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The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease-specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial-predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement.

Subacute sclerosing panencephalitis (SSPE) occurs in some individuals after measles infection, following a symptom-free period of several years. It resembles chronic traumatic encephalopathy (CTE), which happens after repetitive head impacts or exposure to blast waves, following a symptom-free period. As in CTE, when present, the neurofibrillary changes of SSPE are concentrated in superficial cortical layers. Here we used electron cryo-microscopy of tau filaments from two cases of SSPE to show that the tau folds of SSPE and CTE are identical. Two types of filaments were each made of two identical protofilaments with an extra density in the β-helix region. Like in CTE, the vast majority of tau filaments were Type I, with a minority of Type II filaments. These findings suggest that the CTE tau fold can be caused by different environmental insults, which may be linked by inflammatory changes.

BACKGROUND Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.

Methionine/methionine type 1 (MM1-type) sporadic Creutzfeldt-Jakob disease (sCJD), known as the ‘classic type,’ shows typical clinicopathological sCJD findings. In general, patients reach an akinetic mutism state within a few months of disease onset and die soon after if supportive therapies are not administered. Here, we describe remarkable neuropathologic observations of MM1-type sCJD in a 48-year-old, Japanese man with an unusually prolonged akinetic mutism state. In the early disease stages, the patient exhibited abnormal behaviour with gait disturbance and rapidly progressive cognitive dysfunction. Diffusion-weighted magnetic resonance imaging revealed extensive cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed no mutations, and the polymorphic codon 129 exhibited methionine homozygosity. Although the patient remained stable with tube feeding for more than 2 years after reaching the akinetic mutism state, he died because of central respiratory failure 30 months after disease onset. Neuropathologic investigation showed extensive devastating lesions, such as status spongiosus, and typical spongiform changes could no longer be observed in the cerebral neocortex. Conspicuous pyramidal tract degeneration was observed. However, the regions commonly preserved in MM1-type sCJD pathology were still relatively preserved. Immunostaining revealed extensive diffuse synaptic-type PrP deposition in the grey matter. The pathological findings suggested that sCJD is a neurodegenerative disease that shows system degeneration; there are primary and secondary degenerative regions and distinct preserved regions, even in cases with prolonged disease duration. In addition, it is considered that there is a limited survival period for MM1-type sCJD, even if active symptomatic treatment is provided.

Subacute sclerotic panencephalitis (SSPE) is a refractory neurological disorder after exposure to measles virus. Recently, SSPE cases have been treated with antiviral therapies, but data on the efficacy are inconclusive. Abnormal tau accumulation has been reported in the brain tissue of SSPE cases, but there are few reports in which this is amply discussed. Five autopsied cases diagnosed as definite SSPE were included in this study. The subject age or disease duration ranged from 7.6 to 40.9 years old or from 0.5 to 20.8 years, respectively. Cases 3 and 4 had been treated with antiviral therapies. All evaluated cases showed marked brain atrophy with cerebral ventricle dilatation; additionally, marked demyelination with fibrillary gliosis were observed in the cerebral white matter. The brainstem, cerebellum, and spinal cord were relatively preserved. Immunoreactivity (IR) against measles virus was seen in the brainstem tegmentum, neocortex, and/or limbic cortex of the untreated cases but was rarely seen in the two treated cases. Activated microglia were broadly observed from the cerebrum to the spinal cord and had no meaningful difference among cases. Neurofibrillary tangles characterized by a combination of 3- and 4-repeat tau were observed mainly in the oculomotor nuclei, locus coeruleus, and limbic cortex. IR against phosphorylated tau was seen mainly in the cingulate gyrus, oculomotor nuclei, and pontine tegmentum, and tended to be observed frequently in cases with long disease durations but also tended to decrease along with neuronal loss, as in Case 5, which had the longest disease duration. Since the distribution of phosphorylated tau was independent from that of measles virus, the tauopathy following SSPE was inferred to be the result of diffuse brain inflammation triggered by measles rather than a direct result of measles virus. Moreover, antiviral therapies seemed to suppress measles virus but not the progression of tauopathy.

We describe an autopsied patient with familial parkinsonism and unclassified four repeat-tau (4R-tau) aggregation. She presented with bradykinesia, truncal dystonia, and mild amnesia at the age of 61 and then exhibited body weight loss (15 kg over 8 months), sleep disturbances, and progressive respiratory failure with CO2 narcosis. She died of respiratory failure at the age of 62, 14 months after disease onset. Her brother also showed parkinsonism at the age of 58 and suddenly died 6 months later. Postmortem examination revealed 4R-tau aggregation, which was characterized by neuronal globose-type tangles or pretangles, bush-like or miscellaneous astrocytic inclusions, and coiled bodies. The temporal tip, the striatum, the substantia nigra, the tegmentum of the midbrain, the medullary reticular formation, and the spinal cord were severely involved with tau aggregation. Argyrophilic grains and ballooned neurons were also found in the medial temporal structures, however, extensions of the 4R-aggregations in the case were clearly broader than those of the argyrophilic grains. Western blot analysis of sarkosyl-insoluble fractions from brain lysates revealed prominent bands of tau at both 33 kDa and 37 kDa. Genetic examinations did not reveal any known pathogenic mutations in MAPT, DCTN-1, PSEN-1, or familial or young-onset parkinsonism-related genes. The clinical manifestations, pathologic findings, and biochemical properties of aggregated tau in our patient cannot be explained by argyrophilic grain disease or other known 4R-tauopathies alone. Our results further extend the clinical and neuropathologic spectra of 4R-tauopathy.

TDP-43 is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in cases of amyotrophic lateral sclerosis. TDP-43 pathology has also been found in brain tissues under non-amyotrophic lateral sclerosis conditions, suggesting mechanistic links between TDP-43-related amyotrophic lateral sclerosis and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (n = 26), corticobasal degeneration (n = 12), globular glial tauopathy (n = 5), Alzheimer’s disease (n = 21) or Pick's disease (n = 6) and neurologically healthy controls (n = 36). Ten of the progressive supranuclear palsy cases (38%) and seven of the corticobasal degeneration cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43 aggregates were found to be skein-like, round-shaped, granular or dot-like and contained insoluble C-terminal fragments showing blotting pattern of amyotrophic lateral sclerosis or frontotemporal lobar degeneration. The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in haematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and four-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the Alzheimer’s disease, Pick's disease, globular glial tauopathy and control groups. Next, we assessed SFPQ expression in spinal cord motor neurons; SFPQ is a recently identified regulator of amyotrophic lateral sclerosis/frontotemporal lobar degeneration pathogenesis, and it is also reported that interaction between SFPQ and FUS regulates splicing of MAPT exon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of progressive supranuclear palsy, corticobasal degeneration and amyotrophic lateral sclerosis-TDP cases but not in Alzheimer’s disease, Pick's disease and globular glial tauopathy cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of progressive supranuclear palsy and corticobasal degeneration cases. Our results indicate that progressive supranuclear palsy and corticobasal degeneration may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with amyotrophic lateral sclerosis-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.

MYC amplification is common in Group 3 medulloblastoma and is associated with poor survival. Group 3 and Group 4 medulloblastomas are also known to have elevated levels of histone H3-lysine 27-tri-methylation (H3K27me3), at least in part due to high expression of the H3K27 methyltransferase enhancer of zest homologue 2 (EZH2), which can be regulated by MYC. We therefore examined whether MYC expression is associated with elevated EZH2 and H3K27me3 in medulloblastoma, and if high-MYC medulloblastomas are particularly sensitive to pharmacological EZH2 blockade. Western blot analysis of low (DAOY, UW228, CB SV40) and high (DAOY-MYC, UW228-MYC, CB-MYC, D425) MYC cell lines showed that higher levels of EZH2 and H3K27me3 were associated with elevated MYC. In fixed medulloblastoma samples examined using immunohistochemistry, most MYC positive tumors also had high H3K27me3, but many MYC negative ones did as well, and the correlation was not statistically significant. All high MYC lines tested were sensitive to the EZH2 inhibitor EPZ6438. Many low MYC lines also grew more slowly in the presence of EPZ6438, although DAOY-MYC cells responded more strongly than parent DAOY cultures with lower MYC levels. We find that higher MYC levels are associated with increased EZH2, and pharmacological blockade of EZH2 is a potential therapeutic strategy for aggressive medulloblastoma with elevated MYC.

Summary Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5′ UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID., Graphical abstract, Highlights • NIID is a neurodegenerative disease caused by expansion of GGC repeats in NOTCH2NLC • These GGC repeats are translated into a polyglycine (polyG) protein • The polyG protein is toxic and forms intranuclear inclusions in cells and animals • Similarities between FXTAS and NIID define a new set of disorders: polyG diseases, The neurodegenerative disease NIID is caused by an expansion of GGC repeats in NOTCH2NLC. Boivin et al. found that these repeats are translated into a toxic polyglycine (polyG) protein that forms intranuclear inclusions. An identical mechanism exists in FXTAS, unveiling a novel group of genetic pathologies, the polyG diseases.

We previously reported observing GLI3 in medulloblastomas expressing neuronal markers (NM) and/or glial fibrillary acidic protein (GFAP). Furthermore, patients with medulloblastomas expressing NM or GFAP tended to show favorable or poor prognosis, respectively. In the present study, we focused on the role of topoisomerase IIβ (TOP2β) as a possible regulator for neuronal differentiation in medulloblastomas and examined the pathological roles of GLI3, NM, GFAP, and TOP2β expressions in a larger population. We divided 124 medulloblastomas into three groups (NM−/GFAP−, NM +/GFAP−, and GFAP +) based on their immunoreactivity (IR) against NM and GFAP. The relationship among GLI3, NM, GFAP, and TOP2β was evaluated using fluorescent immunostaining and a publicly available single-cell RNA sequencing dataset. In total, 87, 30, and 7 medulloblastomas were classified as NM−/GFAP−, NM + /GFAP−, and GFAP +, and showed intermediate, good, and poor prognoses, respectively. GLI3-IR was frequently observed in NM +/GFAP− and GFAP + , and TOP2β-IR was frequently observed only in NM +/GFAP− medulloblastomas. In fluorescent immunostaining, TOP2β-IR was mostly co-localized with NeuN-IR but not with GFAP-IR. In single-cell RNA sequencing, TOP2β expression was elevated in CMAS/DCX-positive, but not in GFAP-positive, cells. NM-IR and GFAP-IR are important for estimating the prognosis of patients with medulloblastoma; hence they should be assessed in clinical practice.

To assess the induction of autophagy in the human umbilical cord for physiological adaptation against starvation.The expression of autophagy-related proteins (LC3-II, p62) in umbilical cord tissues from 40 neonates was assessed by Western blotting. The correlation between the expression of autophagy-related proteins and maternal findings (height, weight, body mass index [BMI]), placental weight, neonatal findings (gestational age, height, weight, Apgar score at 1 min and 5 min), and the pH of the umbilical arterial blood were analyzed using Spearman's rank correlation coefficient test (The expression of LC3-II was positively correlated with serum total protein (The LC3-II or p62 expression in the umbilical cord may suggest the autophagy reaction for the homeostasis of protein or amino acid metabolism in the perinatal period.

An 83-year-old Japanese man presented with gait disturbance followed by rapidly-progressive cognitive impairment. Magnetic resonance diffusion-weighted images showed extensive hyperintense regions in the cerebral cortex. Four weeks after symptom onset, myoclonus appeared, and the patient developed difficulty swallowing; intravenous peripheral continuous infusions without vitamin supplementation were administered during the last two months of the patient’s life. The patient reached the akinetic mutism state and died 12 weeks after symptom onset due to sepsis. The brain weighed 940 g and showed general cerebral atrophy. Extensive spongiform change were observed in the cerebral cortex, striatum, thalamus, and cerebellar cortex, but gliosis was generally mild. Numerous newly-developed hemorrhage foci were observed in the mammillary body, the areas adjacent to the third and fourth ventricles, and the periaqueduct of the midbrain; however, proliferation of capillaries and endothelium and collections of macrophages were relatively inconspicuous. These findings suggested comorbidity with the acute stage of Wernicke encephalopathy (WE). Immunostaining showed extensive diffuse synaptic-type prion protein deposition in the gray matter. According to the neuropathological, genetic, and molecular findings, the present case was finally diagnosed as MM1-type sporadic Creutzfeldt-Jakob disease (CJD) with WE. We should remain alert to the diagnosis of WE when CJD is suspected, and it is necessary to consider the complications of both diseases. This report emphasizes the importance of pathological investigations for the diagnosis of CJD, WE, and the coexistence of both.

Cerebral infarction in children is rare and often occurs secondary to moyamoya disease, hereditary coagulopathies, vasculitis, antiphospholipid antibody syndrome, heart disease, mitochondrial disease. However, in some cases, the causes of cerebral infarction is unknown. In this study, we detected increased levels of serum anti-phosphatidylcholine and anti-phosphatidylethanolamine IgG antibodies in three pediatric patients with cerebral infarction whose primary disorders are unknown by routine examination. For the five disease control patients of cerebral infarction due to other primary disorders, there was no such increase in these antibodies levels. Phosphatidylcholine and phosphatidylethanolamine are major components of the phospholipids of vascular endothelial cells, while cardiolipin is a minor component. Anti-phosphatidylcholine and anti-phosphatidylethanolamine antibodies, as well as anti-cardiolipin antibody, might also be risk factors with cerebral infarction.

Objective To elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block. Patient A long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33 years. He then survived another 2.5 years after the onset of paroxysmal AV block and pacemaker implantation. Methods and results His cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches. Conclusion HS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block.

22q13 deletion syndrome is a genetic disorder caused by the deletion or disruption of the segment of the long arm of chromosome 22. The characteristic clinical features of this syndrome include delayed expressive speech, autistic behavior and hypotonia, and clinically severe complications associated with autoimmunity are rarely reported. We herein report a girl with 22q13 deletion syndrome complicated with multiple inflammatory and autoimmune diseases during early childhood. We performed whole-exome sequencing to identify the genes responsible for her autoimmune diseases and identified the de novo variant p.R512W in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) gene. We suspected it to be the disease-causing variant at the conserved residue in PIK(3)C p110δ. Alternatively, haplo-insufficiency of SHANK3 or other genes by 22q13 deletion and the PIK3CD variant might have synergistically contributed to the onset of the distinctive clinical manifestations in this patient.

The existence of affected subjects with both abnormal prion protein (PrPSc) types has been reported, and their clinical features were somewhat similar to the dominant PrPSc type but varied in sporadic Creutzfeldt-Jakob disease (sCJD). Presently, the antemortem identification of both PrPSc types in sCJD is not possible. In this study, we attempted to clinically predict the concurrence of MM-type sCJD with another PrPSc type in the same individual. We retrospectively identified seven MM-type sCJD cases with both fine vacuole-type spongiform (FV) and large confluent vacuole-type spongiform change (LCV) among 49 sCJD cases. We reviewed clinical features, pathological findings, and radiological abnormalities in these seven cases. We also conducted a regional systemic study with five brains to associate the spongiform-change pattern with hyperintensity on magnetic resonance diffusion-weighted imaging (DWI) using the signal intensity index (SII). In the case series study, the one patient with dominant LCV showed longer disease duration, later onset of typical symptoms, no periodic sharp wave complexes in electroencephalography, and negative 14-3-3 protein findings compared to the six FV-dominant patients. LCV-dominant lesions tended to show higher intensity on DWI than did the FV-dominant lesions in respective patients. In the regional systemic study, LCV-dominant regions showed significantly higher SII on DWI than did the FV-dominant regions. In conclusion, mixed MM-type sCJD generally showed the clinical features of the phenotype that was dominant in pathological distribution. The SII may be clinically useful for investigating the concurrence of PrPSc type 2 in cases with the typical clinical course of MM1-type sCJD.

Rathke's cleft cysts (RCCs) are non-neoplastic, sellar or suprasellar epithelium-lined cysts originating from Rathke's pouch in the pituitary gland. Patients with RCCs are usually asymptomatic, but some have only been identified when symptoms manifested in middle age. The characteristics of these patients during childhood or adolescence remains unknown. We describe an 18-year-old girl who had occasionally suffered from malicious fatigue in the morning since her early teens. Brain magnetic resonance imaging (MRI) revealed T1 hyperintense/T2 hypointense signals between the anterior and posterior pituitary glands, indicating the presence of RCC. Based on an authentic endocrinological evaluation, her adrenal function seemed normal; nevertheless, her serum cortisol level strangely dropped around noon. Furthermore, daily supplementation of oral hydrocortisone bizarrely suppressed ACTH secretion to below the detection range in the morning. These data appeared compatible with the presence of central adrenal dysfunction. We also review the literature for previously reported cases. In conclusion, the symptoms and endocrinological data for dysfunction of the hypothalamic pituitary system might be non-specific and vary among patients, especially in teenagers. Brain MRI and daily cortisol profiling in blood are key to obtaining a diagnosis of an impaired hypothalamic adrenal function due to RCC.

Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKTS473 and p-S6S240/244 and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment.

Patients with COL4A1 mutation-related disorders demonstrate a variety of disease phenotypes, which caused by small-vessel dysfunction in the brain, eyes, kidney, muscle, or heart. The involvement of organs mainly depends on the expression of the COL4A1 gene. Complication or dysfunction of the alveolar tissue has not been reported in the literature on COL4A1 mutation-related disorders. We herein report the case of a boy with schizencephaly, renovascular hypertension, and retinal arteriosclerosis of unknown origin, who suffered from severe and repetitive alveolar hemorrhage at 9 years of age. A novel COL4A1 mutation was finally identified as the genetic cause. The pulmonary complication in the present case represents an important pathophysiological mechanism COL4A1 mutation-related disorders; lung tissue with COL4A1 gene mutations may be vulnerable and environmental substances and microorganisms in the air could accumulate to cause chronic damage in the alveolar tissues, especially in patients with tracheostoma and renovascular hypertension.

Background : Xeroderma pigmentosum group A (XPA) is a rare autosomal-recessive disorder caused by a defect in nucleotide excision repair. Progressive dysautonomia in patients with XPA is rarely described. Patients Two juvenile male patients with XPA suffered from dysphagia, sleep interruption, and dysuria from the age of 10 to 19 years, successively. These autonomic symptoms might have been caused by progressive descending degeneration of cranial nerves IX and X and the sacral parasympathetic nerve, including Onuf's nucleus. One patient died from sudden cardiopulmonary arrest during postural change and tracheal suction. Results Heart rate variability analyses of these patients revealed parasympathetic dysautonomia, based on decreased high-frequency values. Conclusions The insidiously progressive dysautonomia in these two patients with XPA suggested progressive descending degeneration extending from the medulla oblongata to the sacral spinal cord, which is an ominous sign of end-stage disease and a risk factor of sudden death attributable to XPA.

A 15-month-old infant presented with thrombocytopenic purpura after sequential administration of measles-rubella combined vaccine, varicella vaccine and mumps vaccine every 4 weeks. Her thrombocytopenia persisted for more than 12 months. Both anti-measles and anti-rubella virus IgG antibodies were detected in the patient's-isolated platelets on day 154 of illness, which were not detected when there was a reduction of the serum IgG antibody titers on days 298 and 373 of illness, respectively.We also detected the isolated platelet-binding anti-measles and anti-rubella virus IgG antibodies in two other pediatric patients. This is the first report demonstrating direct evidence of vaccine-induced thrombocytopenic purpura.

Cockayne syndrome presents senescence-like changes starting in early infancy; however, the mechanism of premature aging remains unclear. In an autopsy of a 23-year-old woman with Cockayne syndrome, we evaluated the correlation between Cockayne pathology and the expression patterns of the senescence-associated proteins p53 and Rb. Neuropathological findings in this case revealed basal ganglia calcification, tigroid leukodystrophy, bizarre reactive astrocytes, severe cerebellar atrophy with loss of Purkinje cells, and arteriolar/neuronal calcifications in the hypothalamus. Multiple arteriolar calcifications and sclerotic changes were seen in the central nervous system and kidney, but the endothelium of the aorta and coronary arteries remained intact appropriately for the individual's age without any finding of arteriosclerosis. Overexpression of p53 protein was confirmed in the cytoplasm of neurons in the basal ganglia, thalamus, hypothalamus, hippocampus and cerebellum, of arteriolar endothelial cells of the cerebrum and renal glomerular capillaries, and of cutaneous epithelial cells. The distribution of p53 overexpression was coincident with that of pathological alteration, such as neuronal loss, calcification and atrophy. High expression of p53 was localized in the cytoplasm, not in the nucleus. In contrast to p53, Rb was not expressed in any senescence lesion. In terms of senescence, distinct differences are found among organs in a patient with Cockayne syndrome. This segmental progeria differs from natural aging, and implicates p53 overexpression in the etiology of CS.

Introduction Because the optic nerve is mainly comprised from phospholipids such as phosphatidylcholine, the association between optic neuritis, anti-phospholipids antibodies and vaccination was examined. Subjects Two female pediatric patients suddenly presented bilateral optic neuritis after administration of trivalent inactivated influenza vaccine. Methods These two patients and another 11 patients with central nervous system demyelinating diseases were examined these anti-phospholipids antibodies. And immune histopathology was examined using serum derived from a patient with optic neuritis. Results High serum titer of anti-phosphatidylcholine antibody levels were detected during acute phase in patients with optic neuritis. The patient's serum IgG antibodies were found to have stained the capillary endotheliums in the preserved autopsied optic nerve. Patients with optic neuritis had significantly elevated serum levels of anti-phosphatidylcholine antibody in comparison to the other patients without optic neuritis. Conclusion Anti-phosphatidylcholine antibodies may be one of the causes of optic neuritis.

The spread of human immunodeficiency virus (HIV) infection has exploded over the past two decades and such infections in young people are no longer uncommon. However, the major infection route of pediatric patients remains vertical transmission, and sexual, especially homosexual transmission, is highly unusual. We herein describe the case of a 17-year-old boy who developed hemophagocytic lymphohistiocytosis (HLH). Although HLH was remitted soon with dexamethasone therapy, an HIV infection caused by homosexual transmission was detected.

Medulloblastoma (MB) is a malignant cerebellar tumor arising in children, and its ontogenesis is regulated by Sonic Hedgehog (Shh) signaling. No data are available regarding the correlation between expression of Gli3, a protein lying downstream of Shh, and neuronal differentiation of MB cells, or the prognostic significance of these features. We re-evaluated the histopathological features of surgical specimens of MB taken from 32 patients, and defined 15 of them as MB with neuronal differentiation (ND), three as MB with both glial and neuronal differentiation (GD), and 14 as differentiation-free (DF) MB. Gli3-immunoreactivity (IR) was evident as a clear circular stain outlining the nuclei of the tumor cells. The difference in the frequency of IR between the ND+GD (94.4%) and DF (0%) groups was significant (P0.001). The tumor cells with ND showed IR for both Gli3 and neuronal nuclei. Ultrastructurally, Gli3-IR was observed at the nuclear membrane. The overall survival and event-free survival rates of the patients in the ND group were significantly higher than those in the other groups. The expression profile of Gli3 is of considerable significance, and the association of ND with this feature may be prognostically favorable in patients with MB.

A male infant with trisomy 21 simultaneously showed clinical features of hypomelanosis of Ito and hemimegalencephaly, with related intractable epileptic seizures. The epileptic seizures were refractory to conventional antiepileptic drugs and persisted until the patient underwent functional hemispherotomy. It is well known that patients with hypomelanosis of Ito may also have cortical dysplasia and hemimegalencephaly and that approximately half of these patients have chromosomal abnormalities. However, to our knowledge, there is no previous report of a patient with trisomy 21 associated with hemimegalencephaly. Here, we describe a rare case of coexisting trisomy 21 and hypomelanosis of Ito, associated with hemimegalencephaly.

Hypertrophic and dysmorphic neurons have been identified in the hippocampal end folium of patients with mesial temporal lobe epilepsy (mTLE). No data are available regarding the correlation between these cellular alterations and the severity of hippocampal sclerosis (HS), and the significance of this phenomenon has been unclear. We evaluated both the perikaryon and nuclear areas of residual neurons in the hippocampal end folium of 47 patients with mTLE, seven with lesional neocortical temporal lobe epilepsy (LTLE), and 10 controls without seizure episodes. According to the severity of neuron loss in the end folium, we defined mTLE cases showing slight (10%) or no, moderate (10-50%) and severe (50%) loss as groups A, B and C, respectively. We also performed immunohistochemistry with antibodies against heat shock protein 70 and the phosphorylated epitope of neurofilament. In both mTLE and LTLE cases, the perikaryon and nuclear areas of the end folium neurons were significantly greater than those in the controls (P 0.0001), and those in mTLE were significantly greater than those in LTLE. There were no differences in areas between groups A and B, but the areas in group C were significantly greater than those of both groups A and B. Neurons with large, bizarre morphology were labeled with both antibodies. Neuronal hypertrophy is evident in patients with epilepsy, and appears to advance gradually as the hippocampal sclerosis becomes more severe. This alteration may be a consequence of cellular stress incurred by neurons.

Autophagy is a dynamic process of protein degradation. Induction of autophagy by temozolomide (TMZ) has been noted in glioma cell lines. Twenty-eight specimens, obtained from 14 patients before and after TMZ treatment, were analyzed to investigate whether induction of autophagy could be detected in surgical specimens by immunohistochemical analysis. Macroautophagy was monitored by immunohistochemical analysis employing anti-light chain 3 isoform B (LC3B) and anti-lysosome-associated membrane protein 1 (LAMP1) antibodies; chaperone-mediated autophagy was monitored by anti-LAMP2A antibody immunostaining. Furthermore, detection of LC3B protein by Western blotting was performed on six specimens obtained from the preserved frozen tissues of three patients. All specimens showed dot-like staining for each immunostain in the cytoplasm of glioma cells, indicating induction of autophagy. LC3B, LAMP1 and LAMP2A immunostains were semiquantitatively scored from 1 to 3 points. Combination of the three scores after TMZ treatment (6.4 ± 1.2) showed a significant increase (P = 0.020) compared to pre-treatment scores (5.2 ± 1.5). Western blotting for LC3B showed increased LC3B-I and LC3B-II expression after TMZ treatment. The present study proved that autophagy monitoring by immunohistochemical staining of surgical specimens was feasible. These results suggest that autophagy is induced by TMZ.

Angiocentric glioma (AG) is an epileptogenic benign cerebral tumor primarily affecting children and young adults, and characterized histopathologically by an angiocentric pattern of growth of monomorphous bipolar cells with features of ependymal differentiation (WHO grade I). We report an unusual cerebral glial tumor in a 66-year-old woman with generalized tonic-clonic seizure; the patient also had a 6-year history of headache. On MRI, the tumor appeared as a large T2-hyperintense lesion involving the right insular gyri-anterior temporal lobe, with post-contrast enhancement in the insula region. Histopathologically, the tumor involving the insular cortex-subcortical white matter was composed of GFAP-positive glial cells showing two different morphologies: one type had monomorphous bipolar cytoplasm and was angiocentric with circumferential alignment to the blood vessels, with dot-like structures positive for epithelial membrane antigen and a Ki-67 labeling index of1%, and the other was apparently astrocytic, being diffusely and more widely distributed in the parenchyma, showing mitoses and a Ki-67 labeling index of5%. In the anterior temporal lobe, a diffuse increase in the number of astrocytic cells was evident in part of the cortex and subcortical white matter. On the basis of these findings, we considered whether the present tumor may represent an unusual example of AG with infiltrating astrocytic cells showing primary anaplastic features (AG with anaplastic features), or anaplastic astrocytoma showing primary vascular-associated ependymal differentiation (anaplastic astrocytoma with angiocentric ependymal differentiation). At present, the latter appears to be the more appropriate interpretation.

The presence of balloon cells, a pathognomonic cellular feature of focal cortical dysplasia type IIB, in a background of hippocampal sclerosis is rare. Here we report the surgical pathologic features of the hippocampus resected from a 32-year-old woman with mesial temporal lobe epilepsy and a precipitating history of non-herpetic acute limbic encephalitis. Histologically, the resected specimen showed features of hippocampal sclerosis with granule cell dispersion. Characteristically, many balloon cells, immunoreactive for nestin, vimentin, glial fibrillary acidic protein (GFAP), GFAP-delta and CD34, were observed in the molecular and granule cell layers of the dentate gyrus. In the present case hippocampal sclerosis was an apparently acquired alteration, rather than a result of maldevelopment. The appearance of balloon cells raises questions regarding their origin and morphogenesis.

An 11-year-old female patient, whose systemic type juvenile idiopathic arthritis (JIA) had maintained in remission for the previous 4 years while taking only a small amounts of ibuprofen, showed an abrupt 2nd relapse with congestive heart failure five days after receiving a live-attenuated rubella vaccine, which was a primary immunization. Her serum levels of anti-rubella IgM and IgG antibodies increased, and her laboratory findings such as a leukocytosis, elevated serum levels of CRP, IL-6 and other inflammatory cytokine profiles were similar to the findings observed during her previous JIA active stage. After being administration of co-therapy with steroid pulse, ibuprofen, methotrexate and phosphodiesterase inhibitor gradually improved her clinical symptoms such as spiky fever, heart failure and arthralgia. Her intermittent fever and increased serum levels of CRP and IL-6, however, have been sustained for more than 2 years, and this prolonged active clinical course therefore differed from her previous JIA active stage.This abrupt relapse only five days after vaccination was suggested not to be directly related with rubella infection, but instead to be related with the molecular mimicry between rubella and JIA.

Background For the treatment of bronchial asthma, two types of fluticasone inhaler devices are available, namely, metered-dose inhaler with spacer (MDI-S) and the dry powder inhaler (DPI). The former is recommended for young children with a low peak inspiratory flow (PIF) and the latter for adolescents and adults. But the difference in the therapeutic efficacy between them has been studied only rarely in adolescent patients. Methods In the present study, 21 post-elementary school-age patients with moderate persistent bronchial asthma (age 8-15 years, 10.3 +/- 2.1 years), who all had a sufficient PIF of 114 +/- 29 L/min, were examined in order to compare the two types of fluticasone inhalers. Eleven of 21 patients inhaled 200 microg/day Flutide using the MDI-S twice daily for 1 month in the first month, and the same dose using the DPI for the next month. The other 10 patients inhaled the opposite regimens. At the end of the each treatment, spirometry was examined. Results Measurements done before therapy and then at the end of MDI-S and DPI therapy, respectively, were as follows: forced expiratory volume in 1 s (FEV(1.0)), 72.4 +/- 18.2%, 91.5 +/- 18.2% and 84.1 +/- 16.3% (MDI-S vs DPI, P > 0.040); maximal mid-expiratory flow (MMEF), 62.0 +/- 23.6%, 88.7 +/- 26.5%, 79.3 +/- 33.4% (P > 0.044) and the peak expiratory flow (PEF) was 73.9 +/- 25.0%, 95.6 +/- 32.8%, and 90.5 +/- 29.5%, respectively (n.s.). MDI-S was thus found to be more effective in terms of %FEV(1.0) and in %MMEF. Conclusions High therapeutic efficacy was obtained with the use of the MDI-S in fluticasone inhalation for post-elementary school-age patients with sufficient inspiration ability.

Background: To elucidate the basic mechanism of theophylline-associated seizures (TAS), the clinical symptoms, electroencephalogram (EEG) and neuroradiological imaging of eight pediatric patients were all retrospectively evaluated. Methods: Patients whose seizures represented their first episode were selected, while patients with cerebrospinal fluid abnormalities including pleocytosis and protein elevation, present illness of head trauma, epilepsy, febrile convulsion or any psychomotor retardation were excluded although they were given theophylline. Results: Eight patients, 3.5 ± 1.7 years of age, thus fulfilled the definition of TAS in the past 5 years. Based on their seizure patterns, EEG findings, brain single-photon emission computed tomography and head magnetic resonance imaging, a total of seven of eight patients had either localized or unilateral dominant lesions. They all had fever, ≥38°C, and six of eight patients had a family history of febrile convulsions and/or idiopathic epilepsy. Thereafter none of them had convulsions after the cessation of theophylline administration. Through the TAS event, a 6-year-old female patient was found to have a right deep lateral cerebral venous angioma. Conclusion: In infants with idiopathic low seizure threshold and fever, theophylline administration might possibly trigger a seizure. Moreover, based on these patients’ clinical findings, some kind of cerebral vascular involvements is speculated to be related with TAS.

The central nervous system (CNS) inflammation of Kawasaki disease (KD) has not been sufficiently evaluated in spite of the complications of irritability and CSF pleocytosis.Cerebrospinal fluid (CSF) and serum inflammatory cytokine values were simultaneously examined in 10 patients (2.6 +/- 2.1 year of age) during the acute phase. They were all irritable and demonstrated mild consciousness disturbance.The CSF IL6 was elevated (3.0 pg/mL) in 6 patients, and 4 of them showed higher CSF than serum values. The CSF sTNFR1 was elevated (0.5 microg/mL) in 6 patients, and 1 showed higher CSF than serum values. These CSF cytokine (IL6; 81.4 +/- 192.8 pg/mL, sTNFR1; 1.1 +/- 0.8 microg/mL) and CSF/serum ratio (IL6; 2.8 +/- 5.2, sTNFR1 0.4 +/- 0.4) in patients with KD were the same as those of patients with acute encephalitis/acute encephalopathy.The differences in the inflammatory cytokine value between CSF and serum suggest that the degree of systemic vasculitis is different between CSF and the circulating blood, and some patients with KD showed a higher degree of CSF inflammation.

The interaction of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase-1 has been implicated in the formation of coronary aneurysms in Kawasaki disease. MMP-9 and tissue inhibitor of matrix metalloproteinase-1 were distributed predominantly in the granulocytes and platelets, respectively, in patients with Kawasaki disease. The plasma values of MMP-9 correlated positively with the circulating neutrophil count. Inhibiting the activity of granulocytes and maintaining the platelet activity might prevent coronary aneurysms.