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1.
Arch. argent. pediatr ; 122(2): e202310149, abr. 2024. ilus
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1537741

RESUMO

La sepsis es un problema global de salud y la progresión hacia el shock séptico se asocia con un incremento marcado de la morbimortalidad. En este escenario, el aumento del lactato plasmático demostró ser un indicador de gravedad y un predictor de mortalidad, y suele interpretarse casi exclusivamente como marcador de baja perfusión tisular. Sin embargo, últimamente se produjo un cambio de paradigma en la exégesis del metabolismo y propiedades biológicas del lactato. En efecto, la adaptación metabólica al estrés, aun con adecuado aporte de oxígeno, puede justificar la elevación del lactato circulante. Asimismo, otras consecuencias fisiopatológicas de la sepsis, como la disfunción mitocondrial, se asocian con el desarrollo de hiperlactatemia sin que necesariamente se acompañen de baja perfusión tisular. Interpretar el origen y la función del lactato puede resultar de suma utilidad clínica en la sepsis, especialmente cuando sus niveles circulantes fundamentan las medidas de reanimación.


Sepsis is a global health problem; progression to septic shock is associated with a marked increase in morbidity and mortality. In this setting, increased plasma lactate levels demonstrated to be an indicator of severity and a predictor of mortality, and are usually interpreted almost exclusively as a marker of low tissue perfusion. However, a recent paradigm shift has occurred in the exegesis of lactate metabolism and its biological properties. Indeed, metabolic adaptation to stress, even with an adequate oxygen supply, may account for high circulating lactate levels. Likewise, other pathophysiological consequences of sepsis, such as mitochondrial dysfunction, are associated with the development of hyperlactatemia, which is not necessarily accompanied by low tissue perfusion. Interpreting the origin and function of lactate may be of great clinical utility in sepsis, especially when circulating lactate levels are the basis for resuscitative measures.


Assuntos
Humanos , Choque Séptico , Sepse/diagnóstico , Hiperlactatemia/complicações , Hiperlactatemia/etiologia , Ácido Láctico/metabolismo
2.
Arch. argent. pediatr ; 122(2): e202310144, abr. 2024. tab, ilus
Artigo em Inglês, Espanhol | LILACS, BINACIS | ID: biblio-1537966

RESUMO

El dengue es una enfermedad viral transmitida por la picadura del mosquito Aedes aegypti. El comportamiento del dengue en Argentina es epidémico; la mayoría de los casos se observan en los meses de mayor temperatura. Hasta la semana epidemiológica (SE) 20/2023, se registraron en Argentina 106 672 casos; se vieron afectadas 18 de las 24 provincias que conforman el país. Dentro de los principales grupos de riesgo, se incluyen los menores de 2 años. Reconocer los signos, síntomas e identificar los factores de riesgo es fundamental para el manejo de casos con mayor riesgo de gravedad. Presentamos el caso de una paciente de 32 días de vida que se internó por síndrome febril sin foco, con diagnósticos diferenciales de meningitis viral y sepsis, evolucionó con leucocitosis, plaquetopenia, hipoalbuminemia, asociado a exantema y edemas. Se llegó al diagnóstico de dengue por la clínica, epidemiologia e IgM positiva.


Dengue fever is a viral disease transmitted by the Aedes aegypti mosquitoes. In Argentina, dengue fever is an epidemic disease; most cases are reported during the hot months.Until epidemiological week (EW) 20/2023, 106 672 cases were reported across 18 of the 24 provinces of Argentina. Children younger than 2 years are among the main groups at risk. Recognizing signs and symptoms and identifying risk factors is fundamental for the management of cases at a higher risk of severity. Here we describe the case of a 32-day-old female patient who was hospitalized due to febrile syndrome without a source, who had a differential diagnosis of viral meningitis and sepsis and progressed to leukocytosis, thrombocytopenia, hypoalbuminemia in association with rash and edema. The diagnosis of dengue fever was established based on clinical, epidemiological, and positive IgM data.


Assuntos
Humanos , Animais , Feminino , Lactente , Aedes , Dengue/complicações , Dengue/diagnóstico , Dengue/epidemiologia , Argentina , Fatores de Risco , Diagnóstico Diferencial
3.
Actas urol. esp ; 48(3): 204-209, abr. 2024. tab
Artigo em Espanhol | IBECS | ID: ibc-231925

RESUMO

Objetivos Este estudio evalúa el impacto del uso de una vaina de acceso ureteral (VAU) durante la ureteroscopia flexible (URSf) para el tratamiento de la litiasis urinaria, centrándose en resultados como la tasa libre de litiasis, el tiempo quirúrgico y las complicaciones. Métodos Este estudio prospectivo y aleatorizado se llevó a cabo en el Hospital de Badr en la Universidad de Helwan y en los hospitales de la Universidad de Ain Shams, desde agosto de 2021 hasta agosto de 2022. Los pacientes se aleatorizaron sistemáticamente a 2 grupos (URSf con VAU: 33 pacientes y URSf sin VAU: 31 pacientes), y se sometieron a evaluaciones preoperatorias y postoperatorias, incluyendo pruebas de laboratorio y de imagen. Se controlaron los posibles riesgos asociados al procedimiento, como el fracaso en el acceso al cálculo, el dolor, el sangrado y la sepsis. Resultados Se observó que los 2 grupos eran comparables en cuanto a características demográficas o hallazgos preoperatorios de la litiasis (p>0,05 para todos). Sin embargo, el tiempo quirúrgico fue menor en el grupo tratado sin VAU (79,4±15,3 vs. 90,4±16,7min en el grupo tratado con VAU; p=0,008). Las tasas de complicaciones intraoperatorias, incluidos el fracaso del acceso, la interrupción de la operación, las lesiones ureterales y el sangrado, fueron comparables en ambos grupos (p>0,05). No se observaron diferencias significativas en cuanto a la tasa libre de litiasis postoperatoria (78,8 vs. 71,0%; p=0,305) y el tamaño litiásico residual medio (2,7±3,5 vs. 3,1±3,1mm; p=0,687). Conclusiones El presente estudio sugiere que URSf sin VAU puede ofrecer una opción eficiente e igualmente efectiva para el tratamiento de los cálculos renales y de uréter superior. Sin embargo, se necesitan más estudios con muestras de mayor tamaño y periodos de seguimiento más largos para validar estos resultados y establecer indicaciones más precisas para este procedimiento. (AU)


Objectives This study evaluates the impact of using an access sheath (AS) during flexible ureteroscopy (fURS) for urolithiasis treatment, focusing on outcomes such as stone-free rate, operation time, and complications. Methods This prospective, randomized study was carried out at Badr Hospital, Helwan University, and Ain Shams University hospitals from August 2021 to August 2022. Patients were systematically randomized into two groups (fURS with AS: 33 patients and without AS: 31 patients) and underwent preoperative and postoperative assessments, including lab tests and imaging. Possible procedure-associated risks, such as failed stone access, pain, bleeding, and sepsis, were monitored. Results The two groups were found to be comparable in terms of demographic characteristics or preoperative stone findings (P>.05 for all). However, operation duration was shorter in the No Sheath group (79.4±15.3minutes vs. 90.4±16.7minutes in the Sheath group, P=.008). Intraoperative complication rates, including failed access, operation termination, ureteric injury, and bleeding, were comparable in both groups (P>.05). Postoperative stone-free rates (78.8% vs. 71.0%, P=.305) and mean residual stone size (2.7±3.5mm vs. 3.1±3.1mm, P=.687) showed no significant differences. Conclusions The present study suggests that fURS without an access sheath may offer an efficient and equally effective option for managing upper ureteric and renal stones. However, more studies with larger sample sizes and longer follow-up periods are required to validate these findings and to establish more precise indications for this approach. (AU)


Assuntos
Humanos , Masculino , Feminino , Ureteroscopia/instrumentação , Ureteroscopia/métodos , Urolitíase/cirurgia
4.
Artigo em Inglês | MEDLINE | ID: mdl-38629462

RESUMO

BACKGROUND: Aminoglycosides (AGs) are important antibiotics in the treatment of Gram-negative sepsis. However, they are associated with the risk of irreversible sensorineural hearing loss (SNHL). Several genetic variants have been implicated in the development of ototoxicity. OBJECTIVES: To evaluate the pharmacogenetic determinants of AG-related ototoxicity. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and was registered on Prospero (CRD42022337769). In Dec 2022, PubMed, Cochrane Library, Embase and MEDLINE were searched. Included studies were those reporting original data on the effect of the AG-exposed patient's genome on the development of ototoxicity. RESULTS: Of 10 202 studies, 31 met the inclusion criteria. Twenty-nine studies focused on the mitochondrial genome, while two studied the nuclear genome. One study of neonates found that 30% of those with the m.1555A > G variant failed hearing screening after AG exposure (level 2 evidence). Seventeen additional studies found the m.1555A > G variant was associated with high penetrance (up to 100%) of SNHL after AG exposure (level 3-4 evidence). Nine studies of m.1494C > T found the penetrance of AG-related SNHL to be up to 40%; however, this variant was also identified in those with SNHL without AG exposure (level 3-4 evidence). The variants m.1005T > C and m.1095T > C may be associated with AG-related SNHL; however, further studies are needed. CONCLUSIONS: This review found that the m.1555A > G and m.1494C > T variants in the MT-RNR1 gene have the strongest evidence in the development of AG-related SNHL, although study quality was limited (level 2-4). These variants were associated with high penetrance of a SNHL phenotype following AG exposure.

5.
J Palliat Med ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38629826

RESUMO

Guidelines are lacking for patients with calciphylaxis on renal replacement therapy, often leading to difficulty optimally treating these patients. A 60-year-old male veteran receiving hemodialysis presented with calciphylaxis of the left lower extremity and intractable pain. His condition was complicated by chronic back pain, long-term opioid therapy, and psychological trauma history. He was ultimately transferred to a calciphylaxis treatment center but was unable to tolerate further treatments due to sepsis and hemodynamic instability. He was transitioned to comfort measures and died in the hospital. Addressing complicated pain physiologies and complex trauma is challenging even in well-resourced tertiary medical centers. Despite the availability of calciphylaxis therapies and trauma-informed care, there remains a high rate of suffering and mortality in this patient population. There is much work to be done in this cohort, particularly when considering the implications of past traumatic experiences on health care engagement and pain management.

6.
Inflamm Res ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630134

RESUMO

OBJECTIVE: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms. METHODS: The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry. RESULTS: SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells. CONCLUSION: PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.

7.
Surg Endosc ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630177

RESUMO

BACKGROUND: Leaks following bariatric surgery, while rare, are potentially fatal due to risk of peritonitis and sepsis. Anastomotic leaks and gastro-gastric fistulae following Roux-En-Y gastric bypass (RYGB) as well as staple line leaks after sleeve gastrectomy have historically been treated multimodally with surgical drainage, aggressive antibiotic therapy, and more recently, endoscopically. Endoscopic clipping using over-the-scope clips and endoscopic suturing are two of the most common approaches used to achieve full thickness closure. METHODS: A systematic literature search was performed in PubMed to identify articles on the use of endoscopic clipping or suturing for the treatment of leaks and fistulae following bariatric surgery. Studies focusing on stents, and those that incorporated multiple closure techniques simultaneously, were excluded. Literature review and meta-analysis were performed with the PRISMA guidelines. RESULTS: Five studies with 61 patients that underwent over-the-scope clip (OTSC) closure were included. The pooled proportion of successful closure across the studies was 81.1% (95% CI 67.3 to 91.7). The successful closure rates were homogeneous (I2 = 39%, p = 0.15). Three studies with 92 patients that underwent endoscopic suturing were included. The weighted pooled proportion of successful closure across the studies was shown to be 22.4% (95% CI 14.6 to 31.3). The successful closure rates were homogeneous (I2 = 0%, p = 0.44). Three of the studies, totaling 34 patients, examining OTSC deployment reported data for reintervention rate. The weighted pooled proportion of reintervention across the studies was 35.0% (95% CI 11.7 to 64.7). We noticed statistically significant heterogeneity (I2 = 68%, p = 0.04). One study, with 20 patients examining endoscopic suturing, reported rate of repeat intervention 60%. CONCLUSION: Observational reports show that patients managed with OTSC were more likely to experience healing of their defect than those managed with endoscopic suturing. Larger controlled studies comparing different closure devices for bariatric leaks should be carried out to better understand the ideal endoscopic approach to these complications.

8.
J Microbiol ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630349

RESUMO

The human gut houses a diverse and dynamic microbiome critical for digestion, metabolism, and immune development, exerting profound effects on human health. However, these microorganisms pose a potential threat by breaching the gut barrier, entering host tissues, and triggering infections, uncontrolled inflammation, and even sepsis. The intestinal epithelial cells form the primary defense, acting as a frontline barrier against microbial invasion. Antimicrobial proteins (AMPs), produced by these cells, serve as innate immune effectors that regulate the gut microbiome by directly killing or inhibiting microbes. Abnormal AMP production, whether insufficient or excessive, can disturb the microbiome equilibrium, contributing to various intestinal diseases. This review delves into the complex interactions between AMPs and the gut microbiota and sheds light on the role of AMPs in governing host-microbiota interactions. We discuss the function and mechanisms of action of AMPs, their regulation by the gut microbiota, microbial evasion strategies, and the consequences of AMP dysregulation in disease. Understanding these complex interactions between AMPs and the gut microbiota is crucial for developing strategies to enhance immune responses and combat infections within the gut microbiota. Ongoing research continues to uncover novel aspects of this intricate relationship, deepening our understanding of the factors shaping gut health. This knowledge has the potential to revolutionize therapeutic interventions, offering enhanced treatments for a wide range of gut-related diseases.

9.
Vascular ; : 17085381241247881, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38630458

RESUMO

OBJECTIVES: Coronary artery disease (CAD) and abdominal aortic aneurysm (AAA) are common arterial pathologies that might occur simultaneously; however, there is not enough evidence about the optimal strategy for patients with concomitant indications of coronary artery bypass grafting (CABG) and open repair of the AAA (AAOR). This study aims to present the outcomes in low and moderate cardiac surgical risk patients who underwent one-stage or two-stage elective CABG and AAOR in a middle-income country. METHODS: An observational, retrospective case series study was conducted. Patients who had low and moderate cardiac surgical risk (less than 8% mortality risk on the STS score) and had the concomitant indication for CABG and AAOR between December 2005 and August 2021 were included. Patients were assigned to one of three strategies: Group 1 underwent one-stage surgery for CABG and AAOR, Group 2 underwent two-stage surgery within the same in-patient stay, and Group 3 underwent two-stage surgery in a new in-patient stay within 6 months. RESULTS: Twenty seven, patients with simultaneous requirements of CABG and AAOR were identified, with a mean age of 69.5 ± 6.1 years and 92.6% were male. The most common comorbidities were hypertension at 77.8% and dyslipidemia at 55.6%. The average mortality risk calculated by the STS score was 2.09% ± 1.53%. In Group 1 (n = 9), 1/9 had in-hospital mortality and no reinterventions were needed. In Group 2 (n = 10), 1/10 had in-hospital mortality, and the most common postoperative complication was acute kidney injury 2/10. Furthermore, 2/10 required a reintervention. In Group 3 (n = 8), no in-hospital mortality was present, however, complications such as sepsis, atrial fibrillation, and acute kidney injury occurred in 2/8 patients each, and 2/8 required a reintervention. CONCLUSION: Patients with CAD and AAA that need a concomitant surgical correction with CABG and an AAOR are uncommon in contemporary practice, given the advances in endovascular therapy. When indicated, one-stage surgery can be performed in patients with low cardiac surgical risk, proper patient selection plays a fundamental role and might be performed in experienced centers. However, two-staged surgeries at the same or different inpatient stay may be considered for asymptomatic AAA with close monitoring during the postoperative period. These findings can hold significance for addressing sociodemographic barriers in low and middle-income countries. More robust and extensive studies are needed to make clear comparisons between the different strategies.

10.
Clin Sci (Lond) ; 138(7): 435-487, 2024 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-38571396

RESUMO

Patients with inflammatory liver diseases, particularly alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease (MAFLD), have higher incidence of infections and mortality rate due to sepsis. The current focus in the development of drugs for MAFLD is the resolution of non-alcoholic steatohepatitis and prevention of progression to cirrhosis. In patients with cirrhosis or alcoholic hepatitis, sepsis is a major cause of death. As the metabolic center and a key immune tissue, liver is the guardian, modifier, and target of sepsis. Septic patients with liver dysfunction have the highest mortality rate compared with other organ dysfunctions. In addition to maintaining metabolic homeostasis, the liver produces and secretes hepatokines and acute phase proteins (APPs) essential in tissue protection, immunomodulation, and coagulation. Inflammatory liver diseases cause profound metabolic disorder and impairment of energy metabolism, liver regeneration, and production/secretion of APPs and hepatokines. Herein, the author reviews the roles of (1) disorders in the metabolism of glucose, fatty acids, ketone bodies, and amino acids as well as the clearance of ammonia and lactate in the pathogenesis of inflammatory liver diseases and sepsis; (2) cytokines/chemokines in inflammatory liver diseases and sepsis; (3) APPs and hepatokines in the protection against tissue injury and infections; and (4) major nuclear receptors/signaling pathways underlying the metabolic disorders and tissue injuries as well as the major drug targets for inflammatory liver diseases and sepsis. Approaches that focus on the liver dysfunction and regeneration will not only treat inflammatory liver diseases but also prevent the development of severe infections and sepsis.


Assuntos
Hepatopatias Alcoólicas , Hepatopatia Gordurosa não Alcoólica , Sepse , Humanos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Cirrose Hepática/metabolismo , Hepatopatias Alcoólicas/metabolismo , Sepse/complicações
11.
Viral Immunol ; 37(3): 149-158, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38573237

RESUMO

Hepatitis B Virus (HBV) is posing as a serious public health threat mainly due to its asymptomatic nature of infection in pregnancy and vertical transmission. Viral sensing toll-like receptors (TLR) and Interleukins (IL) are important molecules in providing an antiviral state. The study aimed to assess the role of TLR7-mediated immune modulation, which might have an impact in the intrauterine transmission of HBV leading to mother to child transmission of the virus. We investigated the expression pattern of TLR7, IL-3, and IL-6 by RT-PCR in the placentas of HBV-infected pregnant women to see their role in the intrauterine transmission of HBV. We further validated the expression of TLR7 in placentas using Immunohistochemistry. Expression analysis by RT-PCR of TLR7 revealed significant downregulation among the Cord blood (CB) HBV DNA positive and negative cases with mean ± standard deviation (SD) of 0.43 ± 0.22 (28) and 1.14 ± 0.57 (44) with p = 0.001. IL-3 and IL-6 expression revealed significant upregulation in the CB HBV DNA-positive cases with p = 0.001. Multinomial logistic regression analysis revealed that TLR7 and IL-3 fold change and mother HBeAg status are important predictors for HBV mother to child transmission. Immunohistochemistry revealed the decreased expression of TLR7 in CB HBV DNA-positive cases. This study reveals that the downregulation of TLR7 in the placenta along with CB HBV DNA-positive status may lead to intrauterine transmission of HBV, which may lead to vertical transmission of HBV.


Assuntos
Hepatite B , Complicações Infecciosas na Gravidez , Feminino , Humanos , Gravidez , DNA Viral , Antígenos E da Hepatite B , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Transmissão Vertical de Doenças Infecciosas , Interleucina-3 , Interleucina-6/genética , Receptor 7 Toll-Like/genética , Recém-Nascido
12.
Life Sci ; 345: 122604, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38580196

RESUMO

AIMS: Intestinal barrier dysfunction is the initial and propagable factor of sepsis in which acute kidney injury (AKI) has been considered as a common life-threatening complication. Our recent study identifies the regulatory role of Pellino1 in tubular death under inflammatory conditions in vitro. The objective of our current study is to explore the impact of Pellino1 on gut-kidney axis during septic AKI and uncover the molecular mechanism (s) underlying this process. MATERIALS AND METHODS: Immunohistochemistry (IHC) was conducted to evaluate Pellino1 and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels in renal biopsies from critically ill patients with a clinical diagnosis of sepsis. Functional and mechanistic studies were characterized in septic models of the Peli-knockout (Peli1-/-) mice by histopathological staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunofluorescence, biochemical detection, CRISPR/Cas9-mediated gene editing and intestinal organoid. KEY FINDINGS: Pellino1, together with NLRP3, are highly expressed in renal biopsies from critically ill patients diagnosed with sepsis and kidney tissues of septic mice. The Peli1-/- mice with sepsis become less prone to develop AKI and have markedly compromised NLRP3 activation in kidney. Loss of Peli1 endows septic mice refractory to intestinal inflammation, barrier permeability and enterocyte apoptosis that requires stimulator of interferons genes (STING) pathway. Administration of STING agonist DMXAA deteriorates AKI and mortality of septic Peli1-/- mice in the presence of kidney-specific NLRP3 reconstitution. SIGNIFICANCE: Our studies suggest that Pellino1 has a principal role in orchestrating gut homeostasis towards renal pathophysiology, thus providing a potential therapeutic target for septic AKI.


Assuntos
Injúria Renal Aguda , Sepse , Humanos , Animais , Camundongos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estado Terminal , Rim/metabolismo , Injúria Renal Aguda/metabolismo , Sepse/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
13.
Front Immunol ; 15: 1379967, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38585264

RESUMO

Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.


Assuntos
Heme Oxigenase (Desciclizante) , Heme , Humanos , Heme Oxigenase (Desciclizante)/metabolismo , Heme/metabolismo , Relevância Clínica , Macrófagos/metabolismo , Ferro/metabolismo , Inflamação/metabolismo
14.
Proc Natl Acad Sci U S A ; 121(17): e2402226121, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38621137

RESUMO

Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr748 as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho-deficient threonine748-to-alanine (T748A) mutant Stat1 are resistant to LPS-induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of Stat1 following LPS-induced lethality, indicating that the Thr748 phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic IκB kinase-mediated Thr748 phosphorylation of Stat1, which promotes macrophage inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr748 phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.


Assuntos
Lipopolissacarídeos , Transdução de Sinais , Animais , Camundongos , Fosforilação , Lipopolissacarídeos/farmacologia , Interferons/metabolismo , Inflamação/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo
15.
Zhongguo Zhong Yao Za Zhi ; 49(4): 884-893, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621895

RESUMO

Sepsis is a systemic inflammatory response syndrome caused by infection, with high morbidity and mortality. Sepsis-induced liver injury(SILI) is one of the manifestations of sepsis-induced multiple organ syndrome. At present, there is no recommended pharmacological intervention for the treatment of SILI. traditional Chinese medicine(TCM), based on the holism and dialectical treatment concept, shows the therapeutic characteristics of multi-target and multi-pathway and can comprehensively prevent and treat SILI by interfering with inflammatory factors, inflammatory signaling pathways, and anti-oxidative stress and inhibiting apoptosis. This article reviewed the experimental studies on the treatment of SILI with TCM to clarify its pathogenic mechanism and therapeutic characteristics, so as to provide more ideas and directions for the development or preparation of new drugs.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Sepse , Humanos , Medicina Tradicional Chinesa , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Sepse/complicações , Sepse/tratamento farmacológico , Apoptose , Transdução de Sinais , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia
16.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1388-1396, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621987

RESUMO

This study aims to systematically review the clinical features and outcome indicators in randomized controlled trial(RCT) of traditional Chinese medicine(TCM) intervention in septic kidney injury and provide a reference for optimizing clinical study design and building the core outcome set(COS) of TCM treatment of septic kidney injury. Computer searches were conducted on PubMed, Cochrane Library, EMbase, Web of Science, CNKI, Wanfang, VIP, and SinoMed to find published RCT of TCM intervention in septic kidney injury in the past five years, extract the basic characteristics, intervention measures, outcome indicators, and other data of included studies, and conduct descriptive analysis. 53 RCTs were included, and the sample size was mostly concentrated in 60-80 cases, with abdominal infection being the most common(15 articles, 83.3%) and the TCM syndrome of blood stasis being the most frequent(9 articles, 50.0%). The frequency of intervention methods from high to low were TCM decoction(28 articles, 52.8%), Chinese patent medicine(22 articles, 41.5%), and combined TCM therapy(3 articles, 7.5%); the intervention time of the trial was more than 7 d(34 articles, 69.4%). The risk of bias in included studies was unclear. A total of 84 outcome indicators were involved, which were divided into 9 fields, including 63 physical and chemical tests(305 times, 72.2%), 4 kinds of disease degree(48 times, 11.6%), 4 kinds of clinical effective rate(15 times, 3.6%), 1 kind of quality of life(1 time, 0.2%), 2 kinds of economic evaluation(14 times, 3.3%), 1 kind of TCM disease(9 times, 2.1%), 2 kinds of long-term prognosis(16 times, 3.8%), 2 kinds of safety events(6 times, 1.4%), and 5 other indicators(8 times, 0.7%). The cumulative frequency was 422 times, among which the outcome indicators with higher frequency were inflammatory factors(42 articles, 79.2%) and markers of renal function and kidney injury(40 articles, 75.5%). Only 1(1.9%) of the included articles mentioned primary and secondary outcome indicators, and 6 articles(11.3%) mentioned safety events, 13 articles(24.5%) mentioned economic assessment. The RCT quality of TCM intervention in septic renal injury was generally low, and the reference standards for sepsis, kidney injury, and TCM syndrome diagnosis were not uniform. There are some problems in outcome indicators, such as unclear distinction between primary and secondary indicators, neglect of endpoint indicators, lack of application of TCM characteristic indicators, and insufficient attention to safety events and economic assessment. It is suggested that the quality of clinical research methodology should be improved in the future, and the COS should be constructed to provide high-level evidence-based evidence for TCM intervention in septic kidney injury.


Assuntos
Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Humanos , Medicamentos de Ervas Chinesas/uso terapêutico , Qualidade de Vida , Síndrome , Rim
17.
AAPS J ; 26(3): 47, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622374

RESUMO

BACKGROUND: Sepsis-induced acute lung injury (ALI) is one of the serious life-threatening complications of sepsis and is pathologically associated with mitochondrial dysfunction. Ginsenoside Rg1 has good therapeutic effects on ALI. Herein, the pharmacological effects of Rg1 in sepsis-induced ALI were investigated. METHODS: Sepsis-induced ALI models were established by CLP operation and LPS treatment. HE staining was adopted to analyze lung pathological changes. The expression and secretion of cytokines were measured by RT-qPCR and ELISA. Cell viability and apoptosis were assessed by MTT assay, flow cytometry and TUNEL staining. ROS level and mitochondrial membrane potential (MMP) were analyzed using DHE probe and JC-1 staining, respectively. FBXO3 m6A level was assessed using MeRIP assay. The interactions between FBXO3, YTHDF1, and PGC-1α were analyzed by Co-IP or RIP. RESULTS: Rg1 administration ameliorated LPS-induced epithelial cell inflammation, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Mechanically, Rg1 reduced PGC-1α ubiquitination modification level by inhibiting FBXO3 expression m6A-YTHDF1 dependently. As expected, Rg1's mitigative effect on LPS-induced inflammation, apoptosis and mitochondrial dysfunction in lung epithelial cells was abolished by FBXO3 overexpression. Moreover, FBXO3 upregulation eliminated the restoring effect of Rg1 on CLP-induced lung injury in rats. CONCLUSION: Rg1 activated PGC-1α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.


Assuntos
Lesão Pulmonar Aguda , Ginsenosídeos , Doenças Mitocondriais , Sepse , Ratos , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/uso terapêutico , Transdução de Sinais , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/complicações , Inflamação , Sepse/complicações , Sepse/tratamento farmacológico , Doenças Mitocondriais/complicações
18.
Methods Mol Biol ; 2782: 81-88, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38622393

RESUMO

Innate monocytes can be trained or reprogrammed to adopt distinct memory states, such as low-grade inflammation and immune exhaustion, bearing fundamental relevance to the pathogenesis of both acute diseases such as sepsis as well as chronic diseases such as atherosclerosis. Therefore, it is critically important to develop a regimen for generating memory monocytes in vitro in order to better define key monocyte memory states with diverse potentials for proliferation, differentiation, and activation, as well as underlying mechanisms. Here, we describe an efficient in vitro system to propagate a large number of highly purified murine memory monocytes through sustaining bone marrow-derived monocytes with macrophage colony-stimulating factor (M-CSF, 10 ng/mL)-containing medium, together with other polarization agents such as lipopolysaccharide (LPS) for a 5-day period. This method can yield high-purity monocytes, capable of exhibiting dynamic memory behaviors upon training with various polarizing agents.


Assuntos
Fator Estimulador de Colônias de Macrófagos , Monócitos , Animais , Camundongos , Células da Medula Óssea , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Medula Óssea , Lipopolissacarídeos/farmacologia , Diferenciação Celular
19.
BMC Pregnancy Childbirth ; 24(1): 278, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622544

RESUMO

BACKGROUND: In 2015, Togo introduced the "test-and-treat" strategy for the prevention of mother-to-child transmission (PMTCT) of HIV. Pediatric HIV infection remains a public health problem in Togo, with a mother-to-child transmission (MTCT) rate of 3.6% in 2020. This study aimed to estimate cases of HIV seroconversion during pregnancy and to identify pregnant women at high risk of transmitting HIV to their children in Lomé, Togo. METHODS: A descriptive cross-sectional study was carried out from 18 March to 22 May 2022 among women who had given birth in five maternity units providing PMTCT services in Lomé. Umbilical cord blood samples were taken from the maternal side by midwives after delivery. HIV serology was performed in the laboratory using the Alere™ HIV Combo SET and First Response HIV 1-2. Card Test version 2.0. A sample was considered positive if both tests were positive. The HIV-1 viral load in HIV-1-positive samples was measured using Cobas/Roche 4800 equipment. Information on the women was extracted from maternal antenatal records and antenatal consultation registers. RESULTS: A total of 3148 umbilical cord blood samples (median maternal age: 28 years (interquartile range [24-32]) were collected. Among them, 99.3% (3145/3148) had presented for at least one antenatal clinic visit before giving birth, and 78.7% (2456/3122) had presented for at least four visits. One hundred and twenty-one (121) cord samples were HIV-1 positive, representing a seroprevalence of 3.8% (95% CI = [3.2-4.6]). Among them, 67.8% (82/121) were known HIV-positive before the current pregnancy, 29.7 (36/121) were diagnosed as HIV-positive at the antenatal visits and 2.5% (3/121) were diagnosed as HIV-positive in the delivery room. Of the HIV-positive women, 85.9% (104/121) were on ARV treatment before delivery. The viral load was < 1000 copies/ml in 97.5% (118/121) cases. CONCLUSION: This study explored the virologic and epidemiological aspects of HIV among pregnant women in Togo. The results show significant viral suppression at delivery in women ART. Surveillance based on umbilical cord blood specimen screening is an interesting approach for monitoring the effectiveness of PMTCT programmes.


Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Complicações Infecciosas na Gravidez , Gravidez , Feminino , Humanos , Adulto , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/prevenção & controle , Gestantes , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Togo/epidemiologia , Estudos Transversais , Estudos Soroepidemiológicos
20.
BMC Womens Health ; 24(1): 243, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622699

RESUMO

INTRODUCTION: Infectious affections are the most frequent post-operative complications, the rate have been reducing due to the administration of perioperative antibiotics and they are rarely serious. They are usually associated to pelvic collections, fistulas, urinary tract stenosis and, exceptionally, necrotizing fasciitis (FN) and pelvic organ necrosis. There is no well-codified treatment. CASE PRESENTATION: A 42-year-old female patient, was referred to our department for a stage IIIC2 adenocarcinoma of the uterine cervix. Two months after surgery, the patient presented with fever. Abdominal CT scan revealed a recto-vaginal fistula. The patient underwent a surgical evacuation of the collection and a bypass colostomy. Post-operative period was marked by the occurrence of an extensive necrosis to pelvic organs and medial left leg's thigh compartments muscles. She also presented a thrombosis of the left external iliac vein and artery. Given the septic conditions, a revascularization procedure was not feasible. A bilateral ureterostomy was required and a ligature of the left external iliac vessels. Then she received palliative treatment.she died one month after surgery because of multivisceral failure due to sepsis. CONCLUSION: Necrotizing fasciitis is extremely rare and serious condition, the diagnosis is clinical and radiological, CT scan is helpful for the. There are predisposing factors such as diabetes, neoadjuvant radiotherapy or chemotherapy. The prognosis can be improved with rapid management and appropriate medical and surgical excisions of necrotic tissue, and antibiotic therapy adapted to the suspected germs, essentially anaerobic ones.


Assuntos
Parede Abdominal , Fasciite Necrosante , Feminino , Humanos , Adulto , Fasciite Necrosante/cirurgia , Fasciite Necrosante/diagnóstico , Parede Abdominal/cirurgia , Prognóstico , Complicações Pós-Operatórias , Necrose/complicações
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