RESUMO
Mitochondria form a dynamic network within skeletal muscle. This network is not only responsible for producing adenosine triphosphate (ATP) through oxidative phosphorylation, but also responds through fission, fusion and mitophagy to various factors, such as increased energy demands, oxidative stress, inflammation, and calcium dysregulation. Mitochondrial dysfunction in skeletal muscle not only occurs in primary mitochondrial myopathies, but also other hereditary and acquired myopathies. As such, this review attempts to highlight the clinical and histopathologic aspects of mitochondrial dysfunction seen in hereditary and acquired myopathies, as well as discuss potential mechanisms leading to mitochondrial dysfunction and therapies to restore mitochondrial function.
RESUMO
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate PTP4A2 (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood-brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50-100% of mice. Our study identifies a promising multi-targetable PTP4A-ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.
RESUMO
Hereditary gelsolin amyloidosis is an adult onset autosomal dominant disease with neurologic, ophthalmologic and dermatologic features that may be mistaken for Sjögren syndrome. We describe a case of a 68 year old female presenting with facial numbness and asymmetry, dry eyes, dry mouth and fatigue, originally diagnosed as Sjögren syndrome and treated with hydroxychloroquine. Due to her insidious progression of facial weakness with associated proximal muscle weakness she underwent a muscle biopsy, which demonstrated features of hydroxychloroquine induced myopathy and amyloid deposition. This subsequently led to targeted genetic testing, revealing an autosomal dominant c.640G > A pathogenic variant of the gelsolin gene. Therefore, this is a unique case of complex muscle pathology with features of a rare hereditary systemic amyloidosis an uncommon drug- induced myopathy.
RESUMO
Brain abscesses (BA) are focal parenchymal infections that remain life-threatening conditions. Polymicrobial BAs (PBAs) are complex coinfections of bacteria or bacterial and nonbacterial pathogens such as fungi or parasites, with diagnostic and therapeutic challenges. In this article, we comprehensively review the prevalence, pathogenesis, clinical manifestations, and microbiological, histopathological, and radiological features of PBAs, as well as treatment and prognosis. While PBAs and monomicrobial BAs have some similarities such as nonspecific clinical presentations, PBAs are more complex in their pathogenesis, pathological, and imaging presentations. The diagnostic challenges of PBAs include nonspecific imaging features at early stages and difficulties in identification of some pathogens by routine techniques without the use of molecular analysis. Imaging of late-stage PBAs demonstrates increased heterogeneity within lesions, which corresponds to variable histopathological features depending on the dominant pathogen-induced changes in different areas. This heterogeneity is particularly marked in cases of coinfections with nonbacterial pathogens such as Toxoplasma gondii. Therapeutic challenges in the management of PBAs include initial medical therapy for possibly underrecognized coinfections prior to identification of multiple pathogens and subsequent broad-spectrum antimicrobial therapy to eradicate identified pathogens. PBAs deserve more awareness to facilitate prompt and appropriate treatment.
RESUMO
OBJECTIVES: The objective of this study was to investigate whether skeletal muscle cystathionine γ-lyase (CTH) contributes to high-fat diet (HFD)-induced metabolic disorders using skeletal muscle Cth knockout (CthΔskm) mice. METHODS: The CthΔskm mice and littermate Cth-floxed (Cthf/f) mice were fed with either HFD or chow diet for 13 weeks. Metabolomics and transcriptome analysis were used to assess the impact of CTH deficiency in skeletal muscle. RESULTS: Metabolomics coupled with transcriptome showed that CthΔskm mice displayed impaired energy metabolism and some signaling pathways linked to insulin resistance (IR) in skeletal muscle although the mice had normal insulin sensitivity. HFD led to reduced CTH expression and impaired energy metabolism in skeletal muscle in Cthf/f mice. CTH deficiency and HFD had some common pathways enriched in the aspects of amino acid metabolism, carbon metabolism, and fatty acid metabolism. CthΔskm+HFD mice exhibited increased body weight gain, fasting blood glucose, plasma insulin, and IR, and reduced glucose transporter 4 and CD36 expression in skeletal muscle compared to Cthf/f+HFD mice. Impaired mitochondria and irregular arrangement in myofilament occurred in CthΔskm+HFD mice. Omics analysis showed differential pathways enriched between CthΔskm mice and Cthf/f mice upon HFD. More severity in impaired energy metabolism, reduced AMPK signaling, and increased oxidative stress and ferroptosis occurred in CthΔskm+HFD mice compared to Cthf/f+HFD mice. DISCUSSION: Our results indicate that skeletal muscle CTH expression dysregulation contributes to metabolism disorders upon HFD.
Assuntos
Cistationina gama-Liase , Dieta Hiperlipídica , Hiperglicemia , Resistência à Insulina , Músculo Esquelético , Obesidade , Animais , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Camundongos , Obesidade/metabolismo , Cistationina gama-Liase/metabolismo , Cistationina gama-Liase/genética , Cistationina gama-Liase/deficiência , Dieta Hiperlipídica/efeitos adversos , Hiperglicemia/metabolismo , Camundongos Knockout , Masculino , Metabolismo EnergéticoRESUMO
Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha-glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α-amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen-free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa-/- mouse lysosomes. Our study identified that a defect in the degradation of glycogenin-exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin-exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro, the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin-exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Glicoproteínas , Humanos , Camundongos , Animais , Doença de Depósito de Glicogênio Tipo II/genética , Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/terapia , Glicogênio/análise , Glicogênio/metabolismo , Glucosiltransferases/metabolismo , Músculo Esquelético/patologia , Lisossomos/metabolismoRESUMO
Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like fibro-osseous lesion that can develop anywhere in the neuraxis. Approximately a half of reported CAPNONs developed in the spinal region, mostly close to the facet joint (FJ). The diagnosis of spinal CAPNONs is challenging given the existence of mimics and associated pathologies including calcific degeneration of the FJ ligaments (DFJL) and synovial cysts (SCs). The pathogenesis of CAPNON remains elusive, although there have been a few hypotheses including degenerative, reactive, proliferative and immune-mediated processes. Our present study examined clinical, radiological and pathological features of 12 spinal CAPNONs in comparison to 9 DFJL foci, and diagnostic and pathogenic relationship between CAPNONs and FJ pathologies. On imaging, CAPNONs were all tumor-like and typically bigger than DFJL foci. All CAPNONs showed pathologically diagnostic features including characteristic cores, consistently identifiable core-surrounding/peripheral palisading of macrophages and other cells including multinucleated giant cells, variable infiltration of CD8+ T-cells, and multifocal immunopositivity of neurofilament light chain (NF-L). These features were absent or limited in the DFJL foci with statistically significant differences from CAPNONs, except calcifications. Spinal CAPNONs co-existed with DFJL foci in all cases; some had transitional foci with overlapping focal CAPNON and DFJL-like features. These findings, along with our previously reported relationship between CAPNONs and SCs, suggest that spinal CAPNONs may occur in association with or in transition from calcifying/calcified degenerative lesions of FJ ligaments and/or SCs when a reactive proliferative process is complemented by other pathogenic changes such as immune-mediated pathology and NF-L deposition/expression.
Assuntos
Neoplasias , Articulação Zigapofisária , Humanos , Linfócitos T CD8-Positivos , Coluna Vertebral , Sistema Nervoso CentralRESUMO
OBJECTIVE: Mitochondrial myopathy without extraocular muscles involvement (MiMy) represents a distinct form of mitochondrial disorder predominantly affecting proximal/distal or axial muscles, with its phenotypic, genotypic features, and long-term prognosis poorly understood. METHODS: A cross-sectional study conducted at a national diagnostic center for mitochondrial disease involved 47 MiMy patients, from a cohort of 643 mitochondrial disease cases followed up at Qilu Hospital from January 1, 2000, to January 1, 2021. We compared the clinical, pathological, and genetic features of MiMy to progressive external ophthalmoplegia (PEO) and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patients. RESULTS: MiMy patients demonstrated a more pronounced muscle involvement syndrome, with lower 6MWT scores, higher FSS, and lower BMI compared to PEO and MELAS patients. Serum levels of creatinine kinase (CK), lactate, and growth and differentiation factor 15 (GDF15) were substantially elevated in MiMy patients. Nearly a third (31.9%) displayed signs of subclinical peripheral neuropathy, mostly axonal neuropathy. Muscle biopsies revealed that cytochrome c oxidase strong (COX-s) ragged-red fibers (RRFs) were a typical pathological feature in MiMy patients. Genetic analysis predominantly revealed mtDNA point pathogenic variants (59.6%) and less frequently single (12.8%) or multiple (4.2%) mtDNA deletions. During the follow-up, a majority (76.1%) of MiMy patients experienced stabilization or improvement after therapeutic intervention. CONCLUSIONS: This study provides a comprehensive profile of MiMy through a large patient cohort, elucidating its unique clinical, genetic, and pathological features. These findings offer significant insights into the diagnostic and therapeutic management of MiMy, ultimately aiming to ameliorate patient outcomes and enhance the quality of life.
Assuntos
Acidose Láctica , Síndrome MELAS , Oftalmoplegia Externa Progressiva Crônica , Acidente Vascular Cerebral , Humanos , Síndrome MELAS/genética , Músculos Oculomotores , Estudos Transversais , Qualidade de Vida , Acidente Vascular Cerebral/patologia , DNA Mitocondrial/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/patologiaRESUMO
Nocardia brain abscesses are rare bacterial infections associated with a high mortality rate, and their preoperative diagnosis can be difficult for various reasons including a nonspecific clinical presentation. While late-stage nocardial brain abscesses may be radiologically characteristic, early-stage lesions are nonspecific and indistinguishable from another inflammatory/infectious process and other mimics. Despite the paucity of previous histopathological descriptions, histopathological examination is critical for the identification of the pathogen, lesion stage(s), and possible coexisting pathology. In this study, we examined the clinical, radiological and histopathological features of 10 patients with brain nocardiosis. Microscopic findings were analysed in correlation with clinical and radiological features in 9 patients, which revealed that brain nocardiosis was characterized by numerous necrotic and non-necrotic foci of various stages (I-IV) along with Nocardia identification, as well as the leptomeningeal involvement in most cases, and co-infection of brain nocardiosis with toxoplasmosis in 2 patients. The imaging features were characteristic with a multilobulated/bilobed ring-enhancing appearance in 8 patients including 2 patients with multiple lobulated and non-lobulated lesions and 1 patient showing the progression from a non-lobulated to lobulated lesion. These findings suggest that nocardial brain abscesses particularly at late-stages share common characteristics. Nevertheless, given the complex pathologic features, including possible co-infection by other pathogens, nocardial brain abscesses remain a therapeutic challenge.
Assuntos
Abscesso Encefálico , Coinfecção , Nocardiose , Nocardia , Humanos , Coinfecção/complicações , Abscesso Encefálico/diagnóstico por imagem , Nocardiose/diagnóstico , Nocardiose/diagnóstico por imagem , Encéfalo/diagnóstico por imagemRESUMO
Brain metastases are a frequent occurrence in neuropathology practices. The literature on their neuroanatomical location is frequently derived from radiological analyses. This work examines brain metastases through the lens of pathology specimens. All brain surgical pathology reports for cases accessioned 2011-2020 were retrieved from a laboratory. Specimens were classified by neuroanatomical location, diagnosis and diagnostic category with a hierarchical free text string-matching algorithm (HFTSMA) and also subsequently audited. All reports classified as probable metastasis were reviewed by a pathologist. The provided history was compared to the final categorization by a pathologist. The cohort had 4,625 cases. The HFTSMA identified 854 cases (including metastases from a definite primary, metastases from primary not known and improperly classified cases). 514/854 cases had one definite primary site per algorithm and on report review 538/854 cases were confirmed as such. The 538 cases originated from 511 patients. Primaries from breast, gynecologic tract, and gastrointestinal tract not otherwise specified were most frequently found in the cerebellum. Kidney metastases were most frequently found in the occipital lobe. Lung, metastatic melanoma and colorectal primaries were most commonly found in the frontal lobe. The provided clinical history predicted the primary in 206 cases (40.3%), was discordant in 17 cases (3.3%) and non-contributory in 280 cases (54.8%). The observed distribution of the metastatic tumours in the brain is dependent on the primary site. In the majority (54.8%) of cases, the provided clinical history was non-contributory; this suggests surgeon-pathologist communication may have the potential for optimization.
Assuntos
Neoplasias Encefálicas , Neoplasias Renais , Melanoma , Humanos , Feminino , Neoplasias Encefálicas/patologia , Melanoma/secundário , Encéfalo/patologia , Neoplasias Renais/patologia , Lobo OccipitalRESUMO
Hydrogen sulfide (H2S) has been implicated to have antidepressive effects. We sought to investigate the prevention effects of H2S donor NaHS on depression-like behavior induced by lipopolysaccharide (LPS) in mice and its potential mechanisms. Sucrose preference, force swimming, open field, and elevate zero maze were used to evaluate depression-like behavior. NF-κB and NLRP3 inflammasome activation and mitochondrial function in the hippocampus were determined. It was found that depression-like behavior induced by LPS was prevented by NaHS pretreatment. LPS caused NF-κB and NLRP3 inflammasome activation in the hippocampus as evidenced by increased phosphorylated-p65 levels and increased NLRP3, ASC, caspase-1, and mature IL-1ß levels in the hippocampus, which were also blocked by NaHS. LPS increased GSDMD-N levels and TUNEL-positive cells in the hippocampus, which was prevented by NaHS. Abnormal mitochondrial morphology in the hippocampus was found in LPS-treated mice. Mitochondrial membrane potential and ATP production were reduced, and ROS production was increased in the hippocampus of LPS-treated mice. NaHS pretreatment improved impaired mitochondrial morphology and increased membrane potential and ATP production and reduced ROS production in the hippocampus of LPS-treated mice. Our data indicate that H2S prevents LPS-induced depression-like behaviors by inhibiting NLRP3 inflammasome activation and pyroptosis and improving mitochondrial function in the hippocampus.
RESUMO
Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs.
Assuntos
Doença de Huntington , Doenças Musculares , Doenças Neuromusculares , Adulto , Humanos , Lactente , Músculo Esquelético/patologia , Doenças Musculares/patologia , Doença de Huntington/patologia , Atrofia Muscular/patologiaRESUMO
Rheumatoid nodules (RNs) are the most common extra-articular manifestation of rheumatoid arthritis and are also seen in patients with other autoimmune and inflammatory diseases. The development of RNs includes histopathological stages of acute unspecified inflammation, granulomatous inflammation with no or minimal necrosis, necrobiotic granulomas typically with central fibrinoid necrosis surrounded by palisading epithelioid macrophages and other cells, and likely an advanced stage of "ghost" lesions containing cystic or calcifying/calcified areas. In this article, we review RN pathogenesis, histopathological features in different stages, diagnostically related clinical manifestations, as well as diagnosis and differential diagnosis of RNs with an in-depth discussion about challenges in distinguishing RNs from their mimics. While the pathogenesis of RN formation remains elusive, it is hypothesized that some RNs with dystrophic calcification may be in transition and may be in coexistence or collision with another lesion in patients with RA or other soft tissue diseases and comorbidities. The diagnosis of typical or mature RNs in usual locations can be readily made by clinical findings often with classic RN histopathology, but in many cases, particularly with atypical or immature RNs and/or unusual locations, the clinical and histopathological diagnosis can be challenging requiring extensive examination of the lesional tissue with histological and immunohistochemical markers to identify unusual RNs in the clinical context or other lesions that may be coexisting with classic RNs. Proper diagnosis of RNs is critical for appropriate treatment of patients with RA or other autoimmune and inflammatory diseases.
Assuntos
Artrite Reumatoide , Nódulo Reumatoide , Humanos , Nódulo Reumatoide/diagnóstico , Nódulo Reumatoide/patologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/complicações , Comorbidade , Necrose/complicações , Inflamação/complicaçõesRESUMO
Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem syndrome caused by mutations in the neurofibromin 1 (NF1) gene that encodes for the protein neurofibromin acting as a tumour suppressor. Neurofibromin functions primarily as a GTPase-activating protein for the Ras family of oncogenes, which activates many signalling pathways for cell proliferation and differentiation; without neurofibromin, Ras is constitutively activated, thereby turning on many downstream signalling pathways related to oncogenesis. Patients with NF1 have a well known predisposition for certain types of malignancies including malignant peripheral nerve sheath tumours, gliomas, and breast cancers, as well as a potential association of NF1 with lymphoproliferative disorders such as lymphomas. In this article, we review the pathophysiology and tumourigenesis of NF1, previously reported cases of cutaneous lymphomas in NF1 patients along with our case demonstration of a NF1-associated scalp B-cell lymphoma, and NF1-associated extra cutaneous lymphomas. The diagnosis of lymphomas particularly cutaneous lymphomas may be difficult in NF1 patients as they often have skin lesions and/or cutaneous/subcutaneous nodules or tumours like neurofibromas, which raises the possibility of underdiagnosed cutaneous lymphomas in NF1 patients. We also comprehensively discuss the association between NF1 and lymphomas. In summary, most studies support a potential association between NF1 and lymphomas. Further investigation is needed to clarify the association between NF1 and lymphomas in order to bring clinical awareness of possibly underdiagnosed NF1-associated lymphomas and individualised management of NF1 patients to practice.
Assuntos
Linfoma , Neurofibromatose 1 , Neoplasias Cutâneas , Humanos , Neurofibromatose 1/complicações , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Mutação , Transdução de Sinais/genética , Neoplasias Cutâneas/complicaçõesRESUMO
Objective: Adrenocortical responsiveness is critical for maintaining glucocorticoids production and homeostasis during stress. We sought to investigate adrenocortical responsiveness during hypoxia in mice and the mechanisms responsible for the regulation of adrenal responsiveness.Methods: (1) Adult male WT mice were randomly divided into four groups: normoxia, hypoxia (24h), hypoxia (72h), hypoxia (72h) + GYY4137(hydrogen sulfide (H2S) donor, 133mmol/kg/day); (2) WT mice were randomly divided into four groups: sham, adrenalectomy (ADX), sham+hypoxia, ADX+hypoxia; (3) Cse-/- mice were randomly divided into two groups: Cse-/-, Cse-/- +GYY4137.Results: The circulatory level of corticosteroid induced by ACTH stimulation was significantly reduced in the mice with hypoxia compared with control mice. The mortality rate induced by lipopolysaccharide (LPS) increased during hypoxia. Cystathionine-γ-lyase (CSE) expression was significantly reduced in adrenal glands during hypoxia. GYY4137 treatment significantly increased adrenal responsiveness and attenuated NLRP3 inflammasome activation in mice treated by hypoxia and Cse-/- mice. Furthermore, The sulfhydrated level of PSMA7 in adrenal gland was decreased in the mice with hypoxia and Cse-/- mice. PSMA7 was S-sulfhydrated at cysteine 70. Blockage of S-sulfhydration of PSMA7 increased NLRP3 expression in adrenocortical cells.Conclusion: Reduced H2S production mediated hypo-adrenocortical responsiveness and NLRP3 inflammasome activation via PAMA7 S-sulfhydration during hypoxia.
Assuntos
Insuficiência Adrenal , Sulfeto de Hidrogênio , Masculino , Camundongos , Animais , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Sulfetos/farmacologia , HipóxiaRESUMO
BACKGROUND: Intracranial rhabdomyosarcomas represent a rare condition, posing a diagnostic challenge to physicians. Brain intraparenchymal rhabdomyosarcomas are exceptionally rare with poorly understood pathogenesis. METHODS: Here we report the first adult case of intraparenchymal rhabdomyosarcoma (RMS) with brainstem and cranial nerve involvement. We conducted a literature search using Embase, MEDLINE, and PubMed for published cases of patients with rhabdomyosarcoma of the brain. The keywords used were 'rhabdomyosarcoma' combined with 'intraparenchymal', 'parenchymal', 'cerebral' or 'brain' for title/abstract. Included cases were adult patients (>18 years of age). RESULTS: A 59-year-old man presents with multiple cranial nerve palsies. MRI revealed a solitary pontine lesion that was not responsive to steroids. No systemic lesions were identified with an extensive imaging workup. A wide range of serum and cerebrospinal fluid tests were non-diagnostic during a ten-month workup until, ultimately, the patient died as a result of aspiration pneumonia. At autopsy, pathological examination on whole-brain autopsy revealed RMS, centred in the left side of pons with extension to the left side of the midbrain and the right side of pons with multiple cranial nerve involvement. There are only 20 adult cases of primary intraparenchymal RMS reported in the literature. Our present case is the first reported adult RMS in this location, with novel molecular information, providing some insight into the pathogenesis of this rare diagnosis. CONCLUSIONS: Intraparenchymal rhabdomyosarcoma without evidence of systemic primary disease is extremely rare, resulting in delayed diagnosis in some cases, particularly those not amenable to biopsy. The diagnostic challenge posed by this complementary case highlights the importance of maintaining a differential of neoplasm in the face of non-diagnostic investigations to the contrary.
RESUMO
The problem of enhancing the robust performance of nonlinear fault estimation (FE) is addressed by proposing a novel real-time gain-scheduling mechanism for discrete-time Takagi-Sugeno fuzzy systems. The real-time status of the operating point for the considered nonlinear plant is characterized by using these available normalized fuzzy weighting functions at both the current and the past instants of time. To achieve this, the developed fuzzy real-time gain-scheduling mechanism produces different switching modes by introducing key tunable parameters. Thus, a pair of exclusive FE gain matrices is designed for each switching mode on the strength of time-varying balanced matrices developed in this study, respectively. Since the implementation of more FE gain matrices can be scheduled according to the real-time status of the operating point at each sampling instant, the robust performance of nonlinear FE will be enhanced over the previous methods to a great extent. Finally, considerable numerical comparisons are implemented in order to illustrate that the proposed method is much superior to those existing ones reported in the literature.
RESUMO
Calcifying pseudoneoplasm of the neuraxis (CAPNON) is thought to be a rare tumefactive lesion with unknown pathogenesis. Its prevalence is questionable with few previously reported cases of incidental CAPNON, and likely underdiagnosis. We report a unique case of incidental multifocal CAPNON. A 64-year-old female was admitted with loss of consciousness due to a ruptured right middle cerebral artery aneurysm with subarachnoid and intraventricular hemorrhage. She has a craniotomy and clipping. At time of operation, numerous small dural-based nodules were found, and one was excised for biopsy and was diagnosed as CAPNON. Retrospective review of her CT images identified nodules that were all ipsilateral to the ruptured aneurysm. A literature review revealed that incidental and/or multifocal CAPNONs are rare but likely underreported. Our case suggests a reactive process in the pathogenesis of CAPNON.