RESUMO
We report a patient from Panama who had lobomycosis caused by Paracoccidioides (Lacazia) loboi. We used combined clinical-epidemiologic and phylogenetic data, including a new gene sequence dataset on this fungus in Panama, for analysis. Findings contribute useful insights to limited knowledge of this fungal infection in the Mesoamerican Biologic Corridor.
Assuntos
Lacazia , Lobomicose , Paracoccidioides , Humanos , Lobomicose/diagnóstico , Lobomicose/microbiologia , Paracoccidioides/genética , Filogenia , Panamá/epidemiologiaRESUMO
In 2022, a global outbreak of mpox (formerly known as monkeypox) was reported outside of areas considered endemic for the disease, predominantly in persons identifying as men who have sex with men, gay, or bisexual. To date, 3 cases of mpox in solid organ transplant recipients have been published; however, no instances of secondary transmission among solid organ transplant recipients have been reported. Here, we report a case of a 53-year-old male kidney transplant recipient who contracted mpox while caring for a household contact with the disease. The patient's clinical and laboratory findings during his rapidly fatal course, autopsy findings, and genomics analysis are presented, emphasizing the need for expanded pre-exposure prophylaxis efforts in patient populations without the risk factors prioritized by public health authorities for vaccination.
Assuntos
Transplante de Rim , Mpox , Minorias Sexuais e de Gênero , Masculino , Humanos , Pessoa de Meia-Idade , Homossexualidade Masculina , Transplante de Rim/efeitos adversos , Surtos de DoençasRESUMO
Monkeypox (MPOX) is a zoonotic disease that affects humans and other primates, resulting in a smallpox-like illness. It is caused by monkeypox virus (MPXV), which belongs to the Poxviridae family. Clinically manifested by a range of cutaneous and systemic findings, as well as variable disease severity phenotypes based on the genetic makeup of the virus, the cutaneous niche and respiratory mucosa are the epicenters of MPXV pathogenicity. Herein, we describe the ultrastructural features of MPXV infection in both human cultured cells and cutaneous clinical specimens collected during the 2022-2023 MPOX outbreak in New York City that were revealed through electron microscopy. We observed typical enveloped virions with brick-shaped morphologies that contained surface protrusions, consistent with the classic ultrastructural features of MPXV. In addition, we describe morpho-functional evidence that point to roles of distinct cellular organelles in viral assembly during clinical MPXV infection. Interestingly, in skin lesions, we found abundant melanosomes near viral assembly sites, particularly in the vicinity of mature virions, which provides further insight into virus-host interactions at the subcellular level that contribute to MPXV pathogenesis. These findings not only highlight the importance of electron microscopic studies for further investigation of this emerging pathogen but also in characterizing MPXV pathogenesis during human infection.
Assuntos
Mpox , Dermatopatias , Animais , Humanos , Monkeypox virus/genética , Virulência , Primatas , GenômicaRESUMO
Monkeypox virus (MPXV) is a zoonotic orthopoxvirus within the Poxviridae family. MPXV is endemic to Central and West Africa. However, the world is currently witnessing an international outbreak with no clear epidemiological links to travel or animal exposure and with ever-increasing numbers of reported cases worldwide. Here, we evaluated and validated a new, sensitive, and specific real-time PCR-assay for MPXV diagnosis in humans and compare the performance of this novel assay against a Food & Drug Administration-cleared pan-Orthopox RT-PCR assay. We determined specificity, sensitivity, and analytic performance of the PKamp™ Monkeypox Virus RT-PCR assay targeting the viral F3L-gene. In addition, we further evaluated MPXV-PCR-positive specimens by viral culture, electron microscopy, and viral inactivation assays. The limit of detection was established at 7.2 genome copies/reaction, and MPXV was successfully identified in 20 clinical specimens with 100% correlation against the reference method with 100% sensitivity and specificity. Our results demonstrated the validity of this rapid, robust, and reliable RT-PCR assay for specific and accurate diagnosis of MPXV infection in human specimens collected both as dry swabs and in viral transport media. This assay has been approved by NYS Department of Health for clinical use.
Assuntos
Monkeypox virus , Mpox , Animais , Humanos , Monkeypox virus/genética , Mpox/epidemiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Técnicas de Amplificação de Ácido Nucleico/métodos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND & AIMS: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. METHODS: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. RESULTS: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. CONCLUSIONS: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
Assuntos
COVID-19/virologia , Gastroenteropatias/virologia , Imunidade nas Mucosas , Mucosa Intestinal/virologia , SARS-CoV-2/patogenicidade , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/mortalidade , Estudos de Casos e Controles , Células Cultivadas , Citocinas/sangue , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/imunologia , Gastroenteropatias/mortalidade , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/sangue , Mucosa Intestinal/imunologia , Itália , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Prognóstico , Medição de Risco , Fatores de Risco , SARS-CoV-2/imunologia , Carga ViralRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome COVID-19 are causing overwhelming morbidity and mortality around the globe and disproportionately affected New York City between March and May 2020. Here, we report on the first 100 COVID-19-positive autopsies performed at the Mount Sinai Hospital in New York City. Autopsies revealed large pulmonary emboli in six cases. Diffuse alveolar damage was present in over 90% of cases. We also report microthrombi in multiple organ systems including the brain, as well as hemophagocytosis. We additionally provide electron microscopic evidence of the presence of the virus in our samples. Laboratory results of our COVID-19 cohort disclose elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8, and TNFα. Our autopsy series of COVID-19-positive patients reveals that this disease, often conceptualized as a primarily respiratory viral illness, has widespread effects in the body including hypercoagulability, a hyperinflammatory state, and endothelial dysfunction. Targeting of these multisystemic pathways could lead to new treatment avenues as well as combination therapies against SARS-CoV-2 infection.
Assuntos
COVID-19/fisiopatologia , Pulmão/fisiopatologia , Embolia Pulmonar/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Coagulação Sanguínea , COVID-19/sangue , COVID-19/patologia , COVID-19/virologia , Causas de Morte , Citocinas/sangue , Feminino , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/sangue , Pulmão/patologia , Pulmão/virologia , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Embolia Pulmonar/sangue , Embolia Pulmonar/patologia , Embolia Pulmonar/virologia , SARS-CoV-2/patogenicidadeRESUMO
Neurologic sequelae can be devastating complications of respiratory viral infections. We report the presence of virus in neural and capillary endothelial cells in frontal lobe tissue obtained at postmortem examination from a patient infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Our observations of virus in neural tissue, in conjunction with clinical correlates of worsening neurologic symptoms, pave the way to a closer understanding of the pathogenic mechanisms underlying central nervous system involvement by SARS-CoV-2.
Assuntos
Ageusia/diagnóstico , Ataxia/diagnóstico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Transtornos do Olfato/diagnóstico , Pneumonia Viral/diagnóstico , Convulsões/diagnóstico , Idoso , Ageusia/complicações , Ageusia/fisiopatologia , Ageusia/virologia , Ataxia/complicações , Ataxia/fisiopatologia , Ataxia/virologia , Betacoronavirus/genética , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Células Endoteliais/patologia , Células Endoteliais/virologia , Evolução Fatal , Lobo Frontal/irrigação sanguínea , Lobo Frontal/patologia , Lobo Frontal/virologia , Hospitalização , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Pulmão/virologia , Masculino , Neurônios/patologia , Neurônios/virologia , Transtornos do Olfato/complicações , Transtornos do Olfato/fisiopatologia , Transtornos do Olfato/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Convulsões/complicações , Convulsões/fisiopatologia , Convulsões/virologiaRESUMO
Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision, and limited therapeutic options. Optic gliomas contain various amounts of myxoid matrix, which can represent most of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. We reviewed histological features and clinical imaging properties, analyzed vasculature by immunohistochemistry and electron microscopy, and performed liquid chromatography-mass spectrometry on optic gliomas, which varied in the amount of myxoid matrix. We found that although subtypes of optic gliomas are indistinguishable on imaging, the microvascular network of pilomyxoid astrocytoma, a subtype of optic glioma with abundant myxoid matrix, is characterized by the presence of endothelium-free channels in the myxoid matrix. These tumors show normal perfusion by clinical imaging and lack histological evidence of hemorrhage organization or thrombosis. The myxoid matrix is composed predominantly of the proteoglycan versican and its linking protein, a vertebrate hyaluronan and proteoglycan link protein 1. We propose that pediatric optic gliomas can maintain blood supply without endothelial cells by using invertebrate-like channels, which we termed primitive myxoid vascularization. Enzymatic targeting of the proteoglycan versican/hyaluronan and proteoglycan link protein 1 rich myxoid matrix, which is in direct contact with circulating blood, can provide novel therapeutic avenues for optic gliomas of childhood.
Assuntos
Vasos Sanguíneos/patologia , Células Endoteliais/patologia , Neovascularização Patológica/patologia , Glioma do Nervo Óptico/patologia , Endotélio/patologia , Humanos , Glioma do Nervo Óptico/irrigação sanguínea , Estudos RetrospectivosRESUMO
We report a case of combined squamomelanocytic tumor of the skin. Clinically, the lesion was felt to be a squamous cell carcinoma. Histologically, it was characterized by large epithelioid cells admixed with basaloid cells with central squamous differentiation. Immunohistochemical staining showed both cell populations to be reactive with Melan A, BEREP4, and Pan Keratins. Ultrastructural studies revealed simultaneous features of squamous differentiation (dense cytoplasmic tonofilaments with well-developed desmosomes) and melanocytic differentiation (mature/pigmented melanosomes) in the same cell population. This is the second reported case in the English literature with documented biphenotypic or divergent differentiation at the ultrastructural level. The behavior of squamomelanocytic tumor is uncertain given the rarity of reported cases.
Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Complexas Mistas/patologia , Neoplasias Cutâneas/patologia , Idoso , Biomarcadores Tumorais/análise , Humanos , Imuno-Histoquímica , Masculino , Melanoma/patologiaRESUMO
A 48 year-old African American woman presented to her physician complaining of a rapidly evolving epigastric and right upper quadrant abdominal pain. A PET-CT of the abdomen and pelvis demonstrated hypermetabolic, polypoid masses within the gallbladder and several tumors in the left lobe of the liver for which she underwent diagnostic laparoscopy. The gallbladder revealed a 3.5 × 3.3 × 2.4 tan-brown exophytic mass located at the fundus and growing into the lumen with multiple contiguous papillary projections arising from the mucosal surface. A concurrent large cell neuroendocrine carcinoma and papillary adenocarcinoma of the gallbladder was revealed histologically. There was shared reactivity to antibodies directed against the distinct antigens for each morphological component with transitional tumor cells (of both histological components) located at the areas where the two tumor types merged, revealing common immunoreactivity for carcinoembryonic antigen, cancer antigen 19-9, keratin 19, c-kit (cluster of differentiation protein 117 (CD117)) and epithelial cell adhesion molecule. Ultrastructurally, individual cells were demonstrated to have overlapping features of neuroendocrine and glandular differentiation. The aforementioned histological, ultrastructural and immunohistochemical profile is strongly suggestive of a biphenotypic stem/progenitor cell tumor of the gallbladder.
Assuntos
Adenocarcinoma Papilar/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Células-Tronco Neoplásicas/patologia , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/secundário , Biomarcadores Tumorais/metabolismo , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/secundário , Colecistectomia , Grânulos Citoplasmáticos/ultraestrutura , Feminino , Vesícula Biliar/patologia , Vesícula Biliar/cirurgia , Neoplasias da Vesícula Biliar/metabolismo , Hepatectomia , Humanos , Neoplasias Hepáticas/secundário , Microscopia Eletrônica de Transmissão , Microvilosidades/ultraestrutura , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/secundário , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/ultraestrutura , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND & AIMS: Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients. METHODS: The current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy. RESULTS: The liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury. CONCLUSIONS: On the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.
Assuntos
COVID-19/virologia , Hepatite/virologia , Fígado/patologia , Fígado/virologia , SARS-CoV-2/patogenicidade , Adulto , Apoptose/fisiologia , Biópsia , Feminino , Hepatite/patologia , Humanos , Hepatopatias/virologia , Masculino , Pessoa de Meia-IdadeRESUMO
Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome-associated Coronavirus 2 (SARS-CoV-2), has become a global threat to public health. COVID-19 is more pathogenic and infectious than the prior 2002 pandemic caused by SARS-CoV-1. The pathogenesis of certain disease manifestations in COVID-19 such as diffuse alveolar damage (DAD) are thought to be similar to SARS-CoV-1. However, the exact pathogenesis of COVID-19 related deaths remains poorly understood. The aim of this article was to systematically summarize the rapidly emerging literature regarding COVID-19 autopsies. A meta-analysis was also conducted based on data accrued from preprint and published articles on COVID-19 (n=241 patients) and the results compared with postmortem findings associated with SARS-CoV-1 deaths (n=91 patients). Both autopsy groups included mostly adults of median age 70 years with COVID-19 and 50 years with SARS-CoV-1. Overall, prevalence of DAD was more common in SARS-CoV-1 (100.0%) than COVID-19 (80.9%) autopsies (P=0.001). Extrapulmonary findings among both groups were not statistically significant except for hepatic necrosis (P <0.001), splenic necrosis (P<0.006) and white pulp depletion (P <0.001) that were more common with SARS-CoV-1. Remarkable postmortem findings in association with COVID-19 apart from DAD include pulmonary hemorrhage, viral cytopathic effect within pneumocytes, thromboembolism, brain infarction, endotheliitis, acute renal tubular damage, white pulp depletion of the spleen, cardiac myocyte necrosis, megakaryocyte recruitment, and hemophagocytosis.
Assuntos
COVID-19/patologia , Pulmão/patologia , Síndrome Respiratória Aguda Grave/patologia , Autopsia , Encéfalo/patologia , COVID-19/mortalidade , Estudos de Casos e Controles , Saúde Global , Humanos , Rim/patologia , Miocárdio/patologia , Síndrome Respiratória Aguda Grave/mortalidade , Baço/patologiaRESUMO
The autonomic nervous system plays a role in a variety of liver regenerative and metabolic functions, including modulating bile secretion and cholangiocyte and hepatobiliary progenitors of the canals of Hering. However, the nature and location of nerves which link to the proximal biliary tree have remained uncertain. We investigate the anatomic relationship of nerves to the proximal biliary tree including the putative stem/progenitor cell niche of the canal of Hering. Using double immunostaining (fluorescence, histochemistry) to highlight markers of cholangiocytes (biliary-type keratins), nerves (S100, neurofilament protein, PGP9.5, tyrosine hydroxylase), and stellate cells (CRBP-1), we examined sections from normal adult livers from autopsy or surgical resections. There is extensive contact between nerves and interlobular bile ducts, bile ductules, and canals of Hering (CoH). In multiple serial sections from 4 normal livers, biliary-nerve contacts were seen in all of these structures and were more common in the interlobular bile ducts (78/137; 57%) than in the ductules and CoH (95/294; 33%) (p < 0.001). Contacts appear to consist of nerves in juxtaposition to the biliary basement membrane, though crossing through basement membrane to interface directly with cholangiocytes is also present. These nerves are positive for tyrosine hydroxylase and are, thus, predominately adrenergic. Electron microscopy confirms nerves closely approximating ductules. Nerve fiber-hepatic stellate cell juxtaposition is observed but without stellate cell approximation to cholangiocytes. We present novel findings of biliary innervation, perhaps mediated in part, by direct cholangiocyte-nerve interactions. The implications of these findings are protean for studies of neuromodulation of biliary physiology and hepatic stem/progenitor cells.
Assuntos
Sistema Biliar/inervação , Sistema Biliar/fisiologia , Adulto , Ductos Biliares/inervação , Ductos Biliares/fisiologia , Sistema Biliar/metabolismo , Vesícula Biliar/inervação , Vesícula Biliar/fisiologia , Humanos , Imuno-Histoquímica/métodos , Fígado/inervação , Fígado/fisiologia , Células-Tronco/metabolismo , Células-Tronco/fisiologiaRESUMO
Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated intestinal infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its effect on disease pathogenesis. SARS-CoV-2 was detected in small intestinal enterocytes by immunofluorescence staining or electron microscopy, in 13 of 15 patients studied. High dimensional analyses of GI tissues revealed low levels of inflammation in general, including active downregulation of key inflammatory genes such as IFNG, CXCL8, CXCL2 and IL1B and reduced frequencies of proinflammatory dendritic cell subsets. To evaluate the clinical significance of these findings, examination of two large, independent cohorts of hospitalized patients in the United States and Europe revealed a significant reduction in disease severity and mortality that was independent of gender, age, and examined co-morbid illnesses. The observed mortality reduction in COVID-19 patients with GI symptoms was associated with reduced levels of key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation but was not associated with significant differences in nasopharyngeal viral loads. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit. ONE SENTENCE SUMMARY: Intestinal infection with SARS-CoV-2 is associated with a mild inflammatory response and improved clinical outcomes.
RESUMO
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
RESUMO
Confocal laser endomicroscopy (pCLE) provides real-time histologic imaging of human tissues at a depth of 60-70 µm during endoscopy. pCLE of the extrahepatic bile duct after fluorescein injection demonstrated a reticular pattern within fluorescein-filled sinuses that had no known anatomical correlate. Freezing biopsy tissue before fixation preserved the anatomy of this structure, demonstrating that it is part of the submucosa and a previously unappreciated fluid-filled interstitial space, draining to lymph nodes and supported by a complex network of thick collagen bundles. These bundles are intermittently lined on one side by fibroblast-like cells that stain with endothelial markers and vimentin, although there is a highly unusual and extensive unlined interface between the matrix proteins of the bundles and the surrounding fluid. We observed similar structures in numerous tissues that are subject to intermittent or rhythmic compression, including the submucosae of the entire gastrointestinal tract and urinary bladder, the dermis, the peri-bronchial and peri-arterial soft tissues, and fascia. These anatomic structures may be important in cancer metastasis, edema, fibrosis, and mechanical functioning of many or all tissues and organs. In sum, we describe the anatomy and histology of a previously unrecognized, though widespread, macroscopic, fluid-filled space within and between tissues, a novel expansion and specification of the concept of the human interstitium.
Assuntos
Fáscia/ultraestrutura , Sistema Linfático/ultraestrutura , Mucosa/ultraestrutura , Ductos Biliares/ultraestrutura , Colágeno/análise , Endoscopia , Fluoresceína/análise , Humanos , Linfa/química , Microscopia Confocal , Pele/ultraestrutura , Bexiga Urinária/ultraestruturaAssuntos
Adenocarcinoma/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Glândulas Sudoríparas/patologia , Neoplasias Vulvares/patologia , Adenocarcinoma/química , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Glândulas Mamárias Humanas/patologia , Microscopia Eletrônica , Valor Preditivo dos Testes , Neoplasias das Glândulas Sudoríparas/química , Glândulas Sudoríparas/química , Neoplasias Vulvares/químicaAssuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/etiologia , Células Epiteliais Alveolares/ultraestrutura , Células Epiteliais Alveolares/virologia , Autopsia , COVID-19 , Infecções por Coronavirus/epidemiologia , Evolução Fatal , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Artéria Pulmonar/patologia , Embolia Pulmonar/patologia , SARS-CoV-2RESUMO
PURPOSE: The aim of this study was to describe clinical, imaging, molecular genetic, histopathologic, immunohistochemical, and ultrastructural characteristics of coexistent amyloid and spheroidal degeneration-type deposits in a family with histidine-626-arginine transforming growth factor beta-induced (H626R TGFBI) variant lattice dystrophy. METHODS: This is a retrospective clinical-pathological and genetic analysis of one family with H626R variant lattice dystrophy. RESULTS: Pedigree analysis showed an autosomal dominant inheritance pattern of the disease. Examination of 3 affected family members revealed asymmetric, thick, branching lattice-like deposits associated with corneal haze. Sequencing of the TGFBI gene revealed a high-penetrance disease-causing sequence variation (H626R CAT>CGT heterozygous). Optical coherence tomography demonstrated fusiform, poorly demarcated hyperechoic stromal deposits with focal hypoechoic central regions. Histology of the corneal discs from 2 affected family members showed stromal deposits consistent with TGFBI amyloid. Some amyloid deposits contained a central nidus of spheroidal degeneration-type material that demonstrated autofluorescence, stained with elastic and Masson trichrome stains, did not stain with periodic acid-Schiff or Congo red stains, was nonbirefringent, and did not immunoreact with keratoepithelin antibodies. Transmission electron microscopy confirmed the presence of amyloid fibrils with central, electrodense, homogeneous, discrete, spheroidal degeneration-type deposits. CONCLUSIONS: The presence of spheroidal deposits in a subset of affected patients, variability in presentation within an individual and between family members, predominant anterior corneal stromal location and nonimmunoreactivity of deposits for keratoepithelin suggest that these deposits are degenerative in nature. The deposits may arise from ultraviolet light-altered proteins diffused from the limbus, which form a nidus for keratoepithelin deposition.
Assuntos
Amiloidose Familiar/genética , Distrofias Hereditárias da Córnea/genética , Proteínas da Matriz Extracelular/genética , Imagem Multimodal , Polimorfismo de Nucleotídeo Único , Tomografia de Coerência Óptica , Fator de Crescimento Transformador beta/genética , Adolescente , Adulto , Idoso , Amiloide/ultraestrutura , Amiloidose Familiar/patologia , Amiloidose Familiar/cirurgia , Criança , Pré-Escolar , Distrofias Hereditárias da Córnea/patologia , Distrofias Hereditárias da Córnea/cirurgia , Substância Própria/ultraestrutura , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Ceratoplastia Penetrante , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
Primary cutaneous carcinosarcoma is a rare biphenotypic neoplasm exhibiting both epithelial and sarcomatous elements. Even though its origin and biological aspects remain poorly understood, it has been postulated that this tumor may arise from progenitor cells, which subsequently differentiate into distinct tumor components. We have investigated the histological and immunohistochemical staining patterns of a cutaneous carcinosarcoma case, as well as its ultrastructural aspects. In addition, sarcomatous and epithelial tumor components were separated by laser capture microdissection and subjected to targeted, high-depth, next-generation sequencing of a 46-cancer gene panel to asses the gene mutational pattern amongst both components. There were transitional cells at the epithelial/mesenchymal transition that labeled with putative progenitor cell markers (K19, c-kit, CD34 and Bcl-2). There was shared reactivity to antibodies directed against the progenitor cell marker EpCAM (epithelial cell adhesion molecule) in both components. Ultrastructurally, individual cells were demonstrated to have overlapping features of epithelial and mesenchymal differentiation. The mutational analysis revealed point mutations in exon 5 of TP53, which were identical in both the epithelial and sarcomatous components, and which were concordant with p53 expression at a tissue level. The aforementioned histological, ultrastructural, immunohistochemical and mutational pattern is strongly suggestive of a common clonal origin to the distinct elements of this tumor.