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1.
Int J Mol Sci ; 24(19)2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37834023

RESUMO

The ACTN2 gene encodes α-actinin 2, located in the Z-disc of the sarcomeres in striated muscle. In this study, we sought to investigate the effects of an ACTN2 missense variant of unknown significance (p.A868T) on cardiac muscle structure and function. Left ventricular free wall samples were obtained at the time of cardiac transplantation from a heart failure patient with the ACTN2 A868T heterozygous variant. This variant is in the EF 3-4 domain known to interact with titin and α-actinin. At the ultrastructural level, ACTN2 A868T cardiac samples presented small structural changes in cardiomyocytes when compared to healthy donor samples. However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac tissue displayed higher myofilament Ca2+ sensitivity of isometric force, reduced sinusoidal stiffness, and faster rates of tension redevelopment at all Ca2+ levels. Small-angle X-ray diffraction indicated increased separation between thick and thin filaments, possibly contributing to changes in muscle kinetics. Molecular dynamics simulations indicated that while the mutation does not significantly impact the structure of α-actinin on its own, it likely alters the conformation associated with titin binding. Our results can be explained by two Z-disc mediated communication pathways: one pathway that involves α-actinin's interaction with actin, affecting thin filament regulation, and the other pathway that involves α-actinin's interaction with titin, affecting thick filament activation. This work establishes the role of α-actinin 2 in modulating cross-bridge kinetics and force development in the human myocardium as well as how it can be involved in the development of cardiac disease.


Assuntos
Actinina , Miofibrilas , Humanos , Actinina/genética , Actinina/metabolismo , Conectina/genética , Conectina/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Sarcômeros/metabolismo
2.
PLoS Pathog ; 11(3): e1004693, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25738608

RESUMO

Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral σ3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing σ3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, σ3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing σ3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with σ3-Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses.


Assuntos
Proteínas do Capsídeo/metabolismo , Capsídeo/metabolismo , Orthoreovirus de Mamíferos/genética , Orthoreovirus de Mamíferos/metabolismo , Animais , Camundongos , Mutação/genética , Vírion/metabolismo , Montagem de Vírus/genética
3.
Am J Respir Cell Mol Biol ; 55(1): 128-34, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26807608

RESUMO

Sarcoidosis is a granulomatous disease of unknown cause. Prior molecular and immunologic studies have confirmed the presence of mycobacterial virulence factors, such as catalase peroxidase and superoxide dismutase A, within sarcoidosis granulomas. Molecular analysis of granulomas can identify targets of known antibiotics classes. Currently, major antibiotics are directed against DNA synthesis, protein synthesis, and cell wall formation. We conducted molecular analysis of 40 sarcoidosis diagnostic specimens and compared them with 33 disease control specimens for the presence of mycobacterial genes that encode antibiotic targets. We assessed for genes involved in DNA synthesis (DNA gyrase A [gyrA] and DNA gyrase B), protein synthesis (RNA polymerase subunit ß), cell wall synthesis (embCAB operon and enoyl reductase), and catalase peroxidase. Immunohistochemical analysis was conducted to investigate the locale of mycobacterial genes such as gyrA within 12 sarcoidosis specimens and 12 disease controls. Mycobacterial DNA was detected in 33 of 39 sarcoidosis specimens by quantitative real-time polymerase chain reaction compared with 2 of 30 disease control specimens (P < 0.001, two-tailed Fisher's test). Twenty of 39 were positive for three or more mycobacterial genes, compared with 1 of 30 control specimens (P < 0.001, two-tailed Fisher's test). Immunohistochemistry analysis localized mycobacterial gyrA nucleic acids to sites of granuloma formation in 9 of 12 sarcoidosis specimens compared with 1 of 12 disease controls (P < 0.01). Microbial genes encoding enzymes that can be targeted by currently available antimycobacterial antibiotics are present in sarcoidosis specimens and localize to sites of granulomatous inflammation. Use of antimicrobials directed against target enzymes may be an innovative treatment alternative.


Assuntos
Anti-Infecciosos/uso terapêutico , Granuloma/tratamento farmacológico , Terapia de Alvo Molecular , Sarcoidose/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , DNA Bacteriano/análise , Demografia , Feminino , Granuloma/microbiologia , Granuloma/patologia , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Mycobacterium/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Sarcoidose/microbiologia , Sarcoidose/patologia , Adulto Jovem
4.
Arterioscler Thromb Vasc Biol ; 34(12): 2527-36, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25278290

RESUMO

OBJECTIVE: Atherosclerosis is the primary driver of cardiovascular disease, the leading cause of death worldwide. Identification of naturally occurring atheroprotective genes has become a major goal for the development of interventions that will limit atheroma progression and associated adverse events. To this end, we have identified small proline-rich repeat protein (SPRR3) as selectively upregulated in vascular smooth muscle cells (VSMCs) of atheroma-bearing arterial tissue versus healthy arterial tissue. In this study, we sought to determine the role of SPRR3 in atheroma pathophysiology. APPROACH AND RESULTS: We found that atheroprone apolipoprotein E-null mice lacking SPRR3 developed significantly greater atheroma burden. To determine the cellular driver(s) of this increase, we evaluated SPRR3-dependent changes in bone marrow-derived cells, endothelial cells, and VSMCs. Bone marrow transplant of SPRR3-expressing cells into SPRR3(-/-)apolipoprotein E-deficient recipients failed to rescue atheroma burden. Similarly, endothelial cells did not exhibit a response to SPRR3 loss. However, atheromas from SPRR3-deficient mice exhibited increased TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive VSMCs compared with control. Cell death in SPRR3-deficient VSMCs was significantly increased in vitro. Conversely, SPRR3-overexpressing VSMCs exhibited reduced apoptosis compared with control. We also observed a PI3K (phosphatidylinositol 3-kinase)/Akt-dependent positive association between SPRR3 expression and levels of active Akt in VSMCs. The survival advantage seen in SPRR3-overexpressing VSMCs was abrogated after the addition of a PI3K/Akt pathway inhibitor. CONCLUSIONS: These results indicate that SPRR3 protects the lesion from VSMC loss by promoting survival signaling in plaque VSMCs, thereby significantly decreasing atherosclerosis progression. As the first identified atheroma-specific VSMC prosurvival factor, SPRR3 represents a potential target for lesion-specific modulation of VSMC survival.


Assuntos
Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adaptação Fisiológica , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células , Sobrevivência Celular , Proteínas Ricas em Prolina do Estrato Córneo/deficiência , Proteínas Ricas em Prolina do Estrato Córneo/genética , Progressão da Doença , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos de Músculo Liso/patologia , Fosforilação , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Transdução de Sinais
5.
Cardiovasc Res ; 120(8): 899-913, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38377486

RESUMO

AIMS: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. METHODS AND RESULTS: Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1ß) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling and AF susceptibility, while IL-1ß inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. CONCLUSION: These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.


Assuntos
Potenciais de Ação , Proteínas Adaptadoras de Transdução de Sinal , Fibrilação Atrial , Modelos Animais de Doenças , Interleucina-1beta , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos , Animais , Feminino , Humanos , Masculino , Potenciais de Ação/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/genética , Benzilaminas/farmacologia , Predisposição Genética para Doença , Frequência Cardíaca/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fenótipo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética
6.
Res Sq ; 2023 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-37292825

RESUMO

Background: Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis. Result: By harnessing pathogenic mucosa from an international iSGS patient cohort and single-cell RNA sequencing, we unbiasedly characterize the cell subsets in the proximal airway scar and detail their molecular phenotypes. Results show that the airway epithelium in iSGS patients is depleted of basal progenitor cells, and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disrupted bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched iSGS patients and healthy controls. Clinical outcome data from iSGS patients suggests surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis. Conclusion: Our data support an iSGS disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. These results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases.

7.
Nat Med ; 11(4): 409-17, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15793582

RESUMO

Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling.


Assuntos
Proteínas Quinases Dependentes de Cálcio-Calmodulina/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Baixo Débito Cardíaco , Cardiomegalia , Camundongos , Camundongos Transgênicos , Contração Miocárdica , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Fosforilação , Remodelação Ventricular
8.
J Clin Rheumatol ; 18(7): 363-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23047537

RESUMO

Chloroquine and hydroxychloroquine are used to chronically treat certain rheumatologic diseases and are generally considered safe. We describe 2 patients with skeletal myopathy and fatal cardiomyopathy-uncommon and underrecognized adverse effects of these agents. Both patients developed arrhythmias and heart failure, and 1 patient had documented diaphragmatic involvement. Muscle specimens showed typical vacuolar myopathy (indicative of impaired autophagy) with myeloid bodies in both patients and curvilinear bodies in 1 patient. Antimalarial-induced cardiomyopathy should be considered in patients receiving these medications with otherwise unexplained muscle weakness or cardiac symptoms. Whether autophagy enhancers can be used to manage such myopathies merits investigation.


Assuntos
Antimaláricos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico , Adulto , Antimaláricos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Evolução Fatal , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pessoa de Meia-Idade
9.
JACC Basic Transl Sci ; 5(6): 602-615, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32613146

RESUMO

Oxidative damage is implicated in atrial fibrillation (AF), but antioxidants are ineffective therapeutically. The authors tested the hypothesis that highly reactive lipid dicarbonyl metabolites, or isolevuglandins (IsoLGs), are principal drivers of AF during hypertension. In a hypertensive murine model and stretched atriomyocytes, the dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) prevented IsoLG adducts and preamyloid oligomers (PAOs), and AF susceptibility, whereas the ineffective analog 4-hydroxybenzylamine (4-HOBA) had minimal effect. Natriuretic peptides generated cytotoxic oligomers, a process accelerated by IsoLGs, contributing to atrial PAO formation. These findings support the concept of pre-emptively scavenging reactive downstream oxidative stress mediators as a potential therapeutic approach to prevent AF.

10.
Am J Pathol ; 173(5): 1577-88, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18832573

RESUMO

Atherosclerotic plaques express high levels of small proline-rich repeat protein (SPRR3), a previously characterized component of the cornified cell envelope of stratified epithelia, where it is believed to play a role in cellular adaptation to biomechanical stress. We investigated the physiological signals and underlying mechanism(s) that regulate atheroma-enriched SPRR3 expression in vascular smooth muscle cells (VSMCs). We showed that SPRR3 is expressed by VSMCs in both human and mouse atheromas. In cultured arterial VSMCs, mechanical cyclic strain, but neither shear stress nor lipid loading induced SPRR3 expression. Furthermore, this upregulation of SPRR3 expression was dependent on VSMC adherence to type I collagen. To link the mechanoregulation of SPRR3 to specific collagen/integrin interactions, we used blocking antibodies against either integrin alpha1 or alpha2 subunits and VSMCs from mice that lack specific collagen receptors. Our results showed a dependence on the alpha1beta1 integrin for SPRR3 expression induced by cyclic strain. Furthermore, we showed that integrin alpha1 but not alpha2 subunits were expressed on VSMCs within mouse lesions but not in normal arteries. Therefore, we identified the enrichment of the mechanical strain-regulated protein SPRR3 in VSMCs of both human and mouse atherosclerotic lesions whose expression is dependent on the collagen-binding integrin alpha1beta1 on VSMCs. These data suggest that SPRR3 may play a role in VSMC adaptation to local biomechanical stress within the plaque microenvironment.


Assuntos
Aterosclerose/metabolismo , Colágeno/metabolismo , Integrina alfa1beta1/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Peptídeos/metabolismo , Animais , Aterosclerose/patologia , Humanos , Lipídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Peptídeos/genética , Domínios Proteicos Ricos em Prolina , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Estresse Mecânico , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
11.
J Am Heart Assoc ; 8(21): e011902, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31662020

RESUMO

Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Distrofia Muscular de Duchenne/complicações , Oxazóis/uso terapêutico , Antagonistas de Prostaglandina/uso terapêutico , Receptores de Tromboxanos/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Distribuição Aleatória
12.
Arch Pathol Lab Med ; 143(4): 513-517, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30500295

RESUMO

CONTEXT.­: Developing skills related to use of computer-based tools is critical for practicing genomic pathology. However, given the relative novelty of genomics education, residency programs may lack faculty members with adequate expertise and/or time to implement training. A virtual team-based learning (TBL) environment would make genomic pathology education available to more trainees. OBJECTIVE.­: To translate an extensively implemented in-person TBL genomic pathology workshop into a virtual environment and to evaluate both knowledge and skill acquisition. DESIGN.­: Using a novel interactive simulation approach, online modules were developed translating aspects of the TBL experience into the virtual environment with a goal of acquisition of necessary computer-related skills. The modules were evaluated at 10 postgraduate pathology training programs using a pre-post test design with participants deidentified. A postmodule anonymous survey obtained participant feedback on module quality and efficacy. RESULTS.­: There were 147 trainees who received an email request to voluntarily participate in the study. Of these, 43 trainees completed the pretest and 15 (35%) subsequently completed the posttest. Mean overall scores were 45% on the pretest compared with 70% on the posttest ( P < .001; effect size = 1.4). Posttest improvement of results was similar for questions testing acquisition of knowledge versus skills. Regarding the 19 participants who took the survey, 18 (95%) would recommend the modules to others and believed they met the stated objectives. CONCLUSIONS.­: A simulation-based approach allows motivated pathology trainees to acquire computer-related skills for practicing genomic pathology. Future work can explore efficacy in a nonvoluntary setting and adaptation to different specialties, learners, and computer tools.


Assuntos
Simulação por Computador , Educação de Pós-Graduação em Medicina/métodos , Genômica/educação , Patologia/educação , Humanos
13.
Ultrastruct Pathol ; 32(1): 25-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18300035

RESUMO

Sarcomas of the adult liver are unusual neoplasms, and can sometimes pose a difficult differential diagnosis. The authors report a myxoid spindle cell tumor arising in the liver of a 26-year-old woman. Histopathologic, immunohistochemical, and ultrastructural analysis demonstrated features of smooth muscle differentiation. Neoplastic nuclei were positive for estrogen receptor-beta and androgen receptor, but not estrogen receptor-alpha or progesterone receptor. Based on the large size of the tumor and the presence of conspicuous mitotic activity, the diagnosis of myxoid leiomyosarcoma was made. This case represents the third documented example of this tumor in the liver. The differential diagnosis in relation to this particular site of origin is discussed.


Assuntos
Leiomiossarcoma/ultraestrutura , Neoplasias Hepáticas/ultraestrutura , Actinas/análise , Adulto , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Feminino , Fibrossarcoma/diagnóstico , Hepatectomia , Humanos , Leiomiossarcoma/química , Leiomiossarcoma/cirurgia , Neoplasias Hepáticas/química , Neoplasias Hepáticas/cirurgia , Neoplasias Embrionárias de Células Germinativas/diagnóstico
14.
Per Med ; 15(3): 199-208, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29843583

RESUMO

Genomic medicine is transforming patient care. However, the speed of development has left a knowledge gap between discovery and effective implementation into clinical practice. Since 2010, the Training Residents in Genomics (TRIG) Working Group has found success in building a rigorous genomics curriculum with implementation tools aimed at pathology residents in postgraduate training years 1-4. Based on the TRIG model, the interprofessional Undergraduate Training in Genomics (UTRIG) Working Group was formed. Under the aegis of the Undergraduate Medical Educators Section of the Association of Pathology Chairs and representation from nine additional professional societies, UTRIG's collaborative goal is building medical student genomic literacy through development of a ready-to-use genomics curriculum. Key elements to the UTRIG curriculum are expert consensus-driven objectives, active learning methods, rigorous assessment and integration.


Assuntos
Educação de Graduação em Medicina/métodos , Genômica/educação , Currículo , Humanos , Modelos Educacionais , Médicos , Aprendizagem Baseada em Problemas , Estudantes de Medicina
15.
Circ Res ; 97(1): 62-9, 2005 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-15947250

RESUMO

Although atrial fibrillation is the most common serious cardiac arrhythmia, the fundamental molecular pathways remain undefined. Mutations in KCNQ1, one component of a sympathetically activated cardiac potassium channel complex, cause familial atrial fibrillation, although the mechanisms in vivo are unknown. We show here that mice with deletion of the KCNQ1 protein partner KCNE1 have spontaneous episodes of atrial fibrillation despite normal atrial size and structure. Isoproterenol abolishes these abnormalities, but vagomimetic interventions have no effect. Whereas loss of KCNE1 function prolongs ventricular action potentials in humans, KCNE1-/- mice displayed unexpectedly shortened atrial action potentials, and multiple potential mechanisms were identified: (1) K+ currents (total and those sensitive to the KCNQ1 blocker chromanol 293B) were significantly increased in atrial cells from KCNE1-/- mice compared with controls, and (2) when CHO cells expressing KCNQ1 and KCNE1 were pulsed very rapidly (at rates comparable to the normal mouse heart and to human atrial fibrillation), the sigmoidicity of IKs activation prevented current accumulation, whereas cells expressing KCNQ1 alone displayed marked current accumulation at these very rapid rates. Thus, KCNE1 deletion in mice unexpectedly leads to increased outward current in atrial myocytes, shortens atrial action potentials, and enhances susceptibility to atrial fibrillation.


Assuntos
Fibrilação Atrial/etiologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Potenciais de Ação , Animais , Fibrilação Atrial/fisiopatologia , Suscetibilidade a Doenças , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética
16.
J Heart Valve Dis ; 16(4): 410-6, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17702367

RESUMO

Cryopreserved aortic allograft tissue is used to correct aortic valve disease in adults and to reconstruct the right ventricular outflow tract in children with congenital heart disease. In adults, allograft durability is regarded as comparable to or better than that of manufactured bioprostheses, with failure usually due to slow fibrocalcific degeneration. Normally, allograft semilunar valves have excellent hemodynamics and low rates of infectious endocarditis and thromboembolism. The role of immune-mediated inflammation in post-implant allograft valve performance is slow in onset, and variable. Herein is presented the case of a male adult with rapid deterioration of the aortic valve homograft wall, without loss of the valve leaflets, resulting in severe aortic regurgitation. The pathological findings were consistent with classical marantic (sterile) endocarditis with acute and chronic inflammatory changes associated with advanced atherosclerotic lesions in the allograft aortic wall tissue resulting in thrombosis and subsequent cerebral embolization.


Assuntos
Aorta/transplante , Aterosclerose/etiologia , Trombose Coronária/etiologia , Endocardite/etiologia , Cardiopatias Congênitas/cirurgia , Complicações Pós-Operatórias , Adulto , Aorta/anormalidades , Aterosclerose/patologia , Aterosclerose/terapia , Trombose Coronária/patologia , Trombose Coronária/terapia , Criopreservação , Endocardite/patologia , Endocardite/terapia , Humanos , Masculino , Fatores de Tempo
17.
Ann Clin Lab Sci ; 37(2): 177-81, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17522375

RESUMO

Diploid/triploid mosaicism is an uncommon malformation syndrome thought to result from incorporation of the second polar body into a blastomere nucleus of the developing embryo. Clinical manifestations include mental and growth retardation, truncal obesity, body asymmetry, hypotonia, syndactyly, clino-/camptodactyly, malformed low-set ears, and small phallus. Although muscular atrophy has been documented in 35% of cases of diploid/triploid mosaicism, to our knowledge histologic evidence of myopathy has not been reported. We present a novel case of diploid/triploid mosaicism with evidence of central core disease and nemaline bodies (rods). The histologic and ultrastructural features are described. A review of the literature is provided, including discussion of the various theories regarding the co-expression of central cores and nemaline rods.


Assuntos
Anormalidades Múltiplas/genética , Mosaicismo , Miopatias da Nemalina/genética , Miopatia da Parte Central/genética , Ploidias , Anormalidades Múltiplas/patologia , Adenosina Trifosfatases/metabolismo , Adulto , Feminino , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Miofibrilas/ultraestrutura , Miopatias da Nemalina/patologia , Miopatias da Nemalina/fisiopatologia , Miopatia da Parte Central/patologia , Miopatia da Parte Central/fisiopatologia , Succinato Desidrogenase/metabolismo , Síndrome
18.
PLoS One ; 12(9): e0184620, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28886156

RESUMO

Vascular smooth muscle cells (VSMCs) represent important modulators of plaque stability in advanced lesions. We previously reported that loss of small proline-rich repeat protein 3 (Sprr3), leads to VSMC apoptosis in a PI3K/Akt-dependent manner and accelerates lesion progression. Here, we investigated the role of Sprr3 in modulating plaque stability in hyperlipidemic ApoE-/- mice. We show that loss of Sprr3 increased necrotic core size and reduced cap collagen content of atheromas in brachiocephalic arteries with evidence of plaque rupture and development of intraluminal thrombi. Moreover, Sprr3-/-ApoE-/- mice developed advanced coronary artery lesions accompanied by intraplaque hemorrhage and left ventricle microinfarcts. SPRR3 is known to reduce VSMC survival in lesions by promoting their apoptosis. In addition, we demonstrated that Sprr3-/- VSMCs displayed reduced expression of procollagen in a PI3K/Akt dependent manner. SPRR3 loss also increased MMP gelatinase activity in lesions, and increased MMP2 expression, migration and contraction of VSMCs independently of PI3K/Akt. Consequently, Sprr3 represents the first described VSMC modulator of each of the critical features of cap stability, including VSMC numbers, collagen type I synthesis, and protease activity through Akt dependent and independent pathways.


Assuntos
Apolipoproteínas E/metabolismo , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Miócitos de Músculo Liso/metabolismo , Animais , Apolipoproteínas E/genética , Proteínas Ricas em Prolina do Estrato Córneo/genética , Feminino , Fibronectinas/metabolismo , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/citologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
20.
Am J Surg Pathol ; 30(12): 1624-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17122521

RESUMO

Neoplasms that commonly affect patients with neurofibromatosis type 2 (NF2) include schwannomas, meningiomas, astrocytomas, ependymomas, and neurofibromas. Perineuriomas are rare tumors of the peripheral nerve sheath that share some characteristics with meningioma. As in both NF2-associated and sporadic cases of schwannoma and meningioma, perineuriomas often harbor mutations or deletions of the NF2 gene. However, perineuriomas have not previously been reported in the clinical setting of NF2. A 30-year-old man with a history of bilateral vestibular schwannomas, a parasagittal meningioma, an intraspinal ependymoma, and multiple other neoplasms involving both cranial and peripheral nerves (thereby fulfilling the diagnostic criteria for NF2) presented with an enlarging thigh mass. The diagnosis of cellular soft tissue perineurioma was confirmed by both immunohistochemical and ultrastructural analysis. This case represents the first report of a soft tissue perineurioma arising in the setting of NF2.


Assuntos
Neoplasias de Bainha Neural/complicações , Neurofibromatose 2/complicações , Neoplasias de Tecidos Moles/complicações , Adulto , Biomarcadores Tumorais/análise , Citoplasma/ultraestrutura , Diagnóstico Diferencial , Humanos , Masculino , Neoplasias Primárias Múltiplas , Neoplasias de Bainha Neural/química , Neoplasias de Bainha Neural/diagnóstico , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/cirurgia , Neurofibromatose 2/patologia , Neoplasias do Sistema Nervoso Periférico/diagnóstico , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia
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