 6 s-OPCA cases and in none of the control cases by immunohistochemistry for glial fibrillary acidic protein. The astrocytosis localized in the primary motor cortex and its distribution pattern were clearly different from those of so-called glial cytoplasmic inclusion. This cortical astrocytosis appears to be characteristic of s-OPCA and may reflect the pathology of the primary motor cortex.

Complicated Mechanisms of Class II Transactivator Transcription Deficiency in Small Cell Lung Cancer and Neuroblastoma

Small cell lung cancer (SCLC) and neuroblastoma (NB), the most aggressive adult and infant neuroendocrine cancers, respectively, are immunologically characterized by a severe reduction in major histocompatibility complex (MHC) that is indispensable for anti-tumor immunity. We had reported that the severe reduction of MHC in SCLC was caused by a deficient interferon (IFN)-gamma-inducible expression of class II transactivator (CIITA) that is known as a very important transcription factor for IFN-gamma-inducible class II and class I MHC expression (Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, Fujimoto M, Yokohama K, Ogata T: Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 1999, 187:191-199). Here, we demonstrate that the reduction of MHC in NB was also caused by a deficient IFN-gamma-inducible expression of CIITA and that the deficiency in SCLC and NB was caused by similar mechanisms. Human achaete-scute complex homologue (HASH)-1, L-myc, and N-myc, which are specifically overexpressed in SCLC and NB, bound to the E-box in CIITA promoter IV and reduced the transcriptional activity. Anti-sense oligonucleotide experiments revealed that overexpressed L-myc and N-myc lie upstream in the regulatory pathway of HASH-1 expression. The expression of HASH-1 was also up-regulated by IFN-gamma. Our results suggest that SCLC and NB have complicated mechanisms of IFN-gamma-inducible CIITA transcription deficiency through the overexpressed HASH-1, L-myc, and N-myc. These complicated mechanisms may play an important role in the escape from anti-tumor immunity.