RESUMEN
BACKGROUND: To validate the hypothesis that cryptogenic stroke with multiple infarcts included embolic stroke due to left atrial appendage (LAA) dysfunction, the present retrospective observational study was aimed to clarify the association between LAA flow velocity (LAA-FV) and multiple infarcts in patients with cryptogenic stroke. METHODS: From consecutive patients with cryptogenic stroke admitted to our hospital within 7 days after onset, patients without brain magnetic resonance imaging (MRI) on admission or without transesophageal echocardiography (TEE) during acute hospitalization were excluded, and the remaining patients were enrolled. Multiplicity of fresh infarcts was assessed using diffusion-weighted images from brain MRI. LAA-FV was defined as LAA peak emptying flow velocity on TEE. RESULTS: Of 786 enrolled patients, 522 patients (66%) had a single infarct, and the remaining 264 patients (34%) had multiple infarcts. The percentage of multiple infarcts decreased with increasing quartiles of LAA-FV (p for trend <0.001). The adjusted odds ratio for multiple infarcts decreased with increasing quartiles of LAA-FV (adjusted odds ratio in the fourth quartile, 0.39; 95% confidence interval, 0.25-0.60; compared with the first quartile). LAA-FV as a continuous variable was negatively associated with multiple infarcts (adjusted odds ratio per 10 cm/s, 0.87; 95% confidence interval, 0.81-0.92). CONCLUSIONS: Reduced LAA-FV on TEE was associated with multiple infarcts in patients with cryptogenic stroke. The present findings indicate that cryptogenic stroke with multiple infarcts includes embolic stroke due to LAA dysfunction.
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Apéndice Atrial/fisiopatología , Función del Atrio Izquierdo , Accidente Cerebrovascular Embólico/etiología , Cardiopatías/complicaciones , Anciano , Anciano de 80 o más Años , Apéndice Atrial/diagnóstico por imagen , Ecocardiografía Doppler de Pulso , Ecocardiografía Transesofágica , Accidente Cerebrovascular Embólico/diagnóstico por imagen , Femenino , Cardiopatías/diagnóstico por imagen , Cardiopatías/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease-free and overall survival were significantly worse in the low-FBXW7 group than in the high-FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease-free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal. Interestingly, when cells were stimulated with cis-diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7-mediated ubiquitylation is context-dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.
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Neoplasias de los Conductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Cisplatino/farmacología , Proteína 7 que Contiene Repeticiones F-Box-WD/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Receptor Notch1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Pronóstico , Análisis de SupervivenciaRESUMEN
The protein µ-crystallin (CRYM) is a novel component of the marsupial lens that has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. In this study, we examined changes of the expression pattern of CRYM in different rat organs during development using immunohistochemistry and immunoblotting. As CRYM is reportedly expressed in the corticospinal tract, we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS) using immunohistochemistry. In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and corticospinal tract in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. Even within the same regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In the kidney, CRYM was expressed in epithelial cells of the proximal tubule and mesenchymal cells of the medulla in the early postnatal period; however, CRYM expression in the medulla was lost as mesenchymal cell numbers decreased with the rapid growth of the medulla. In human ALS brains, we observed marked loss of CRYM in the corticospinal tract, especially distally. Our results suggest that CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and in the later period, performs cell-specific functions in selected neuronal populations. In the kidney, CRYM may play roles in maturation of renal function. The expression patterns of CRYM may reflect significance of its interactions with T3 or ketimines in these cells and organs. The results also indicate that CRYM may be used as a marker of axonal degeneration in the corticospinal tract.
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Esclerosis Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Cristalinas/metabolismo , Riñón/metabolismo , Tractos Piramidales/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/patología , Animales , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Femenino , Humanos , Riñón/crecimiento & desarrollo , Masculino , Neuronas/metabolismo , Tractos Piramidales/patología , Ratas Sprague-Dawley , Adulto Joven , Cristalinas muRESUMEN
Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology.
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Encéfalo/patología , Complejo Dinactina/metabolismo , Cuerpos de Lewy/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/patologíaRESUMEN
BACKGROUND AND PURPOSE: Recent studies show that successful endovascular thrombectomy 6 to 12 hours after stroke onset enhances functional outcomes 3 months later. In this study, we investigated the effects of reperfusion after ischemia on repair processes in the ischemic areas, as well as on functional recovery, using mouse stroke models. METHODS: We examined time-dependent histological changes and functional recovery after transient middle cerebral artery occlusion of different durations, including permanent middle cerebral artery occlusion, using the CB-17 (CB-17/lcr-+/+Jcl) mouse strain, which has poor pial collateral blood flow. RESULTS: Large microtubule-associated protein 2-negative areas of neuronal death were produced in mice subjected to ≥60 minutes of ischemia followed by reperfusion on day 1, while restricted microtubule-associated protein 2-negative regions were observed in mice subjected to a 45-minute period of ischemia. A substantial reduction in microtubule-associated protein 2-negative areas was observed on day 7 in mice given early reperfusion and was associated with better functional recovery. Klüver-Barrera staining demonstrated that white matter injury on day 1 was significantly lesser in mice with reperfusion. Immunohistochemistry and electron microscopy revealed that a greater number of endothelial cells were present in the infarct areas in mice with earlier reperfusion and were associated with a more rapid recruitment of platelet-derived growth factor receptor ß-positive pericytes and subsequent intrainfarct fibrosis. Early reperfusion also resulted in a greater accumulation of glial fibrillary acidic protein-positive astrocytes in peri-infarct areas. Peri-infarct astrogliosis was attenuated in platelet-derived growth factor receptor ß heterozygous knockout mice. CONCLUSIONS: Early reperfusion after ischemia enhances the survival of endothelial cells and pericytes within ischemic areas even after the infarct is established, resulting in efficient intrainfarct fibrosis and peri-infarct astrogliosis. These effects might be associated with efficient peri-infarct reorganization and functional recovery.
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Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Neuronas/metabolismo , Reperfusión/métodos , Animales , Astrocitos/metabolismo , Astrocitos/patología , Isquemia Encefálica/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neuronas/patología , Pericitos/metabolismo , Pericitos/patología , Distribución Aleatoria , Resultado del TratamientoRESUMEN
Over 60% of all patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been diagnosed in Japan. The incubation period has ranged from 1 to 30 years and the age at onset from 15 to 80 years. Here, we report a 77-year-old male Japanese autopsied dCJD case with the longest incubation period so far in Japan. He received a cadaveric dural graft at the right cranial convexity following a craniotomy for meningioma at the age of 46. At 30 years post-dural graft placement, disorientation was observed as an initial symptom of dCJD. He rapidly began to present with inconsistent speech, cognitive impairment and tremor of the left upper extremity. Occasional myoclonic jerks were predominantly observed on the left side. Brain MRI presented hyperintense signals on diffusion-weighted and T2-weighted images, at the right cerebral cortex. The most hyperintense lesion was located at the right parietal lobe, where the dura mater graft had been transplanted. Single-photon emission CT scan showed markedly decreased cerebral blood flow at the right parietal lobe. EEG revealed diffuse and slow activities with periodic sharp-wave complex discharges seen in the right parietal, temporal and occipital lobes. He died of pneumonia 9 months after onset. Brain pathology revealed non-plaque-type dCJD. Laterality of neuropathological changes, including spongiform change, neuronal loss, gliosis or PrP deposits, was not evident. Western blot analysis showed type 1 PrPCJD . Alzheimer-type pathology and PSP-like pathology were also observed.
Asunto(s)
Aloinjertos/patología , Trasplante de Tejido Encefálico/efectos adversos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/patología , Duramadre/trasplante , Anciano , Aloinjertos/diagnóstico por imagen , Pueblo Asiatico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/fisiopatología , Humanos , Japón , Masculino , Proteínas Priónicas/metabolismo , Trasplante Homólogo/efectos adversosRESUMEN
We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998-2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend <0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2%, 11.9%, 17.3%, 20.6% and 33.1%, respectively; P for trend <0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases.
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Demencia/epidemiología , Demencia/patología , Anciano , Autopsia , Encéfalo/patología , Femenino , Humanos , Japón/epidemiología , Masculino , Prevalencia , Estudios Prospectivos , Factores de RiesgoRESUMEN
Prion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt-Jakob disease (sCJD), Gerstmann-Sträussler-Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8-9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.
Asunto(s)
Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Enfermedades Neurodegenerativas , Enfermedades por Prión , Priones , Humanos , Proteínas Priónicas , Proteínas PrPSc/metabolismo , Adhesión en Parafina , Enfermedades por Prión/diagnóstico , Enfermedades por Prión/metabolismo , Síndrome de Creutzfeldt-Jakob/patología , Priones/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Endopeptidasa K , Anticuerpos , FormaldehídoRESUMEN
Fused in sarcoma (FUS), coded by FUS, is a heterogeneous nuclear ribonucleoprotein (hnRNP). FUS mutations are among the major mutations in familial amyotrophic lateral sclerosis (ALS-FUS: ALS6). The pathological hallmarks of ALS-FUS are FUS-positive neuronal cytoplasmic inclusions (NCI). We examined various hnRNPs in FUS NCIs in the hippocampus in ALS-FUS cases with different FUS mutations (Case 1, H517P; Case 2, R521C). We also examined TDP43-positive NCIs in sporadic ALS hippocampi. Immunohistochemistry was performed using primary antibodies against FUS, p-TDP43, TDP43, hnRNPA1, hnRNPD, PCBP1, PCBP2, and p62. Numerous FUS inclusions were found in the hippocampal granule and pyramidal cell layers. Double immunofluorescence revealed colocalization of FUS and p-TDP43, and FUS and PCBP2 (p-TDP43/FUS: 64.3%, PCBP2/FUS: 23.9%). Colocalization of FUS and PCBP1, however, was rare (PCBP1/FUS: 7.6%). In the hippocampi of patients with sporadic ALS, no colocalization was observed between TDP43-positive inclusions and other hnRNPs. This is the first study to show that FUS inclusions colocalize with other hnRNPs, such as TDP43, PCBP2, and PCBP1. These findings suggest that in ALS-FUS, FUS inclusions are the initiators, followed by alterations of multiple other hnRNPs, resulting in impaired RNA metabolism.
Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína FUS de Unión a ARN , Humanos , Esclerosis Amiotrófica Lateral/patología , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Cuerpos de Inclusión/patología , Mutación/genética , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Post-stroke intra-infarct repair promotes peri-infarct neural reorganization leading to functional recovery. Herein, we examined the remodeling of extracellular matrix proteins (ECM) that constitute the intact basal membrane after permanent middle cerebral artery occlusion (pMCAO) in mice. Among ECM, collagen type IV remained localized on small vessel walls surrounding CD31-positive endothelial cells within infarct areas. Fibronectin was gradually deposited from peri-infarct areas to the ischemic core, in parallel with the accumulation of PDGFRß-positive cells. Cultured PDGFRß-positive pericytes produced fibronectin, which was enhanced by the treatment with PDGF-BB. Intra-infarct deposition of fibronectin was significantly attenuated in pericyte-deficient Pdgfrb+/-mice. Phagocytic activity of macrophages against myelin debris was significantly enhanced on fibronectin-coated dishes. In contrast, laminin α2, produced by GFAP- and aquaporin 4-positive astrocytes, accumulated strongly in the boundary of peri-infarct areas. Pericyte-conditioned medium increased the expression of laminin α2 in cultured astrocytes, partly through TGFß1. Laminin α2 increased the differentiation of oligodendrocyte precursor cells into oligodendrocytes and the expression of myelin-associated proteins. Peri-infarct deposition of laminin α2 was significantly reduced in Pdgfrb+/-mice, with attenuated oligodendrogenesis in peri-infarct areas. Collectively, intra-infarct PDGFRß-positive cells may orchestrate post-stroke remodeling of key ECM that create optimal environments promoting clearance of myelin debris and peri-infarct oligodendrogenesis.
Asunto(s)
Laminina , Accidente Cerebrovascular , Animales , Ratones , Células Endoteliales/metabolismo , Fibronectinas , Infarto de la Arteria Cerebral Media/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismoRESUMEN
Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.
Asunto(s)
Síndrome de Creutzfeldt-Jakob , Priones , Humanos , Síndrome de Creutzfeldt-Jakob/tratamiento farmacológico , Síndrome de Creutzfeldt-Jakob/genética , Priones/genética , Proteínas Priónicas/genética , Poliéster Pentosan Sulfúrico/farmacología , Poliéster Pentosan Sulfúrico/uso terapéutico , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Péptido Hidrolasas/uso terapéutico , Mutación/genéticaRESUMEN
Paraneoplastic tumefactive demyelination (TD) is a rare disorder of the central nervous system that can be challenging to diagnose. Here, we describe a 32-year-old Japanese man with a TD associated with testicular seminoma. He presented with symptoms of right-sided motor and sensory impairment 2 days after vaccination for coronavirus disease 2019 (COVID-19). Brain magnetic resonance imaging (MRI) showed a high-intensity lesion in the left internal capsule. He had a 3-year history of enlargement of the left testicle. Blood examination showed tumor marker elevation and the presence of anti-amphiphysin antibodies. Whole-body computed tomography (CT) revealed mass lesions in the left testicle and enlargement of the retroperitoneal lymph nodes. Radical orchiectomy was performed. As the pathology showed testicular seminoma, chemotherapy was administered. After surgery, his neurological symptoms deteriorated. MRI revealed that the brain lesion had enlarged and progressed to a tumefactive lesion without gadolinium enhancement. The cerebrospinal fluid (CSF) examination was normal without pleocytosis or protein elevation. Steroid pulse therapy was added; however, his symptoms did not improve. A brain stereotactic biopsy was performed and the sample showed demyelinating lesions without malignant cells. As the initial corticosteroid therapy was ineffective, gamma globulin therapy was administered in parallel with chemotherapy, and the clinical symptoms and imaging findings were partially ameliorated. TD seldom appears as a paraneoplastic neurological syndrome. In addition, there are few reports of COVID-19 vaccination-associated demyelinating disease. Clinicians should recognize paraneoplastic TD, and the further accumulation of similar cases is needed.
RESUMEN
Myotonic dystrophy type 1 (DM1) is an inherited autosomal-dominant condition that induces altered splicing of transcripts, including MAPT, leading to a distinctive abnormal deposition of tau protein in the CNS. We characterized the tau isoforms of abnormal depositions in the brains of 4 patients with classic DM1 by immunohistochemistry using isoform-specific antibodies. All patients, including those of presenile age, showed numerous neurofibrillary tangles (NFTs) of both 3-repeat and 4-repeat tau in the limbic area and mild involvement in the cerebral cortex. Amyloid-ß deposition was only seen in 1 senile case while cortical tauopathy in all other cases was consistent with primary age-related tauopathy (PART). In the putamen and globus pallidus, only a few tau deposits were observed. Tau deposits in the brainstem frequently showed a DM1-specific pattern with 3-repeat tau dominant NFTs. Additionally, tau-positive astrocytes morphologically similar to tufted astrocytes and astrocytic plaques were occasionally observed in the brainstem; however, they were predominantly composed of 3-repeat tau. Thus, the classic DM1 showed both early onset of PART-like pathology in the limbic areas as a progeroid syndrome of DM1 and an abnormal splicing event in the brainstem leading to 3-repeat tau dominant accumulation with both neuronal and astrocytic involvement.
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Tronco Encefálico , Hipocampo , Distrofia Miotónica , Tauopatías , Proteínas tau , Humanos , Tronco Encefálico/metabolismo , Tronco Encefálico/patología , Hipocampo/metabolismo , Hipocampo/patología , Distrofia Miotónica/metabolismo , Distrofia Miotónica/patología , Ovillos Neurofibrilares/patología , Isoformas de Proteínas/metabolismo , Proteínas tau/metabolismo , Tauopatías/patologíaRESUMEN
Prion disease is an infectious and fatal neurodegenerative disease. Human prion disease autopsy studies have revealed abnormal prion protein (PrPSc) deposits in the central nervous system and systemic organs. In deer, chronic wasting disease has also become a global problem, with PrPSc in saliva and feces. Therefore, understanding normal cellular prion proteins (PrPc) characteristics in human systemic organs is important since they could be a PrPSc source. This study used western blotting and immunohistochemistry to investigate endocrine and exocrine tissues, such as the human pituitary, adrenal, submandibular glands and the pancreas. All tissues had 30-40 kDa PrP signals, which is a slightly higher molecular weight than normal brain tissue. Most cytoplasmic PrP-positive adenohypophyseal cells were immunopositive for nuclear pituitary-specific positive transcription factor 1. The adrenal medulla and islet cells of the pancreas were PrP-positive and colocalized with chromogranin A. The duct epithelium in the submandibular gland and pancreas were immunopositive for PrP. This study reports the characteristic molecular properties and detailed tissue localization of PrPc in endocrine and exocrine tissues, which is important for infection control and diagnosis.
Asunto(s)
Proteínas Priónicas/química , Animales , Ciervos , Humanos , Especificidad de Órganos , Enfermedades por Prión/metabolismoRESUMEN
Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. ß amyloid (Aß) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aß phase score (A2-3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V-VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/patología , Humanos , Ovillos Neurofibrilares/metabolismo , Placa Amiloide/patología , Prealbúmina/metabolismoRESUMEN
GPI anchorless prion diseases (GPIALPs) show numerous coarse prion protein (PrP) deposits in the CNS but neuropil spongiform changes are mild and the incidence of dementia is low. Here, we examined differences in resident microglial phenotypes between GPIALP (D178fs25) and the other prion diseases Gerstmann-Sträussler-Scheinker (GSS) disease and sporadic Creutzfeldt-Jakob disease (sCJD) with respect to homeostasis and activation. Immunohistochemistry was performed on 2 GPIALP (D178fs25), 4 GSS (P102L), and 4 sCJD cases. Homeostatic microglia expressing TMEM119 and P2RY12 were preserved in GPIALP compared to GSS and sCJD. Microglia/macrophage activation in GSS and sCJD was associated with the extent of spongiform change. Immunoelectron microscopy revealed TMEM119 and P2RY12 in PrP plaque cores. Activated microglia/macrophages expressing HLA-DR and CD68 were predominant in GSS and sCJD whereas in GPIALP, homeostatic microglia were retained and activated microglia/macrophages were rarely observed. These data suggest that PrP deposition in GPIALP is less toxic and that microglia may be immune-tolerant to PrP deposition. This may be associated with milder tissue damage and a low incidence of dementia. Whereas microglia/macrophage activation is considered to be a reaction to tissue injury, this study shows that the degree of microglia/macrophage activity might influence the extent of tissue damage.
Asunto(s)
Síndrome de Creutzfeldt-Jakob , Enfermedad de Gerstmann-Straussler-Scheinker , Proteínas de la Membrana , Microglía , Receptores Purinérgicos P2Y12 , Humanos , Síndrome de Creutzfeldt-Jakob/metabolismo , Enfermedad de Gerstmann-Straussler-Scheinker/genética , Microglía/metabolismo , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismoRESUMEN
We experienced the case of successful conversion to distal gastrectomy for gastric cancer with direct invasion to the pancreatic head after the pre-operative chemotherapy. Esophagogastroduodenoscopy in a 66-year-old man revealed a tumor at the gastric antrum. Abdominal computed tomography (CT) showed that the tumor of the antrum was in contact with the pancreatic head. A biopsy of the tumor confirmed an adenocarcinoma and an overexpression of HER2 (3+). Staging laparoscopy showed the direct invasion of the gastric tumor to the pancreatic head. The patient received S-1, oxaliplatin and trastuzumab. After the pre-operative chemotherapy, CT showed a significantly shrinking tumor detached from the pancreatic head. Subsequently, distal gastrectomy was performed. Intra-operative exploration showed that the gastric tumor separated from the pancreatic head. The accumulation of trials for pre-operative chemotherapy for local advanced gastric cancer is expected.
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INTRODUCTION: There are often cases with postoperative complications after laparoscopic cholecystectomy (LC), resulting in severe consequences. This study aimed to identify potential risk factors of postoperative complications in cases of LC for acute cholecystitis. MATERIALS AND METHODS: A total of 423 patients with cholecystitis underwent LC. We divided the patients into two groups: group without postoperative complications (Group A) and group with postoperative complications (Group B). Pre-operative findings, surgical findings, and the methods for evaluating the risk of peri-operative complications were compared between the two groups with a univariate analysis. Independent risk factors of postoperative complications were then evaluated in a multivariate analysis with the factors shown to be statistically significant in the univariate analysis. RESULTS: A Physiological and Operative severity Score for enUmeration of Mortality and morbidity (POSSUM) of ≥ 48.3 and moderate or severe cholecystitis were independent risk factors of postoperative complications in LC. CONCLUSIONS: This study indicated that POSSUM morbidity and moderate or severe cholecystitis were potential risk factors of postoperative complications. The pre-operative management of the general condition and cholecystitis using antibiotics, infusion, percutaneous transhepatic gallbladder drainage, and other approaches may be significant for the prevention of postoperative complications. Once the POSSUM morbidity reaches the threshold after LC, postoperative management becomes difficult, so strict control of the general condition should be performed.
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Colecistectomía Laparoscópica/efectos adversos , Colecistitis Aguda/cirugía , Complicaciones Posoperatorias/epidemiología , Anciano , Femenino , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Factores de RiesgoRESUMEN
Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases.
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Acuaporina 1/metabolismo , Acuaporina 4/metabolismo , Astrocitos/patología , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/patología , Enfermedad de Gerstmann-Straussler-Scheinker/patología , Proteínas Priónicas/metabolismo , Anciano , Anciano de 80 o más Años , Astrocitos/metabolismo , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Femenino , Enfermedad de Gerstmann-Straussler-Scheinker/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage.