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Cerebral malaria is one of the most severe pathologies of malaria; it induces neuro-cognitive sequelae and has a high mortality rate. Although many factors involved in the development of cerebral malaria have been discovered, its pathogenic mechanisms are still not completely understood. Most studies on cerebral malaria have focused on the blood-brain barrier, despite the importance of the blood-cerebrospinal fluid barrier, which protects the brain from peripheral inflammation. Consequently, the pathological role of the blood-cerebrospinal fluid barrier in cerebral malaria is currently unknown. To examine the status of the blood-cerebrospinal fluid barrier in cerebral malaria and malaria without this pathology (non-cerebral malaria), we developed a new method for evaluating the permeabilization of the blood-cerebrospinal fluid barrier during cerebral malaria in mice, using Evans blue dye and a software-assisted image analysis. Using C57BL/6J (B6) mice infected with Plasmodium berghei ANKA strain as an experimental cerebral malaria model and B6 mice infected with P. berghei NK65 strain or Plasmodium yoelii as non-cerebral malaria models, we revealed that the permeability of the blood-cerebrospinal fluid barrier increased during experimental cerebral malaria but not during non-cerebral malaria. We observed haemorrhaging in the cerebral ventricles and hemozoin-like structures in the choroid plexus, which is a key component of the blood-cerebrospinal fluid barrier, in cerebral malaria mice. Taken together, this evidence indicates that the blood-cerebrospinal fluid barrier is disrupted in experimental cerebral malaria, whereas it remains intact in non-cerebral malaria. We also found that P. berghei ANKA parasites and CD8+ T cells are involved in the blood-cerebrospinal fluid barrier disruption in experimental cerebral malaria. An understanding of the mechanisms underlying cerebral malaria might help in the development of effective strategies to prevent and manage cerebral malaria in humans.

GABA is a major neurotransmitter in the mammalian central nervous system. Glutamate decarboxylase (GAD) synthesizes GABA from glutamate, and two isoforms of GAD, GAD65, and GAD67, are separately encoded by the Gad2 and Gad1 genes, respectively. The phenotypes differ in severity between GAD single isoform-deficient mice and rats. For example, GAD67 deficiency causes cleft palate and/or omphalocele in mice but not in rats. In this study, to further investigate the functional roles of GAD65 and/or GAD67 and to determine the contribution of these isoforms to GABA synthesis during development, we generated various kinds of GAD isoform(s)-deficient rats and characterized their phenotypes. The age of death was different among Gad mutant rat genotypes. In particular, all Gad1

The consumption of dietary acrylamide (ACR), a carcinogen, results in the dysfunction of various organs and the immune system. However, the impact of ACR exposure on the progression of infectious diseases is unknown. This study investigated the effect of ACR on the progression of malaria infection using a mouse model of malaria. C57BL/6 mice were continuously treated with ACR at a dose of 20 mg/kg bodyweight/day for six weeks (long-term exposure) or phosphate-buffered saline (PBS). Next, the mice were infected with the rodent malaria parasite, Plasmodium berghei NK65 (PbNK). Parasitemia and survival rate were analyzed in the different treatment groups. Magnetic resonance imaging (MRI) and histopathological analyses were performed to evaluate the effect of ACR exposure on the morphology of various organs. Long-term ACR exposure exacerbated PbNK-induced multiorgan dysfunction. MRI and histopathological analysis revealed signs of encephalomeningitis and acute respiratory distress syndrome in the PbNK-infected long-term ACR exposure mice, which decreased the survival rate of mice, but not in the PbNK-infected long-term PBS exposure group. These findings enhance our understanding of the impact of ACR on the progression of infectious diseases, such as malaria.

Anaplastic ependymoma, World Health Organization grade III, is a malignant glioma with ependymal differentiation characterized by high mitotic activity often accompanied by microvascular proliferation and necrosis, where, generally, much fewer ependymal rosettes are found than in ependymoma, World Health Organization grade II. Ependymal rosettes, forming a single layer of tumor cells, differ from ependymoblastic multilayered rosettes, which are characteristic histologic features of ependymoblastoma, a variant of central nervous system primitive neuroectodermal tumor. Here, we report an autopsy case involving a 24-year-old woman with a frontal lobe tumor, which showed the aggregation of true rosettes with multilayering of tumor cells resembling the ependymoblastoma histology. Molecular and cytogenetic analyses revealed the absence of 19q13.42 amplification, a specific molecular hallmark of ependymoblastoma and embryonal tumor with abundant neuropil and true rosettes, supporting the diagnosis of anaplastic ependymoma.

To elucidate possible abnormalities of cerebellar basket cells of Creutzfeldt-Jakob disease (CJD), seven sporadic cases were examined neuropathologically. Recently, parvalbumin-positive, GABAergic cerebral interneurons have been demonstrated to show early, selective loss in CJD, and the phenomenon is postulated as a cause of characteristic neurological symptoms of CJD. In this study, however, we demonstrated that the basket cells, cerebellar counterparts, were resistant even in patients with severe brain atrophy, and their processes showed intense argyrophilia and immunopositivity to phosphorylated neurofilament. They can newly be listed as CJD-resistant neurons similar to those of the hippocampus and brainstem nuclei. The mechanism to escape cell loss is of great interest, and there might be unknown factors modulating susceptibility within parvalbumin-positive neuronal subgroups. Furthermore, one case showed abnormal positivity with hematoxylin, crystal violet and pyronin in the basket cells. The pyronin positivity was reduced after ribonuclease digestion, suggesting that the causative substance was composed of RNA. Ultrastructurally, the fibers contained free ribosomes and amorphous electron-dense deposits. To our knowledge, such a finding has also not been previously reported.

A report of an unusual esophageal tumor in an 81-year-old man is presented. The primary tumor was diagnosed as undifferentiated carcinoma at biopsy and had disappeared after irradiation treatment. However, multiple metastases were noted in the brain, lungs, kidneys, adrenals and spleen at autopsy. Histologically, metastases showed marked cartilaginous metaplasia as demonstrated by light microscopy, histochemical and immunohistochemical studies, although the initial biopsy sample did not possess chondroid matrix. Furthermore, an apparent transition could be traced from carcinomatous to chondroid cells, suggesting that the chondroid cells were derived from carcinoma cells. The carcinomatous area partially showed both squamous and glandular differentiation, although they were poorly differentiated. A retrospective immunohistochemical study that used a panel of antibodies suggested a phenotypic relevance between primary and metastatic tumors.

アンケートをもとに, 病理解剖された臓器の処理問題について考察した.同時に病理検査室における廃棄物・廃液問題や, 剖検を取り巻く法律や医学界の状況についても言及した.多くの施設では剖検臓器を火葬しており, 感染性廃棄物の処理方法として, さらには人道的立場からも適切と思われた.逆にホルマリンは多くの施設で垂れ流し状態であり, 早急な対策が必要であり, その一つとして安価で簡便な消石灰による中和法を紹介した.厚生省の臨床研修病院やいくつかの臨床系学会の認定医制度や認定施設制度では, 一定数以上の剖検施行が要件として挙げられているなど, 病理解剖は病理だけの問題にとどまらない.多方面の関係者の間で剖検を取り巻く諸問題を討議する必要があると思われる.

Schwannomas, particularly of vestibular origin, often accompany degenerative hypocellular areas known as Antoni B patterns; however, the detailed mechanism is uncertain. Eosinophilic hyaline droplets (EHD), the substantial nature of which are autophagic vacuoles, preferentially appear in acoustic schwannomas and distribute around areas of Antoni B. We investigated their common background using schwannomas with (15 cases) or without (10 cases) EHD, and demonstrated that EHD showed selective immunoreactivity with an anti-nitrotyrosine antibody, suggesting the overproduction of nitric oxide in this condition. The expression of inducible nitric oxide synthase was emphasized in infiltrating macrophages around hyalinized vessels. Protein-bound 4-hydroxy 2-nonenal, another oxidative stress marker, was detected in Antoni B tissue, but not in EHD. Antibodies to cleaved caspase-3 and single strand DNA, indicators of apoptosis, did not label tumors cells in Antoni B areas as well as EHD-bearing cells. The morphology and the mitotically static state of EHD-laden cells are phenotypically similar to autophagic cell death; however, autophagy in normal cells is a cell survival strategy against starvation, so the possibility remains that EHD are formed in that context. In either case, schwannomas may show a characteristic autophagic change by an endogenous mechanism. Tumor growth in a narrow intracranial space and resultant ischemia by self-oppression were postulated to be an initial event, because ischemia-reperfusion injury is a major source of reactive oxygen species and ischemia is also a potent trigger of autophagy as well as of tissue degeneration. Moreover, potential roles of chemokines and hemosiderosis are discussed.

Olig2 is a recently identified transcription factor involved in the phenotype definition of cells in the oligodendroglial lineage. The expression of Olig2 transcript has been demonstrated in human oligodendroglial tumors, although the protein expression has not been studied extensively. We developed a polyclonal antibody to human Olig2 and analyzed it immunohistochemically. The antibody depicted a single distinct band of predicted molecular weight by Western blotting, and did not cross-react with human Olig1. In normal human brain tissue, the nuclei of oligodendrocytes of interfascicular, perivascular, and perineuronal disposition were clearly labeled by the antibody. Similarly, the nuclei of oligodendroglial tumors were labeled. There was no apparent correlation between the staining intensity and histological grade. Astrocytic components within the tumors were generally less or not stained. Astrocytic tumors were also positive with the Olig2 antiserum to a lesser extent, and the difference between oligodendroglial and astrocytic tumors was demonstrated by a statistical analysis. Olig2 and glial fibrillary acidic protein were expressed in a mutually exclusive manner, and Olig2 expression was cell-cycle related. Neither central neurocytoma nor schwannoma cases were stained. Our antibody was demonstrated to be useful in recognizing normal oligodendrocytes on paraffin sections, and applicable in diagnosis of some brain tumors.

In schwannoma, degenerative structures, such as bizarre hyperchromatic nuclei, lipofuscin deposition, hemorrhage, edema, etc., are frequently encountered and are regarded as hallmarks of the benign nature of the neoplasm. Hyaline globules or eosinophilic hyaline droplets (EHDs) have been observed in a large variety of tumors, but they are rare histological manifestations of schwannoma, and the details have not been described as yet. We reviewed 171 cases of schwannoma of conventional histology. We classified them based on the sites where they occurred as follows: 43 acoustic nerves, 9 other cranial nerves, 30 spinal nerve roots, and 89 soft parts. We found EHDs in 8/43, 1/9, 1/30, 2/89 cases, respectively. The droplets were located in both the perikarya and processes. Ultrastructurally, they were electron-dense, round to ovoid organelles, and indistinguishable from secondary lysosomes. MIB-1 immunolabeling of the droplet-bearing cells was almost negative; however, they maintained a viable nuclear appearance without karyorrhexis, pyknosis or apoptotic changes. We therefore conclude that EHD is a new member of degenerative structures in schwannoma, and a hallmark of low growth potential. Furthermore, their higher frequency in acoustic schwannoma may suggest their distinct nature from those originated in the other sites. Possible relevance of EHDs and cellular senescence is also discussed.

Perivascular cells or fluorescent granular perithelial cells of the central nervous system are newly recognized members of monocyte/macrophage populations. In this study a monoclonal antibody, GP-3, that labels proteinous lysosomal antigen of human perivascular cells, has been established. It selectively label the cells in foamy-macrophage infiltrating diseased areas, such as Wallerian degeneration and contusion, without significant reaction to the cells in normal areas, infiltrating macrophages or microglia. These findings suggest that the perivascular cell is an independent cell type and the antigen molecule is fairly specific to perivascular cells and plays an unknown role in immune-nervous system interaction.

Epithelioid angiomyolipoma (AML) is a newly established variant of AML, characterized by monomorphous epithelioid cells that show HMB-45 immunopositivity, and it often displays aggressive behavior. To date, they have mostly appeared in the kidneys; however, the present autopsy case of a 43-year-old female without the stigmata of tuberous sclerosis complex had a huge retroperitoneal mass, accompanied by involvement of the regional lymph nodes. Histopathologically, the tumor was composed of round, polygonal or short spindle-shaped monomorphous cells with abundant eosinophilic cytoplasm and large nuclei with frequent multinucleation. Mitotic figures were scattered. Mature fat cells and thick-walled abnormal blood vessels were totally absent. Immunohistochemically, the tumor cells were reactive with HMB-45 and alpha-smooth muscle actin antibodies. In spite of curative surgery and repeated radio- and chemotherapy, the tumor continued to grow and brought about the patient's death 4 years after the initial symptoms. At autopsy, the peritoneal cavity was filled with the tumor mass exceeding 5.5 kg. Histopathological features were essentially the same as those of biopsy samples, but the cellular pleomorphism and emperipolesis were more easily identified. This report calls attention to this unusual manifestation of AML in the retroperitoneum and the importance of distinguishing it from sarcomas and/or paragangliomas.

Since 1972, many prosthesis for the knee joint have been reported. They are, however, designed only for hinge and rolling functions neglecting the screw-home function. Surgical damage by massive bone resection would not permit secondary operation even if it is required and only osteosynthesis or hinge prosthesis are indicated thereafter. Musculo-tendinous stability being absolutely required on surgery, ligamentous transfer is often accompanyed in those prosthesis.In view of the above, we deviced a new functional endoprosthesis for the knee joint which satisfies all three functional phases of knee motion and maintains sufficient stability.The functional endoprosthesis (Keio type) is indicated for osteoarthritis, rheumatoid arthritis and some type of condylar fracture. Operative damage by this endoprosthesis is fairly less and secondly reconstruction using any type of similar prosthesis may still remain the treatment of second choice.