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Introduction Gerstmann–Sträussler–Scheinker disease P105L (GSS105) is a rare variant of GSS caused by a point mutation of the prion protein (PrP) gene at codon 105 (proline to leucine substitution). It is clinically characterized by spastic paraparesis and dementia and histopathologically defined by PrP‐plaques in the brain. This report describes a clinicopathological analysis of three autopsied kindred from a Japanese GSS105 family, plus a topological analysis of PrP, hyperphosphorylated tau (p‐tau), and beta‐amyloid (Aβ). Methods Using paraffin‐embedded sections, we applied histology and single‐ and multiple‐labeling immunohistochemistry for PrP, p‐tau, and Aβ to the three cases. Comparative semi‐quantitative analyses of tissue injuries and PrP‐plaques were also employed. Results Case 1 (45 years old (yo)) and Case 2 (56 yo) are sisters, and Case 3 (49 yo) is the son of Case 2. Case 1 and Case 2 presented with spastic paraparesis followed by dementia, whereas Case 3 presented, not with spastic paraparesis, but with psychiatric symptoms. In Case 1 and Case 2, the brain showed tissue injuries with many PrP‐plaques in the cerebral cortices, and the pyramidal tract showed myelin loss/pallor. In Case 3, the brain was least degenerated with a number of PrP‐plaques; however, the pyramidal tract remained intact. In addition, p‐tau was deposited in all cases, where p‐tau was present in or around PrP‐plaques. By double‐labeling immunohistochemistry, the colocalization of p‐tau with PrP‐plaques was confirmed. Moreover in Case 2, Aβ was deposited in the cerebral cortices. Interestingly, not only p‐tau but also Aβ was colocalized with PrP‐plaques. In all cases, both three repeat tau and four repeat tau were associated with PrP‐plaques. Conclusions The clinicopathological diversity of GSS105, which is possible even in the same family, was ascertained. Not only p‐tau but also Aβ could be induced by PrP (“secondary degeneration”), facilitating the kaleidoscopic symptoms of GSS.

The patient was born at 38 weeks gestation with body weight of 2700 g from non-consanguineous parents. She was the third child with two healthy brothers. At 2 months of age, she had afebrile seizures. She was admitted to hospital because of an epileptic state. Her chromosomal pattern was 46XX by G-band analysis. A deletion in the Miller-Dieker syndrome (MDS) region was confirmed by fluorescence in situ hybridization (FISH) for chromosomal testing. Brain CT/MRI revealed lissencephaly and dysgenesis of corpus callosum: the absence of rostrum and splenium (Fig. 1). Radiologically, no abnormalities were found in the body except the brain. At the age of 4 years, she was hospitalized at a nursing center. Profound mental and motor retardation, seizures and hypertonia were found. She suffered from repeated episodes of bronchitis/ pneumonia, depletion of carnitine, and chronic insufficiency of digestion. Gastrostomy was performed at 6 years of age owing to feeding problems. She died of pneumonia at 14 years of age.

症例は72歳，男性．嚥下障害から食道癌と診断され，手術を施行した．最終診断はbasaloid carcinoma，T1b（SM3），ly1，v1，N0，M0，StageIであった．術後4カ月で肝転移を認め，肝動注化学療法を開始し，術後12カ月でComplete Responseを得た．術後15カ月で腸閉塞を発症し，CTにて下腹部に腫瘤を認めたため緊急手術を施行した．Treitz靱帯より40cmほどの空腸に腫瘤を認め，上行結腸に浸潤していたため，腫瘤を含む空腸部分切除と右結腸切除を行った．腹膜播種は認めなかった．術後経過は良好であったが，肺転移・骨転移をきたし，食道癌術後40カ月で死亡した．食道癌の小腸転移は検索しえた限りでは本例が17例目であり，類基底細胞癌によるものは本症例が1例目である．非常に稀な症例を経験したので若干の文献的考察を加え報告する．

This report describes the clinical and pathologic findings of 21 patients with subacute necrotizing lymphadenitis (N.L.). Clinical features of all but 2 patients were as typically described in the literature; young age, enlargement of cervical or axillary lymph nodes, slight to moderate fever with poor response to antibiotics, and invariable spontaneous resolution. Two patients showed atypical clinical findings; remittent high fever with profound prostration in both patients, generalized lymphadenopathy in one, and being a Caucasian in the other. Systemic symptoms resolved gradually, and both patients are now doing well. One patient, however, underwent a staging laparotomy due to a misdiagnosis as unclassiflable lymphoma of the lymph node biopsy. Biopsies of the lymph nodes from all patients demonstrated the typical pathologic features of NL.; i.e., an intensive proliferation of activated lymphocytes mottled by necrotic foci in which polymorphonuclear leukocytes were characteristically absent. Bacteriologic and serologic studies were negative. We conclude that some patients with N.L. run a protracted course with remittent high fever before spontaneous resolution and that a correct pathologic diagnosis helps precluding unnecessary diagnostic or therapeutic measures on such patients.

Dentatorubral-pallidoluysian atrophy (DRPLA) is one of the CAG-repeat diseases, and is classified into juvenile and early adult types showing progressive myoclonus epilepsy (PME) in addition to late adult type. We immunohistochemically examined accumulation of oxidative products and expression of superoxide dismutase (SOD) in autopsy cases of DRPLA. Oxidative products to nucleosides, 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanosine, were accumulated in the lenticulate nucleus predominantly in DRPLA cases having PME. Neuronal accumulation of 4-hydroxy nonenal, a reactive lipid aldehyde, was found in the hippocampus, globus pallidus and cerebellar dentate nucleus in adult DRPLA cases and controls. Cytoplasmic immunoreactivity for Cu/ZnSOD was reduced in the external segment of globus pallidus, dentate nucleus and cerebellar cortex in DRPLA cases. Mitochondrial immunoreactivity for MnSOD was reduced in the lenticulate nucleus and cerebellum in DRPLA cases having PME. Some DRPLA cases showed reduced immunoreactivity for MnSOD in the cerebral cortex. Coexistence of reduced SOD expression and polyglutamine was observed in a few cases. It has been discussed in Huntington's disease that expanded polyglutamine can lead to oxidative neurodegeneration. It is likely that oxidative stress can be involved in DRPLA, although relationship with expanded polyglutamine remains to be elusive.

In order to investigate epileptogenesis in hereditary dentatorubral-pallidoluysian atrophy (DRPLA), we immunohistochemically examined the expression of neurotransmitters, neuropeptides, calcium-binding proteins and/or glutamate transporters in the brainstem and cerebral cortex in autopsy cases. The subjects comprised 14 cases of clinicopathologically confirmed DRPLA, including 7 cases of juvenile and 2 cases of early adult types with progressive myoclonus epilepsy (PME), 5 cases of late adult type without PME, and 10 age-matched controls. Serial sections of the brainstem and cerebral cortex were treated with antibodies to tyrosine hydroxylase, tryptophan hydroxylase, substance P, methionine-enkephalin, parvalbumin, calbindin-D28K, calretinin, and excitatory amino acid transporters. Although the size of the tegmentum was small, we failed to find any PME-specific brainstem changes in the expression of neurotransmitters, neuropeptides and calcium-binding proteins. The number of interneurons immunoreactive for calbindin-D28K and parvalbumin, markers of GABAergic inhibitory interneurons, were reduced throughout the cerebral cortex, but there was no significant difference in the density of immunoreactive neurons between DRPLA patients of each type. The expression of glutamate transporters was comparatively spared. The current study revealed an absence of PME-specific brainstem lesions and indicated a possible involvement of the reduced GABAergic interneurons in the cerebral cortex in formation of PME in DRPLA.

Nasu-Hakola disease (NHD) is a form of presenile dementia associated with sclerosing leukoencephalopathy and polycystic lipomembranous osteodysplasia. This extremely rare inherited disease is caused by mutations in either DAP12 or TREM2. The present study was designed to assess the relationship between DAP12/TREM2 genotype, mRNA and protein expression levels by both Western blotting and immunohistochemistry, and the tissue distribution and pathomorphological phenotype of the microglia. Molecular genetic testing performed in three NHD cases confirmed that two cases had mutations in DAP12 and that one case carried a mutation in TREM2. Protein levels were analyzed in four cases. Interestingly, significant DAP12 expression was found in numerous microglia in one NHD case with a homozygous DAP12 single-base substitution, and both real-time PCR and Western blotting confirmed the finding. In contrast, levels of both DAP12 and TREM2, respectively, were much lower in the other cases. Immunohistochemistry using established microglial markers revealed consistently mild activation of microglia in the cerebral white matter although there was no or only little expression of DAP12 in three of the NHD cases. The highly different expression of DAP12 represents the first description of such variable expressivity in NHD microglia. It raises important questions regarding the mechanisms underlying dementia and white matter damage in NHD.

Xeroderma pigmentosum group A (XPA) is a hereditary disorder characterized by cutaneous symptoms and progressive neurodegeneration. Since XPA patients exhibit peripheral neuropathy, neuronal deafness, rigidity, dysphagia, and laryngeal dystonia, it is indispensable for investigation of the neurodegeneration to analyze brainstem and basal ganglia lesions clinically and pathologically; we have previously shown the role of oxidative stress in the development of basal ganglia lesions. Here we immunohistochemically examined the expression of neurotransmitters, calcium-binding proteins, and neuropeptides in the brainstem, basal ganglia, and thalamus in 5 XPA autopsy cases. In the brainstem, immunoreactivity for tyrosine hydroxylase, tryptophan hydroxylase, and calbindin-D28K was severely reduced throughout the brainstem in all the XPA cases. Nevertheless, the expressions of parvalbumin, substance P, and methionine-enkephalin in the brainstem were comparatively preserved; the exception being reduced immunoreactivity for them in the cochlear and dorsal column nuclei in 3 cases. The large cell neurons in the putamen were preferentially reduced, the immunoreactivity for tyrosine hydroxylase reflecting the dopaminergic afferent and efferent pathways was severely affected, and the expression of 3 calcium binding proteins (i.e. parvalbumin, calbindin-D28K, and calretinin) was disturbed in various ways. The expression of substance P and methionine-enkephalin, which are involved in the efferent pathways in the basal ganglia, in the globus pallidus and substantia nigra was spared. It is speculated that the selective damage to the dopamine system in the basal ganglia and the disturbed monoaminergic expression in the brainstem could be related to clinical abnormalities such as the rigidity, laryngeal dystonia, and several neurophysiological changes. Functional analysis of autopsy brains will facilitate clarification of the pathogenesis of the neurodegeneration in XPA.

穿刺吸引細胞診Pap. 染色標本を用いて, 浸潤性乳管癌通常型142例 (乳頭腺管癌23例, 充実腺管癌47例, 硬癌72例) の小型細胞癌例の頻度, 浸潤性小葉癌14例の特徴を分析した. 95%以上の細胞が小型細胞から成る通常型乳管癌例を142例中29例20.4%に認めた. 最も多いのは硬癌で72例中18例25-0%であった. 小型細胞癌例か否かの認識は, 組織標本との問に乖離がみられた.組織で淡明豊富な胞体をもつ細胞が小型核を有する場合, 細胞診では小型細胞癌例として認識される例を乳頭腺管癌, 充実腺管癌でみられた. 細胞診で小型細胞とされるのは核径に左右されることが明らかとなった. 小葉癌細胞の出現パターンをTYPE-IからTYPE-Vに分類した.組織型推定上, TYPE-II: 敷石状の疎な結合を示す立方状・多辺形細胞, TYPE-V: 索状配列が特に有用と考えられたが, それぞれ28.6%, 35.7%と低出現率であった.小型明瞭な核小体を含む, スリガラス状から細顆粒状クロマチンの細胞と, 出現パターンとの組み合わせが大切である.

全身性コクシジオイデス症患者の頸部穿刺細胞診標本に認めたC.immitisの球状体について報告した. 化膿性炎症像を示す背景に, 5～100μ のオレンジG, あるいはエオジン好性を示す各種成熟段階の球状体は二重壁構造を有し, 形態的に花粉と類似していた. 未熟な球状体の内部は無構造な多糖体物質で満たされ, 成熟したものは2～5μ の内生胞子で満たされていた. 球状体には免疫反応により生じるSplendore-Hoepllieffectを認めるものもあった.輸入真菌症に遭遇する機会が増えることが予想されるが, 本症例はC.immitisの形態的特徴を把握するうえで, 貴重な症例である.

Specimens of the extrahepatic biliary trees and wedge liver biopsies were studied in 11 cases of biliary atresia. The hepatic arteries at the porta hepatis were examined with ultrasound in five of the 11 cases. The basic histopathological features were found to be epithelial damage and an inflammatory, sclerosing change of both the intrahepatic and the extrahepatic biliary trees, combined with an arteriopathy manifesting as hyperplasia and hypertrophy of the hepatic arteries in all cases. Based on the results of ultrasonography and histological examination, this arteriopathy was thought to affect the arteries from the trunk of the common hepatic artery to its peripheral branches supplying the entire biliary tree. To determine whether these morphologically abnormal hepatic arteries are related to the pathogenesis of biliary atresia in association with abnormal blood flow and pressure requires further investigation.

子宮頸管ポリープは中年女性の子宮頸部にしぼしばみられる疾患で, その大部分が良性であり, 悪性像を呈することはきわめてまれである.われわれは子宮頸管ポリープに発生した上皮内癌の1例を経験したので報告する.症例は55歳, 主婦. 主訴は不正性器出血. 子宮頸部の擦過細胞診に異型細胞が出現し, 検査のため来院した. 子宮口より有茎ポリープの突出が認められ除去された. 組織学的に上皮内癌は子宮頸管ポリープに限局していることがわかり, その後に行われた切除子宮のどこにも癌は証明されなかった.

Mucopolysaccharidoses (MPS) are inherited disorders caused by the deficiency of lysosomal enzymes. Sanfilippo syndrome (MPS III) and Hunter syndrome (MPS II) are characterized by severe and mild neurological disorders, respectively, in which the neurodegenerative mechanisms remain to be clarified. We immunohistochemically examined the involvement of tauopathy/synucleinopathy, cell death and oxidative damage in the brains of three cases each of MPS IIIB and MPS II and age-matched controls. In cases of MPS IIIB, the density of GABAergic interneurons in the cerebral cortex immunoreactive for calbindin-D28K and parvalbumin was markedly reduced when compared with age-matched controls. The swollen neurons showed immunoreactivity for phosphorylated alpha-synuclein but not for phosphorylated tau protein or beta-amyloid protein; those in the cerebral cortex demonstrated nuclear immunoreactivity for TUNEL, single-stranded DNA and 8-OHdG. Neither lipid peroxidation nor protein glycation was marked in MPS cases. The expression levels of superoxide dismutases (Cu/ZnSOD and MnSOD) and glial glutamate transporters (EAAT1 and EAAT2) were reduced in two MPS II cases. The disturbance of GABAergic interneurons can be related to mental disturbance, while synucleinopathy and/or DNA impairment may be implicated in the neurodegeneration of swelling neurons due to storage materials in MPS IIIB cases. These findings suggest the possibility of neuroprotective therapies other than enzyme replacement in MPS patients.

Xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are caused by a genetic defect of nucleotide excision repair mechanisms, showing cutaneous hypersensitivity to sunlight and progressive neurological disturbances. The cause of neurological abnormalities has yet to be clarified and fundamental treatments have never been established in both disorders. In order to investigate neurodegeneration of XPA and CS, we immunohistochemically examined deposition of oxidative stress-related materials of nucleotides and expression of two types of superoxide dismutase (SOD) in the brains from autopsy cases of XPA and CS. Cases of XPA but not CS demonstrated nuclear deposition of 8-hydroxy-2'-deoxyguanosine and cytoplasmic deposition of 8-hydroxyguanosine, being speculated as oxidative stress-related materials of DNA and RNA, respectively, in the globus pallidus. Four of five XPA cases exhibited reduced neuronal immunoreactivity for Cu/ZnSOD in the cerebral and cerebellar corteces in addition to the basal ganglia, and two XPA cases showed reduced immunoreactivity for MnSOD in the brain regions examined. In contrast, five CS cases demonstrated comparatively preserved immunoreactivity for Cu/ZnSOD and MnSOD. Both XPA and CS cases showed increased cytoplasmic immunoreactivity for Cu/ZnSOD and/or MnSOD in the microglial cells in the cerebral and cerebellar white matters. These findings suggest that oxidative damage to nucleotides and disturbed SOD expression can be involved in neurodegeneration in XPA but not CS.

Xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are hereditary DNA repair disorders complicated by progressive neurodegeneration. Here we immunohistochemically examine the in situ expression of materials that are produced by oxidative stress and glutamate transporters (which can contribute to prevention of glutamate neurotoxicity) in the brains of 5 autopsied patients each of XPA, CS, and control groups. All oxidative products, including nitrotyrosine, advanced glycation end product, and 4-hydroxy-2-nonenal-modified protein (HNE) were deposited in large amounts in the globus pallidus of CS patients compared to XPA patients. They were frequently recognized in the pseudocalcified foci and free minerals in the neuropil, and more rarely in foamy spheroids. In addition, the deposition of HNE was observed also in hippocampal and cerebellar dentate neurons of both CS and XPA patients. The expression of glial glutamate transporters, EAAT1 and GLT-1, was affected in the globus pallidus in 5 CS patients and 3 XPA patients. They were also altered in the cerebellar cortex in most of the CS patients. These data suggest that oxidative stress and disturbed glutamate transport may be involved in pallidal and/or cerebellar degeneration in hereditary nucleotide repair disorders.

Both xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are rare autosomal disorders, have a genetic defect in the step of nucleotide repair, and involve various neurological abnormalities caused by progressive neurodegeneration. We performed comprehensive neuropathological analysis of five cases of XPA and four cases of CS. The XPA cases showed widespread neuronal loss throughout the central nervous system, in sharp contrast to the comparative preservation of neurons in the CS cases, who rather exhibited patchy demyelination in the cerebral and cerebellar white matter, and multifocal calcium deposition in the basal ganglia and cerebral white matter, respectively. Exceptionally in the cerebellar cortex, neuronal loss was more severe in CS than in XPA. Grumose or foamy spheroid bodies occurred in the globus pallidus and substantia nigra, and axonal torpedoes were increased in the cerebellar cortex in both disorders. Neither silver impregnation nor immunohistochemistry for ubiquitin or tau succeeded in visualizing neurofibrillary tangles, senile plaques or augmented ubiquitination in either disorder, and these findings did not support the involvement of facilitated aging in the neurodegeneration in XPA or CS.

a Department of Pediatrics, Tokyo Kita Shakai Hoken Hospital, 4-17-56 Akabanedai, Kita-ku, Tokyo 115-0053, Japan b Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan c Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu-shi, Tokyo 183-8526, Japan d Department of Pediatrics, Tokyo Metropolitan Fuchu Medical Center for the Disabled, 2-9-2 Musashidai, Fuchu-shi, Tokyo 183-8553, Japan e Department of Neuropathology, Saitama Medical College, 38 Morohongo, Moroyamamachi, Iruma-gun, Saitama 350-0495, Japan

Recent findings have focused attention on the role of apoptosis in neurodegenerative diseases, however, the apoptotic process in child-onset brain disorders has been little investigated. Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are hereditary disorders characterized by impaired DNA repair and neurodegeneration. We investigated apoptotic cell death in the cerebellum of five cases of XP group A (XPA), four cases of CS, and twelve controls, using TdT-mediated DIG-dUTP nick-end labeling (TUNEL) and immunohistochemical staining for bcl-2, bcl-x, p53, bax, BDNF and Trk B. The TUNEL-positive cells were found in the granule cells of the cerebellar cortex of two patients with XPA and two patients with CS, whereas such cells were not detected in the cerebellar cortex in controls. Upregulation of bcl-2 or BDNF was not observed, and bcl-x expression was not altered. Some patients showed nuclear expression of p53 in the granule cells and/or molecular layer, bax-positive glial cells in the cerebellar white matter, and a few Trk B-positive cells in the granular layer. These findings suggest that apoptotic cell death can be involved in the cerebellar degeneration in patients with hereditary defects in DNA repair mechanisms.

Immunohistochemical studies were carried out on the new type of cerebral cortical astrocytic inclusions recently discovered in a 20-year-old patient with maldeveloped brain and micropolygyria. The inclusions appeared as eosinophilic structures (hematoxylin and eosin stain) and did not exhibit argyrophilia (modified Bielschowsky method). The inclusions were strongly stained by the antibody against S-100 protein (S 100) and to a lesser extent by the antibody to microtubule-associated protein 1B (MAP 1B). In contrast to Rosenthal fibers, the astrocytic inclusions did not react with antibodies to alpha B-crystallin, glial fibrillary acidic protein and ubiquitin. No positive reactions were obtained with antibodies against heat-shock protein 27 (HSP 27), HSP 72, actin, vimentin, desmin, cytokeratin, myelin basic protein, beta-tubulin, MAP 2, tau protein, paired helical filament, phosphorylated neurofilament protein (NFP), nonphosphorylated NFP, synaptophysin, cathepsin D, alpha 1-antichymotrypsin, alpha 1-antitrypsin and basic fibroblast growth factor. By immunoelectron microscopy, the products of the reaction with the anti-S 100 antibody appeared as heterogeneous granular deposits and with the antibody to MAP 1B they were randomly scattered throughout the astrocytic inclusions. Our results demonstrate that the immunohistochemical profile of the recently described inclusions differs from that of Rosenthal fibers. Whether the novel inclusions are involved in congenital astrocyte dysfunction and cerebral malformation remains to be established.