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1.
J Neuroinflammation ; 16(1): 275, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882005

RESUMO

BACKGROUND: Neuroinflammation, typified by elevated levels of interleukin-1 (IL-1) α and ß, and deficits in proteostasis, characterized by accumulation of polyubiquitinated proteins and other aggregates, are associated with neurodegenerative disease independently and through interactions of the two phenomena. We investigated the influence of IL-1ß on ubiquitination via its impact on activation of the E3 ligase parkin by either phosphorylated ubiquitin (P-Ub) or NEDD8. METHODS: Immunohistochemistry and Proximity Ligation Assay were used to assess colocalization of parkin with P-tau or NEDD8 in hippocampus from Alzheimer patients (AD) and controls. IL-1ß effects on PINK1, P-Ub, parkin, P-parkin, and GSK3ß-as well as phosphorylation of parkin by GSK3ß-were assessed in cell cultures by western immunoblot, using two inhibitors and siRNA knockdown to suppress GSK3ß. Computer modeling characterized the binding and the effects of P-Ub and NEDD8 on parkin. IL-1α, IL-1ß, and parkin gene expression was assessed by RT-PCR in brains of 2- and 17-month-old PD-APP mice and wild-type littermates. RESULTS: IL-1α, IL-1ß, and parkin mRNA levels were higher in PD-APP mice compared with wild-type littermates, and IL-1α-laden glia surrounded parkin- and P-tau-laden neurons in human AD. Such neurons showed a nuclear-to-cytoplasmic translocation of NEDD8 that was mimicked in IL-1ß-treated primary neuronal cultures. These cultures also showed higher parkin levels and GSK3ß-induced parkin phosphorylation; PINK1 levels were suppressed. In silico simulation predicted that binding of either P-Ub or NEDD8 at a singular position on parkin opens the UBL domain, exposing Ser65 for parkin activation. CONCLUSIONS: The promotion of parkin- and NEDD8-mediated ubiquitination by IL-1ß is consistent with an acute neuroprotective role. However, accumulations of P-tau and P-Ub and other elements of proteostasis, such as translocated NEDD8, in AD and in response to IL-1ß suggest either over-stimulation or a proteostatic failure that may result from chronic IL-1ß elevation, easily envisioned considering its early induction in Down's syndrome and mild cognitive impairment. The findings further link autophagy and neuroinflammation, two important aspects of AD pathogenesis, which have previously been only loosely related.


Assuntos
Doença de Alzheimer/metabolismo , Interleucina-1beta/metabolismo , Proteína NEDD8/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia , Idoso , Animais , Ativação Enzimática/fisiologia , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Transporte Proteico/fisiologia , Ratos Sprague-Dawley , Ubiquitina/metabolismo
2.
Alzheimers Dement ; 14(2): 230-242, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28945989

RESUMO

INTRODUCTION: Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs. METHODS: Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. RESULTS: Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. CONCLUSION: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.


Assuntos
Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Autofagia/genética , Encéfalo/metabolismo , Lisossomos/metabolismo , Motivos de Nucleotídeos/genética , Doença de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Linhagem Celular Transformada , Simulação por Computador , Citocinas/metabolismo , Progressão da Doença , Ensaio de Desvio de Mobilidade Eletroforética , Epistasia Genética/genética , Feminino , Genótipo , Humanos , Lisossomos/patologia , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica/genética , RNA Mensageiro/metabolismo
3.
Fetal Pediatr Pathol ; 36(6): 452-456, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29227713

RESUMO

INTRODUCTION: Williams syndrome (WS), an autosomal dominant condition linked to gene deletions on chromosome 7, can cause supravalvular aortic narrowing and death. WS-associated mutations are believed to disrupt arterial elastin fibers, causing smooth muscle malformation, endomysial fibrosis and severe hypertension. Previous studies demonstrated arterial ultrastructural anomalies in adult WS patients. It is not presently known if the arterial phenotype of WS is also present in utero. CASE REPORT: A 34-week stillborn was delivered to a 28-year-old with genetically confirmed WS. Aortic tissue from the patient was compared with non-WS fetal aorta of similar gestational age using EM and light microscopy. Both sections were taken from the proximal aortic root. This demonstrated internal elastic lamina disruption, malformed elastic fibers, smooth muscle proliferation and abnormal collagen fibers, consistent with adult WS phenotype. CONCLUSION: Our analysis indicated the cardiovascular changes of WS in a fetus as young as 34 weeks.


Assuntos
Mutação , Doenças Vasculares/diagnóstico , Doenças Vasculares/genética , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Adulto , Aorta/crescimento & desenvolvimento , Aorta/patologia , Proliferação de Células , Colágeno/química , Feminino , Morte Fetal , Humanos , Masculino , Músculo Liso/metabolismo , Fenótipo , Gravidez , Diagnóstico Pré-Natal , Natimorto , Doenças Vasculares/mortalidade , Síndrome de Williams/mortalidade
4.
J Neural Transm (Vienna) ; 122(7): 1007-18, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25556950

RESUMO

Frontotemporal lobar degeneration with τ pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick's disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8% of non-diseased controls, we found grains, coiled bodies, and/or τ-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Proteínas tau/metabolismo , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Análise de Variância , Encéfalo/metabolismo , Transtornos Cerebrovasculares/etiologia , Estudos de Coortes , Feminino , Degeneração Lobar Frontotemporal/classificação , Degeneração Lobar Frontotemporal/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , Adulto Jovem
5.
Eur Arch Psychiatry Clin Neurosci ; 263 Suppl 2: S137-45, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24077890

RESUMO

Alzheimer's disease (AD) is characterized neuropathologically by the presence of amyloid plaques, neuritic plaques, and neurofibrillary tangles (NFTs). These lesions occur not only in demented individuals with AD but also in non-demented persons. In non-demented individuals, amyloid and neuritic plaques are usually accompanied with NFTs and are considered to represent asymptomatic or preclinical AD (pre-AD) pathology. Here, we defined and characterized neuropathological differences between clinical AD, non-demented pre-AD, and non-AD control cases. Our results show that clinical AD may be defined as cases exhibiting late stages of NFT, amyloid, and neuritic plaque pathology. This is in contrast to the neuropathological changes characteristic of pre-AD, which display early stages of these lesions. Both AD and pre-AD cases often exhibit cerebral amyloid angiopathy (CAA) and granulovacuolar degeneration (GVD), and when they do, these AD-related pathologies were at early stages in pre-AD cases and at late stages in symptomatic AD. Importantly, NFTs, GVD, and CAA were also observed in non-AD cases, i.e., in cases without amyloid plaque pathology. Moreover, soluble and dispersible, high-molecular-weight amyloid ß-protein (Aß) aggregates detected by blue-native polyacrylamide gel electrophoresis were elevated in clinical AD compared to that in pre-AD and non-AD cases. Detection of NFTs, GVD, and CAA in cases without amyloid plaques, presently classified as non-AD, is consistent with the idea that NFTs, GVD, and CAA may precede amyloid plaque pathology and may represent a pre-amyloid plaque stage of pre-AD not yet considered in the current recommendations for the neuropathological diagnosis of AD. Our finding of early stages of AD-related NFT, amyloid, and GVD pathology provides a more clear definition of pre-AD cases that is in contrast to the changes in clinical AD, which is characterized by late stages of these AD-related pathologies. The observed elevation of soluble/dispersible Aß aggregates from pre-AD compared to that in AD cases suggests that, in addition to more widespread AD-related pathologies, soluble/dispersible Aß aggregates in the neuropil play a role in the conversion of pre-AD to clinical AD.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Autopsia , Química Encefálica , Angiopatia Amiloide Cerebral/patologia , Disfunção Cognitiva/patologia , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/patologia , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Adulto Jovem
6.
Cells ; 12(8)2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-37190062

RESUMO

Intracerebral hemorrhage (ICH) is a significant health concern associated with high mortality. Cofilin plays a crucial role in stress conditions, but its signaling following ICH in a longitudinal study is yet to be ascertained. In the present study, we examined the cofilin expression in human ICH autopsy brains. Then, the spatiotemporal cofilin signaling, microglia activation, and neurobehavioral outcomes were investigated in a mouse model of ICH. Human autopsy brain sections from ICH patients showed increased intracellular cofilin localization within microglia in the perihematomal area, possibly associated with microglial activation and morphological changes. Various cohorts of mice were subjected to intrastriatal collagenase injection and sacrificed at time points of 1, 3, 7, 14, 21, and 28 days. Mice suffered from severe neurobehavioral deficits after ICH, lasting for 7 days, followed by a gradual improvement. Mice suffered post-stroke cognitive impairment (PSCI) both acutely and in the chronic phase. Hematoma volume increased from day 1 to 3, whereas ventricle size increased from day 21 to 28. Cofilin protein expression increased in the ipsilateral striatum on days 1 and 3 and then decreased from days 7 to 28. An increase in activated microglia was observed around the hematoma on days 1 to 7, followed by a gradual reduction up to day 28. Around the hematoma, activated microglia showed morphological changes from ramified to amoeboid. mRNA levels of inflammatory [tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), and interleukin-6 (IL-6) and anti-inflammatory markers [interleukin-10 (IL-10), transforming growth factor-ß TGF-ß, and arginase I (Arg1)] increased during the acute phase and decreased in the chronic phase. Blood cofilin levels increased on day 3 and matched the increase in chemokine levels. slingshot protein phosphatase 1 (SSH1) protein, which activates cofilin, was increased from day 1 to 7. These results suggest that microglial activation might be the sequel of cofilin overactivation following ICH, leading to widespread neuroinflammation and consequent PSCI.


Assuntos
Lesões Encefálicas , Acidente Vascular Cerebral , Humanos , Camundongos , Animais , Microglia/metabolismo , Doenças Neuroinflamatórias , Fatores de Despolimerização de Actina/metabolismo , Estudos Longitudinais , Hemorragia Cerebral/patologia , Hematoma/patologia , Lesões Encefálicas/patologia , Acidente Vascular Cerebral/metabolismo
7.
BMC Med ; 10: 35, 2012 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-22502727

RESUMO

BACKGROUND: Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype. METHODS: Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid ß (Aß) precursor protein (ßAPP), synaptophysin, phosphorylated tau, and Aß were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry. RESULTS: Tissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in ßAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aß plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17). CONCLUSIONS: Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).Please see related article: http://www.biomedcentral.com/1741-7015/10/36.


Assuntos
Apolipoproteína E3/genética , Epilepsia/genética , Neurônios/fisiologia , Adolescente , Adulto , Idoso , Alelos , Western Blotting , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Neuroglia/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem
8.
J Neuroinflammation ; 8: 175, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22171672

RESUMO

BACKGROUND: We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), ß-amyloid precursor protein (ßAPP), and fragments of the latter such as amyloid ß-peptide (Aß) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE ε4 allele. METHODS: Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1ß slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1ß, glutamate, Aß, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases--in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)--prior to exposure of cultures to IL-1ß, Aß, sAPP, or glutamate. RESULTS: Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1ß induces expression of ßAPP, IL-1α, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1ß, IL-1ß-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1ß also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents--as well as Aß--stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1ß on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK. CONCLUSION: Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, ßAPP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.


Assuntos
Apolipoproteínas E/biossíntese , Regulação da Expressão Gênica/fisiologia , Interleucina-1beta/metabolismo , Precursor de Proteína beta-Amiloide/biossíntese , Animais , Western Blotting , Imunofluorescência , Ácido Glutâmico/biossíntese , Inflamação/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
9.
Acta Neuropathol ; 120(2): 169-83, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20535486

RESUMO

The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Capilares/metabolismo , Angiopatia Amiloide Cerebral , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Angiopatia Amiloide Cerebral/etiologia , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/patologia , Transportador 2 de Aminoácido Excitatório/metabolismo , Feminino , Genótipo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lipoproteínas LDL/genética , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Razão de Chances , Escalas de Graduação Psiquiátrica
10.
Conn Med ; 74(2): 79-83, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20218042

RESUMO

We report an unusual case of hepatocellular carcinoma with three histologically and immunohistochemically distinct components, arising in a noncirrhotic liver, with a pulmonary tumor embolus from one of the three components. The histological patterns of the three components were fibrolamellar, well-differentiated nodular, and pleomorphic. The immunophenotypes were, respectively CK7- /CK20- /Hep Par1+, CK7+ /CK20- /Hep Par1+, and CK7+ /CK20+ /Hep Par1-. The tumor in the pulmonary embolus showed only the morphological and immunohistochemical features of the pleomorphic component. This unusual case ofmetastasizing hepatocellular carcinoma with three distinct histologic components suggests that the histological and immunophenotype of the tumor might be useful in predicting metastatic potential.


Assuntos
Carcinoma Hepatocelular/secundário , Imuno-Histoquímica/métodos , Queratinas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/secundário , Células Neoplásicas Circulantes/química , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/metabolismo , Diagnóstico Diferencial , Evolução Fatal , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Células Neoplásicas Circulantes/patologia
11.
Case Rep Infect Dis ; 2020: 9727513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670645

RESUMO

Aspergillosis is a commonly diagnosed fungal infection. Histopathologic examination alone can have diagnostic pitfalls due to the overlapping of fungal morphology. We report a case of Scedosporium boydii infection initially misdiagnosed as aspergillosis. The patient presented to the hospital with shortness of breath and chest and abdominal pain. Laboratory tests revealed leukocytosis and elevated serum liver enzymes, myoglobin and lipase. He died of hypotensive shock and brain abscesses despite antibiotic treatment. Autopsy revealed invasive fungal infection in the heart, thyroid, and brain with presence of 45-degree angled, branching hyphae. The initial diagnosis of aspergillosis was made; however, further molecular studies identified the organism as S. boydii. This report reveals the potential pitfalls of morphologic diagnosis alone; and the necessity of other testing modalities to render an accurate diagnosis which is crucial for appropriate.

12.
Magn Reson Med ; 61(1): 28-34, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19097198

RESUMO

Cell membrane abnormalities due to changes in phospholipid (PL) composition and metabolism have been implicated in schizophrenia pathogenesis. That work has generally assessed membrane phospholipids from nonneural tissues such as erythrocytes and platelets. High-resolution (31)P NMR spectroscopy was used to characterize PLs of gray matter in postmortem brain for 20 schizophrenics, 20 controls, and 7 patients with other mental illnesses (psychiatric controls). Tissues from frontal, temporal, and occipital cortices were extracted with hexane-isopropanol, and (31)P NMR spectra were obtained in an organic-solvent system to resolve the major PL classes (based on headgroups) and subclasses (based on linkage at the sn - 1 position). Surprisingly, repeated-measures multivariate analysis of variance revealed no overall differences among the groups. There were no significant differences (P < .05) among the three groups for any individual PL subclass, including lysophospholipids. The sum of all phosphatidylethanolamine headgroups was significantly lower for schizophrenics than for controls or psychiatric controls in the frontal cortex. The present results are minimally correlated with previous results for aqueous PL metabolites on these same samples. The metabolite changes measured by in vivo (31)P MRS in schizophrenia do not appear to reflect PL concentration changes. The present results offer very little support for the phospholipid hypothesis of schizophrenia.


Assuntos
Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Fosfolipídeos/análise , Esquizofrenia/metabolismo , Idoso , Biomarcadores/análise , Cadáver , Feminino , Humanos , Masculino , Isótopos de Fósforo/análise , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
J Neuropathol Exp Neurol ; 67(8): 773-83, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18648325

RESUMO

Theories regarding the initiation and progression of Alzheimer disease (AD) often consider potential roles played by elevations of beta-amyloid precursor protein (betaAPP). Because it is the source of amyloid beta-peptide, betaAPP may simply contribute more pathogenic stimulus when elevated; some analyses have, however, reported a decline in betaAPP in AD. We found a progressive increase in neuronal betaAPP expression with increasing age in the brains of nondemented individuals, whereas in AD patient samples, betaAPP antigenicity decreased in neuronal somata in a manner that correlated with accumulation of mature amyloid beta-peptide plaques. In contrast, apolipoprotein E (ApoE) expression correlated with accumulation of plaques, and even greater amounts of ApoE were detected in plaques. Induction of betaAPP by glutamate in neuronal cell cultures was found to depend upon ApoE levels or activity. Thus, elevations in expression of ApoE and betaAPP by cellular stresses are likely normally linked in vivo, and uncoupling of this link, or other pathologic events in AD initiation, may leave neurons with diminished betaAPP expression, which might in turn reduce their resistance to stressors.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/metabolismo , Placa Amiloide/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Ácido Glutâmico/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Neocórtex/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos
14.
Acad Pathol ; 5: 2374289518798556, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30327790

RESUMO

Assessment of physician workloads has become increasingly important in modern academic physician practice, where it is commonly used to allocate resources among departments, to determine staffing, and to set the compensation of individual physicians. The physician work relative value unit system is a frequently used metric in this regard. However, the application of this system to the practice of pathology has proven problematic. One area of uncertainty is the validity of using work relative value unit norms that were derived from general surgical pathology practice to assess the various subspecialties within anatomic pathology. Here, we used data from the 2017 Association of Pathology Chairs practice survey to assess salary and work relative value unit data for single-subspecialty practitioners in US academic pathology departments in the prior year (2016). Five subspecialties were evaluated: dermatopathology, gastrointestinal pathology, hematopathology/hematology, renal pathology, and neuropathology. Data for general surgical pathologists and cytopathologists were included for comparison. For this analysis, survey data were available for 168 practitioners in 43 US academic departments of pathology. Salary ranges varied little among subspecialties, with the exception of dermatopathology, where salaries were higher. In contrast, work relative value unit productivity varied widely among different subspecialties, with median values differing as much as 4- to 7-fold between subspecialties. These results suggest that the use of a single overall work relative value unit standard is not appropriate for specialty- or subspecialty-based anatomic pathology practice, and that either the benchmark norms should be tailored to individual practice patterns, or an alternative system of workload measurement should be developed.

15.
Acad Pathol ; 5: 2374289518765435, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29637086

RESUMO

American hospitals are increasingly turning to service outsourcing to reduce costs, including laboratory services. Studies of this practice have largely focused on nonacademic medical centers. In contrast, academic medical centers have unique practice environments and unique mission considerations. We sought to elucidate and analyze clinical laboratory outsourcing experiences in US academic medical centers. Seventeen chairs of pathology with relevant experience were willing to participate in in-depth interviews about their experiences. Anticipated financial benefits from joint venture arrangements often eroded after the initial years of the agreement, due to increased test pricing, management fees, duplication of services in support of inpatients, and lack of incentive for utilization control on the part of the for-profit partner. Outsourcing can preclude development of lucrative outreach programs; such programs were successfully launched in several cases after joint ventures were either avoided or terminated. Common complaints included poor test turnaround time and problems with test quality (especially in molecular pathology, microbiology, and flow cytometry), leading to clinician dissatisfaction. Joint ventures adversely affected retention of academically oriented clinical pathology faculty, with adverse effects on research and education, which further exacerbated clinician dissatisfaction due to lack of available consultative expertise. Resident education in pathology and in other disciplines (especially infectious disease) suffered both from lack of on-site laboratory capabilities and from lack of teaching faculty. Most joint ventures were initiated with little or no input from pathology leadership, and input from pathology leadership was seen to have been critical in those cases where such arrangements were declined or terminated.

16.
Cureus ; 10(9): e3272, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30443443

RESUMO

Glioblastoma multiforme (GBM) is a World Health Organization (WHO) grade IV primary malignant astrocytoma. Aneurysms are devastating intracranial neurovascular pathologies. Intracranial dermoid cysts are common, benign lesions which can be clinically silent or associated with seizure disorder. We describe physically adjacent diagnoses of dermoid cyst, intracranial aneurysm, and GBM in a single patient. Records were collected and reviewed to compile the final clinical picture. A 72-year-old male with a long history of seizure disorder, presented with new focal, unilateral neurological deficits. Radiographic evaluation including computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a dermoid cyst with an underlying developing GBM, which also, by happenstance, contained an aneurysm. During open surgical resection, multiple macroscopically distinct tissue types were noted. Histological analysis of tissue from each lesion confirmed the diagnoses including dermoid cyst, GBM, and aneurysm. Pathological analysis revealed the presence of extensive inflammatory cells throughout. Subsequent staining identified CD68 positive cells indicating a probable chronic inflammatory state. Chronic inflammation resulting from the presence of a long term dermoid cyst and ongoing seizures may have led to dystrophic changes in adjacent vasculature and approximating glial tissues, inducing the formation of an aneurysm and a secondary GBM. Therefore, while benign in nature, dermoid cysts can be related to seizure disorder and may cause chronic inflammation in surrounding brain tissue.

17.
J Neuropathol Exp Neurol ; 66(8): 683-6, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17882012

RESUMO

Cortical Lewy body disease as a cause of dementia has been recognized for more than 40 years. Only in the past 15 to 20 years, however, has the true frequency of this entity come to be appreciated, primarily because of the advent of sensitive and specific immunohistochemical diagnostic techniques. We now know that there is frequent and extensive overlap, both clinically and pathologically, between Lewy body and Alzheimer diseases. Although some of this overlap may be attributable to common genetic and environmental risk factors, it is also now apparent that the 2 diseases share common neuroinflammatory mechanisms involving activation of microglia, overexpression of interleukin-1 and other inflammatory mediators, and inflammatory toxicity to neurons. Activated microglia are found in association with alpha-synuclein-containing neurons and glia in Parkinson disease, in dementia with Lewy bodies, and in multiple system atrophy, and these associations are reminiscent of microglial associations with neurofibrillary tangle-containing neurons in Alzheimer disease. In vitro and in vivo experimental work has shown reciprocal induction between alpha-synuclein and injured neurons on one hand and activated microglia and cytokine overexpression on the other. These neuroinflammatory processes may be a common link driving progression in both diseases and explaining the frequent overlap between the 2 diseases.


Assuntos
Doença de Alzheimer/complicações , Encefalite/etiologia , Doença por Corpos de Lewy/complicações , Doença de Alzheimer/genética , Encefalite/genética , Meio Ambiente , História do Século XX , História do Século XXI , Humanos , Interleucina-1/genética , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/história , Fatores de Risco
18.
J Comp Neurol ; 500(6): 1106-16, 2007 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-17183534

RESUMO

The alpha(3) isoform of Na(+),K(+)-ATPase is uniquely expressed in afferent and efferent neurons innervating muscle spindles in the peripheral nervous system (PNS) of adult rats, but the distribution pattern of this isoform in other species has not been investigated. We compared expression of alpha(3) Na(+),K(+)-ATPase in lumbar dorsal root ganglia (DRG), spinal roots, and skeletal muscle samples of amphibian (frog), reptilian (turtle), avian (pigeon and chicken), and mammalian (mouse and human) species. In all species studied, the alpha(3) Na(+),K(+)-ATPase isoform was nonuniformly expressed in peripheral ganglia and nerves. In spinal ganglia, only 5-20% of neurons expressed this isoform, and, in avian and mammalian species, these alpha(3) Na(+),K(+)-ATPase-expressing neurons belonged to a subpopulation of large DRG neurons. In ventral root fibers of pigeons, mice, and humans, the alpha(3) Na(+),K(+)-ATPase was abundantly expressed predominantly in small myelinated axons. In skeletal muscle samples from turtles, pigeons, mice, and humans, alpha(3) Na(+),K(+)-ATPase was detected in intramuscular myelinated axons and in profiles of nerve terminals associated with the equatorial and polar regions of muscle spindle intrafusal fibers. These results show that the expression profiles for alpha(3) Na(+),K(+)-ATPase in the peripheral nervous system of a wide variety of vertebrate species are similar to the profile of rats and suggest that stretch receptor-associated expression of alpha(3) Na(+),K(+)-ATPase is preserved through vertebrate evolution.


Assuntos
Gânglios Espinais/enzimologia , Músculo Esquelético/enzimologia , Filogenia , ATPase Trocadora de Sódio-Potássio/metabolismo , Raízes Nervosas Espinhais/enzimologia , Animais , Vias Eferentes/enzimologia , Humanos , Imuno-Histoquímica , Isoenzimas/classificação , Isoenzimas/metabolismo , Fusos Musculares/enzimologia , Neurônios Aferentes/enzimologia , Sistema Nervoso Periférico/enzimologia , Vertebrados
19.
BMJ Case Rep ; 20172017 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-28578305

RESUMO

INTRODUCTION: Subependymomas are benign intraventricular tumours that most often occur asymptomatically and are found incidentally on autopsy. Symptomatic examples requiring surgical intervention are exceedingly rare. CASE PRESENTATION: A 55-year-old man with no history of neurological symptoms presented with multiple episodes of loss of consciousness and increasing headaches. MRI revealed a lobulated intraventricular mass centred at the right Foramen of Monro. Obstructive hydrocephalus with localised midline shift and a second lesion were noted. Right frontal craniotomy with total removal via transcortical resection was performed. DISCUSSION: Symptomatic subependymomas generally present with signs of hydrocephalus due to obstruction of cerebrospinal fluid pathways. There is only one other reported case of multifocal subependymomas in a symptomatic patient. An example of multiple supratentorial subependymomas causing obstructive hydrocephalus has not been previously reported. CONCLUSIONS: Multiple subependymomas are rare. Judicious surgical management with full excision led to symptomatic improvement in our patient.


Assuntos
Neoplasias do Ventrículo Cerebral/diagnóstico , Ventrículos Cerebrais , Glioma Subependimal/diagnóstico , Hidrocefalia/etiologia , Neoplasias do Ventrículo Cerebral/complicações , Neoplasias do Ventrículo Cerebral/diagnóstico por imagem , Craniotomia , Diagnóstico Diferencial , Glioma Subependimal/complicações , Glioma Subependimal/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
20.
Cureus ; 9(9): e1658, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-29147633

RESUMO

Carotid splaying, also known as the Lyre sign, is a widening of the carotid bifurcation due to the displacement of the internal carotid artery and the external carotid artery just distal to the point of divergence. This phenomenon is classically exhibited by highly vascularized carotid body tumors and, in rare cases, by cervical sympathetic chain schwannomas. Demonstration of the Lyre sign by a cervical vagal neurofibroma, however, is a unique occurrence that has not been previously documented in the literature. Neurofibromas are slow growing, poorly vascularized soft tissue masses and are a hallmark of the autosomal dominant genetic disorder, neurofibromatosis type 1 (NF-1). While targeted genetic therapies are evolving, management is currently dependent on a case-by-case resection of tumors with specific indications for chemo and radiation therapy. These resections rely on magnetic resonance imaging (MRI) to visualize tumor location and infiltration, but even in the setting of an established NF-1 diagnosis, additional imaging can be beneficial in ruling out more precarious tumors and optimizing surgical outcomes. In this case, a 25-year-old female with known NF-1 presented with an enlarging cervical mass that demonstrated splaying of the left internal and external carotid arteries on MRI. Due to the typical association of the Lyre sign with carotid body tumors, magnetic resonance angiography (MRA) was crucial in guiding surgical decision making. Carotid body tumors are highly vascularized, may compress carotid branches, and carry a high risk of intraoperative bleeding. They are best visualized with MRA, which assesses carotid splaying and patency, and demonstrates vascular blushing within the tumor.  This patient's MRA demonstrated the Lyre sign, patency of all carotid vessels, and a lack of vascularity within the mass, thus lowering suspicion for a carotid body tumor. Intraoperative use of imaging results facilitated a successful resection of a soft tissue tumor with minimal blood loss and no complications. Postoperative histologic examination confirmed a neurofibroma and definitively ruled out a carotid body tumor. This case highlights the importance of utilizing MRA whenever carotid splaying is seen on MRI and supports the consideration of neurofibromas in the differential for this finding.

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