RESUMO
Artificial Intelligence (AI) applications have the potential to revolutionize conventional healthcare practices, creating a more efficient and patient-centred approach with improved outcomes. This guide discuses eighteen AI-based applications in clinical decision-making, precision medicine, operational efficiency, and predictive analytics, including a real-world example of AI's role in public health during the early stages of the COVID-19 pandemic. Additionally, we address ethical questions, transparency, data privacy, bias, consent, accountability, and liability, and the strategic measures that must be taken to align AI with ethical principles, legal frameworks, legacy information technology systems, and employee skills and knowledge. We emphasize the importance of informed and strategic approaches to harness AI's potential and manage its challenges. Moreover, this guide underscores the importance of evaluating and integrating new skills and competencies to navigate and use AI-based technologies in healthcare management, such as technological literacy, long-term strategic vision, change management skills, ethical decision-making, and alignment with patient needs.
Assuntos
Inteligência Artificial , COVID-19 , Liderança , SARS-CoV-2 , Inteligência Artificial/ética , Humanos , Pandemias , Assistência ao Paciente/ética , Atenção à Saúde/organização & administraçãoRESUMO
Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) have been broadly linked to the pathogenesis of multiple autoimmune diseases. In the few short years since the discovery of T(H)17 cells, new paradigms about their prominence in chronic inflammation and human autoimmunity have emerged. Recent findings that T(H)17 cells might be capable of regulatory functions and that the associated effector molecules IL-17 and IL-22 aid in restricting tissue destruction during inflammatory episodes illuminate the complexities of IL-17 and T(H)17 biology. In this Perspective we highlight critical differences between IL-17 itself and T(H)17 cells and discuss the protective nature of IL-17 and T(H)17 cells.
Assuntos
Interleucina-17/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Doenças Autoimunes/imunologia , Humanos , Modelos BiológicosRESUMO
Non-traumatic neurological deterioration is a medical emergency that may arise from diverse causes, to include cerebral infarction or intracranial hemorrhage, meningoencephalitis, seizure, hypoxic-ischemic or toxic/metabolic encephalopathy, poisoning, or drug intoxication. We describe the abrupt onset of neurological deterioration in a 53-year-old man with Williams-Beuren syndrome, a sporadically occurring genetic disorder caused by chromosomal microdeletion at 7q11.23. The clinical phenotype of Williams-Beuren syndrome is suggested by distinctive elfin facies, limited intellect, unique personality features, growth abnormalities, and endocrinopathies. The causative microdeletion of chromosomal material will frequently involve loss of the elastin gene, ELN, with resulting arteriopathy, supravalvular aortic stenosis, non-ischemic cardiopathy, and atrial fibrillation. Our patient sustained acute neurological decline within one month after undergoing a cardiac ablative procedure to convert atrial fibrillation to sinus rhythm. We present our findings in the setting of a clinico-pathological correlation, in which we reveal the cause of the abrupt neurological deterioration and discuss how our patient was affected by an uncommon stroke disorder.
Assuntos
Estenose Aórtica Supravalvular , Fibrilação Atrial , Ablação por Cateter , Embolia Aérea , Síndrome de Williams , Estenose Aórtica Supravalvular/genética , Estenose Aórtica Supravalvular/patologia , Fibrilação Atrial/complicações , Ablação por Cateter/efeitos adversos , Humanos , Síndrome de Williams/complicações , Síndrome de Williams/diagnóstico , Síndrome de Williams/genéticaRESUMO
Interleukin 23 (IL-23) and IL-17 have been linked to the pathogenesis of several chronic inflammatory disorders, including inflammatory bowel disease. Yet as an important function for IL-23 is emerging, the function of IL-17 in inflammatory bowel disease remains unclear. Here we demonstrate IL-17A-mediated protection in the CD45RBhi transfer model of colitis. An accelerated wasting disease elicited by T cells deficient in IL-17A correlated with higher expression of genes encoding T helper type 1-type cytokines in colon tissue. IL-17A also modulated T helper type 1 polarization in vitro. Furthermore, T cells deficient in the IL-17 receptor elicited an accelerated, aggressive wasting disease relative to that elicited by wild-type T cells in recipient mice. Our data demonstrate a protective function for IL-17 and identify T cells as not only the source but also a target of IL-17 in vivo.
Assuntos
Colite/imunologia , Interleucina-17/imunologia , Células Th1/imunologia , Síndrome de Emaciação/imunologia , Transferência Adotiva , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Interferon gama , Interleucina-17/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Interleucina-17/imunologia , Proteínas com Domínio T/metabolismoRESUMO
NEW FINDINGS: What is the central question of this study? Does peripheral non-invasive focused ultrasound targeted to the celiac plexus improve inflammatory bowel disease? What is the main finding and its importance? Peripheral non-invasive focused ultrasound targeted to the celiac plexus in a rat model of ulcerative colitis improved stool consistency and reduced stool bloodiness, which coincided with a longer and healthier colon than in animals without focused ultrasound treatment. The findings suggest that this novel neuromodulatory technology could serve as a plausible therapeutic approach for improving symptoms of inflammatory bowel disease. ABSTRACT: Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life. Here, we aim to stimulate the celiac plexus with non-invasive peripheral focused ultrasound (FUS) to modulate the enteric cholinergic anti-inflammatory pathway. This approach may have clinical utility as an efficacious IBD treatment given the non-invasive and targeted nature of this therapy. We employed the dextran sodium sulfate (DSS) model of colitis, administering lower (5%) and higher (7%) doses to rats in drinking water. FUS on the celiac plexus administered twice a day for 12 consecutive days to rats with severe IBD improved stool consistency scores from 2.2 ± 1 to 1.0 ± 0.0 with peak efficacy on day 5 and maximum reduction in gross bleeding scores from 1.8 ± 0.8 to 0.8 ± 0.8 on day 6. Similar improvements were seen in animals in the low dose DSS group, who received FUS only once daily for 12 days. Moreover, animals in the high dose DSS group receiving FUS twice daily maintained colon length (17.7 ± 2.5 cm), while rats drinking DSS without FUS exhibited marked damage and shortening of the colon (13.8 ± 0.6 cm) as expected. Inflammatory cytokines such as interleukin (IL)-1ß, IL-6, IL-17, tumour necrosis factor-α and interferon-γ were reduced with DSS but coincided with control levels after FUS, which is plausibly due to a loss of colon crypts in the former and healthier crypts in the latter. Lastly, overall, these results suggest non-invasive FUS of peripheral ganglion can deliver precision therapy to improve IBD symptomology.
Assuntos
Plexo Celíaco , Colite , Doenças Inflamatórias Intestinais , Animais , Plexo Celíaco/metabolismo , Plexo Celíaco/patologia , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana/metabolismo , Sulfato de Dextrana/uso terapêutico , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , RatosRESUMO
Spontaneous rupture of mesenteric vasculature associated with fibromuscular dysplasia is an unreported phenomenon. We describe a case in a 28-year-old male with a history of chronic abdominal pain who presented to our facility in hemorrhagic shock secondary to a ruptured transverse mesocolon middle colic aneurysm status postemergent transverse colectomy. He was found to have chronic vertebral, renovisceral, and iliac aneurysms as well as acute superior and inferior mesenteric artery dissection and chronic bilateral vertebral artery dissections. He subsequently developed disseminated intravascular coagulopathy, resulting in saddle pulmonary embolus as well as right renal artery and splenic artery thrombosis. Ultimately, the patient expired.
Assuntos
Aneurisma Roto/etiologia , Dissecção Aórtica/etiologia , Displasia Fibromuscular/complicações , Artérias Mesentéricas , Adulto , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/cirurgia , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/cirurgia , Evolução Fatal , Displasia Fibromuscular/diagnóstico por imagem , Displasia Fibromuscular/cirurgia , Humanos , Masculino , Artérias Mesentéricas/diagnóstico por imagem , Artérias Mesentéricas/cirurgia , Ruptura Espontânea , Choque Hemorrágico/etiologia , Resultado do TratamentoRESUMO
During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration, and restore barrier integrity. Inflammatory mediators including TH1/TH17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium and whether the crypt remains responsive to these cytokines during active damage and repair, remain unclear. Here, using laser-capture microdissection and primary colon organoid culture, we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in proinflammatory signaling. IFN-γ induces the TH1-recruiting, proinflammatory chemokine CXCL10/IP10 in primary murine intestinal crypt epithelium. CXCL10 was also induced in colonic organoids derived from mice with active, experimentally induced colitis, suggesting that the crypt can actively secrete CXCL10 in select cytokine environments during colitis. Colon expression of cxcl10 further increased during infectious and noninfectious colitis in Il17a-/- mice, demonstrating that IL-17A exerts a negative effect on CXCL10 in vivo. Furthermore, IL-17A directly antagonized CXCL10 production in ex vivo organoid cultures derived from healthy murine colons. Interestingly, direct antagonism of CXCL10 was not observed in organoids derived from colitic mouse colons bearing active lesions. These data, highlighting the complex interplay between the cytokine milieu and crypt epithelia, demonstrate proinflammatory chemokines can be induced within the colonic crypt and suggest the crypt remains responsive to cytokine modulation during inflammation.NEW & NOTEWORTHY Upon damage, the intestinal epithelium regenerates to restore barrier function. Here we observe that the local colonic cytokine milieu controls the production of procolitic chemokines within the crypt base and colon crypts remain responsive to cytokines during inflammation. IFN-γ promotes, while IL-17 antagonizes, CXCL10 production in healthy colonic crypts, while responses to cytokines differ in inflamed colon epithelium. These data reveal novel insight into colon crypt responses and inflammation-relevant alterations in signaling.
Assuntos
Quimiocina CXCL10/metabolismo , Colite/metabolismo , Colo/efeitos dos fármacos , Interferon gama/farmacologia , Interleucina-17/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Animais , Microambiente Celular , Quimiocina CXCL10/genética , Colite/genética , Colite/imunologia , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Interleucina-17/deficiência , Interleucina-17/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Técnicas de Cultura de Tecidos , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
T helper 17 (Th17) cells are important for host defense against extracellular microorganisms. However, they are also implicated in autoimmune and chronic inflammatory diseases, and as such need to be tightly regulated. The mechanisms that directly control committed pathogenic Th17 cells in vivo remain unclear. We showed here that IL-17A-producing CD4+ T cells expressed interleukin-10 receptor α (IL-10Rα) in vivo. Importantly, T cell-specific blockade of IL-10 signaling led to a selective increase of IL-17A+IFN-γ⻠(Th17) and IL-17A+IFN-γ+ (Th17+Th1) CD4+ T cells during intestinal inflammation in the small intestine. CD4+Foxp3â» IL-10-producing (Tr1) cells and CD4+Foxp3+ regulatory (Treg) cells were able to control Th17 and Th17+Th1 cells in an IL-10-dependent manner in vivo. Lastly, IL-10 treatment of mice with established colitis decreased Th17 and Th17+Th1 cell frequencies via direct signaling in T cells. Thus, IL-10 signaling directly suppresses Th17 and Th17+Th1 cells.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-10/imunologia , Interleucina-10/imunologia , Células Th17/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Colite/imunologia , Colite/patologia , Progressão da Doença , Fatores de Transcrição Forkhead/imunologia , Interferon gama/imunologia , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/imunologia , Transdução de Sinais , Células Th17/citologia , Células Th17/metabolismoRESUMO
New ideas for diagnostics in clinical parasitology are needed to overcome some of the difficulties experienced in the widespread adoption of detection methods for gastrointestinal parasites in livestock. Here we provide an initial evaluation of the performance of a newly developed automated device (Telenostic) to identify and quantify parasitic elements in fecal samples. This study compared the Telenostic device with the McMaster and Mini-FLOTAC for counting of strongyle eggs in a fecal sample. Three bovine fecal samples were examined, in triplicate, on each of the three fecal egg-counting devices. In addition, both manual (laboratory technician) and automated analysis (image analysis algorithm) were performed on the Telenostic device to calculate fecal egg counts (FEC). Overall, there were consistent egg counts reported across the three devices and calculation methods. The Telenostic device compared very favourably to the Mini-FLOTAC and McMaster. Only in sample C, a significant difference (P < 0.05) was observed between the egg counts obtained by Mini-FLOTAC and by the other methods. From this limited dataset it can be concluded that the Telenostic-automated test is comparable to currently used benchmark FEC methods, while improving the workflow, test turn-around time and not requiring trained laboratory personnel to operate or interpret the results.
Assuntos
Testes Diagnósticos de Rotina/veterinária , Gado/parasitologia , Animais , Bovinos , Testes Diagnósticos de Rotina/métodos , Fezes/parasitologia , Helmintíase Animal , Doenças dos Cavalos/parasitologia , Cavalos/parasitologia , Enteropatias Parasitárias , Contagem de Ovos de Parasitas/veterinária , Ovinos/parasitologia , Doenças dos Ovinos/parasitologiaRESUMO
A hydro power plant constructed around a waterfall on a coastal spate river, used the fall as a natural fish pass and applied a previous telemetry study on local Atlantic salmon Salmo salar to determine the abstraction conditions for the site. The current study used the same telemetry approach to monitor the efficacy of S. salar passage and to compare migratory behaviour at the waterfall pre and post the hydro development. The probability of S. salar successfully crossing the waterfall was higher post-hydro when 80% of tagged fish successfully crossed in comparison to the pristine pre-hydro period when 44% of tagged fish ascended. The flow range used by tagged S. salar to cross the waterfall ranged from 2.49-7.87 m3 s-1 in the pre-hydro period but broadened to 1.32-12.91 m3 s-1 during the post-hydro period. This was principally due to the hydro diverting water away from the waterfall during spate conditions, damping the flow across the barrier and facilitating upstream migration within a more suitable discharge range. During 2017-2018 implementation of the hydro-operation protocol elongated the duration of the migratory window for successful upstream migration by 36-128%. A strong diurnal pattern was observed for movements across the Salmon Leap waterfall during both the pre-hydro and post-hydro monitoring periods with most tagged S. salar crossing the complex obstacle in daylight.
Assuntos
Migração Animal , Centrais Elétricas , Salmo salar/fisiologia , Animais , Conservação dos Recursos Naturais , Rios , TelemetriaRESUMO
Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.
Assuntos
Transformação Celular Neoplásica , Inflamassomos/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Receptores de Interleucina/metabolismo , Animais , Colite/complicações , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/complicações , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Regulação para Baixo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Genes APC , Interleucina-18/metabolismo , Interleucinas/deficiência , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Knockout , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Fatores de Tempo , Redução de Peso , Interleucina 22RESUMO
Nutrient stimulation of muscle protein synthesis (MPS) is regulated by the change in extracellular essential amino acid (EAA) concentration. In vivo microdialysis (MD) is a minimally invasive sampling technique, capable of sampling solute in the interstitial space of a target tissue. In a contralateral limb design (REST vs. EX), this study utilised in vivo MD to examine the change in skeletal muscle dialysate amino acid concentration following ingestion of whey protein isolate (WPI) and flavoured water (CON). Four male subjects undertook unilateral, concentric lower limb knee extensor resistance exercise (RE) on two occasions. After RE, an MD catheter (CMA 63) was inserted into m. vastus lateralis of the exercise and resting leg and sampled serially over 7 h. Following a 2.5 h equilibration period subjects consumed either 0.55 g/kg WPI or CON. Peak plasma EAA (2656 ± 152 µM) preceded the peak in dialysate EAA (2345 ± 164 µM) by 30 min in response to WPI ingestion; however, the post-prandial elevation in dialysate EAA extended beyond that of the plasma. This resulted in no difference in the dialysate EAA area under the curve (ΔAUC270) relative to plasma in response to WPI ingestion [220 ± 29 vs. 206 ± 7.9 mmol min/L (p = 0.700)]. A bout of unilateral lower limb RE had no effect of the subsequent dialysate amino acid concentration in response to either WPI or CON ingestion. These data represent a novel report describing the time course and magnitude of change in skeletal muscle dialysate concentration of key nutrient regulators of MPS sampled by in vivo MD, in response to nutrient ingestion with and without RE.
Assuntos
Aminoácidos Essenciais/farmacocinética , Músculo Esquelético/efeitos dos fármacos , Treinamento Resistido , Proteínas do Soro do Leite/metabolismo , Administração Oral , Adulto , Aminoácidos Essenciais/sangue , Área Sob a Curva , Índice de Massa Corporal , Soluções para Diálise/química , Humanos , Masculino , Microdiálise , Músculo Esquelético/metabolismo , Proteínas do Soro do Leite/administração & dosagemRESUMO
Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified CD4(+) T cell subset distinct from T helper type 1 (T(H)1) and T helper type 2 (T(H)2) cells. T(H)17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of T(H)17 cells have been well characterized. However, where and how the immune system controls T(H)17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory T(H)17 cells can be redirected to and controlled in the small intestine. T(H)17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that T(H)17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory T(H)17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rT(H)17). These results identify mechanisms limiting T(H)17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of T(H)17 cells.
Assuntos
Intestino Delgado/imunologia , Células Th17/imunologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Movimento Celular/efeitos dos fármacos , Quimiocina CCL20/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Vírus da Influenza A/imunologia , Interleucina-17/imunologia , Intestino Delgado/citologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infecções por Orthomyxoviridae/imunologia , Receptores CCR6/imunologia , Sepse/imunologia , Infecções Estafilocócicas/imunologiaRESUMO
Acute febrile neutrophilic dermatosis (Sweet syndrome) is a systemic inflammatory condition usually associated with autoimmune or neoplastic processes and characterised by inflammatory dermatologic lesions such as erythematous plaques and papules associated with fever and leukocytosis. Neurological and ophthalmological involvement is rare. The authors describe an unusual case of Sweet syndrome associated with microscopic polyangiitis presenting with papilloedema, anterior uveitis, and skin rash. Years later, he developed acute posterior multifocal placoid pigment epitheliopathy. Treatment with immunosuppressive medications led to a relapsing remitting course with maximum benefit from use of steroids. The authors describe the difficulties in diagnosis and treatment of this rare case.
RESUMO
Angiotensin II (Ang II) promotes development of ascending aortic aneurysms (AAs), but progression of this pathology is undefined. We evaluated factors potentially involved in progression, and determined the temporal sequence of tissue changes during development of Ang II-induced ascending AAs. Ang II infusion into C57BL/6J mice promoted rapid expansion of the ascending aorta, with significant increases within 5 days, as determined by both in vivo ultrasonography and ex vivo sequential acquisition of tissues. Rates of expansion were not significantly different in LDL receptor-null mice fed a saturated fat-enriched diet, demonstrating a lack of effect of hypercholesterolemia. Augmenting systolic blood pressure with norepinephrine infusion had no significant effect on ascending aortic expansion. Pathological changes observed within 5 days of Ang II infusion included increased medial thickness and intramural hemorrhage characterized by erythrocyte extravasation in outer lamellar layers of the media. Intramedial hemorrhage was not observed after prolonged Ang II infusion, although partial medial disruption was present. Elastin fragmentation and transmural medial breaks of the ascending aorta were observed with continued Ang II infusion, which were restricted to anterior aspects. CD45(+) cells accumulated in adventitia but were minimal in media. Similar pathology was observed in tissues obtained from patients with ascending AAs. In conclusion, Ang II promotes ascending AAs through region-specific changes that are independent of hypercholesterolemia or systolic blood pressure.
Assuntos
Angiotensina II/toxicidade , Aorta/patologia , Aneurisma Aórtico/patologia , Túnica Média/patologia , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Skeletal muscle has recently been described as an endocrine organ, capable of releasing cytokines and regulators of metabolism. Microdialysis of the interstitial space of skeletal muscle enables analysis of the release of such cytokines. The purpose of this study was to determine the transient changes in concentration of metabolites and cytokines in human skeletal muscle in a 7h period following the insertion of a microdialysis probe. In total, sixteen microdialysis catheters were inserted into the vastus lateralis of male participants (age 26.2±1.35y, height 180.8±3.89cm, mass 83.9±3.86kg, BMI 25.7±0.87kgm(-2), body fat 26.1±3.0%). Serial samples were analyzed by micro-enzymatic and multiplexed immunoassay. Muscle interstitial glucose and lactate levels remained stable throughout, amino acid concentrations stabilized after 2.5h, however, insertion of a microdialysis catheter induced a 29-fold increase in peak IL-6 (p<0.001) and 35-fold increase in peak IL-8 concentrations (p<0.001) above basal levels 6h post insertion. In contrast to stable amino acid, glucose and lactate concentrations after 2h, commonly reported markers of tissue homeostasis in in vivo microdialysis, the multi-fold increase in IL-6 and IL-8 following insertion of a microdialysis catheter is indicative of a sustained disturbance of tissue homeostasis.
Assuntos
Citocinas/metabolismo , Líquido Extracelular/metabolismo , Músculo Esquelético/metabolismo , Adulto , Aminoácidos/química , Índice de Massa Corporal , Carnosina/química , Catéteres , Glucose/química , Homeostase , Humanos , Imunoensaio , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Ácido Láctico/química , Masculino , Microdiálise , Músculo Quadríceps/patologia , Taurina/químicaRESUMO
Infective endocarditis is a well-described cardiovascular disease that causes significant morbidity and mortality despite medical and surgical advances. Complications of endocarditis include heart failure, systemic embolization, and valvular destruction including valve aneurysms which increase morbidity and mortality. Mitral valve aneurysms are rarely encountered in the clinical setting. We present eight mitral valve aneurysm cases and discuss a new potential pathogenesis of this deadly endocarditis complication. Pathologic evaluation suggests that neovascularization of the anterior mitral valve leaflet predisposes this territory to abscess and aneurysm formation. In conclusion, mitral valve aneurysms appear to be another form of intravalvular abscess which has expanded and should be approached aggressively with surgical intervention if indicated.
Assuntos
Aneurisma Infectado/complicações , Aneurisma Infectado/diagnóstico por imagem , Endocardite Bacteriana/complicações , Endocardite Bacteriana/diagnóstico por imagem , Adulto , Idoso , Aneurisma Infectado/cirurgia , Endocardite Bacteriana/cirurgia , Evolução Fatal , Feminino , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/microbiologia , Valva Mitral/cirurgia , Ultrassonografia , Adulto JovemRESUMO
Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.
Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacologia , Proteínas de Transporte/metabolismo , Inflamação/imunologia , Adjuvantes Imunológicos/química , Animais , Anticorpos/imunologia , Proteínas Reguladoras de Apoptose , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Caspase 1/deficiência , Caspase 1/metabolismo , Morte Celular , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/metabolismo , Ativação Enzimática/efeitos dos fármacos , Imunidade Inata/imunologia , Inflamação/induzido quimicamente , Interleucina-18/biossíntese , Interleucina-18/imunologia , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Potássio/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Background: Lamin A/C gene (LMNA) mutations cause myocardial fibrosis manifesting as arrhythmogenic, non-compaction, or dilated cardiomyopathies. Fibro-fatty replacement largely involves the conduction system and conduction disease commonly occurs prior to contractile dysfunction. Case summary: Two young, unrelated Caucasian males, aged 34 and 25, were referred to our centre for treatment of advanced heart failure. Both patients had a family history of heart failure and sudden cardiac death among their first-degree relatives and were diagnosed with Lamin A/C mutations, but they had not been screened prior to disease onset. Although the initial phenotypes were dilated cardiomyopathy and left ventricular non-compaction cardiomyopathy, both patients' disease progressed rapidly to include ventricular arrhythmias, severe global left ventricular hypokinesis, and dependence on outpatient milrinone to complete activities of daily living. Both patients received heart transplantation within 2 years of initial disease onset. The surgical pathology of the explanted hearts revealed characteristic findings of fibro-fatty degeneration of the conduction system, and using light microscopy, they were found to have nuclear membrane thinning, bubbling, and convolution throughout all areas sampled. Discussion: Lamin A/C-related cardiomyopathy is associated with sudden cardiac death early in the disease course, warranting early consideration of implantable cardioverter defibrillator implantation, and rapid progression to end-stage cardiomyopathy refractory to standard medical therapies, necessitating early referral to an advanced heart failure centre. We report a newly observed and recorded finding of morphologic nuclear alterations in late-stage disease using high-power light microscopy. These alterations underscore the pathophysiology of Lamin A/C-related cardiomyopathy and provide a basis for future research into disease-specific therapies.
RESUMO
This research assesses the capability of texture analysis (TA) derived from high-resolution (HR) T2-weighted magnetic resonance imaging to identify primary sequelae following 1-5 hours of controlled cortical impact mild or severe traumatic brain injury (TBI) to the left frontal cortex (focal impact) and secondary (diffuse) sequelae in the right frontal cortex, bilateral corpus callosum, and hippocampus in rats. The TA technique comprised first-order (histogram-based) and second-order statistics (including gray-level co-occurrence matrix, gray-level run length matrix, and neighborhood gray-level difference matrix). Edema in the left frontal impact region developed within 1 hour and continued throughout the 5-hour assessments. The TA features from HR images confirmed the focal injury. There was no significant difference among radiomics features between the left and right corpus callosum or hippocampus from 1 to 5 hours following a mild or severe impact. The adjacent corpus callosum region and the distal hippocampus region (s), showed no diffuse injury 1-5 hours after mild or severe TBI. These results suggest that combining HR images with TA may enhance detection of early primary and secondary sequelae following TBI.