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1.
Arch Endocrinol Metab ; 68: e230146, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709151

RESUMO

Objective: After initial treatment, up to 30% of patients with papillary thyroid cancer (PTC) have incomplete response, mainly cervical lymph node (LN) disease. Previous studies have suggested that active surveillance (AS) is a possible option for these patients. Our aim was to report the results of AS in patients with PTC and cervical LN disease. Materials and methods: In this retrospective observational study, we included adult patients treated and followed for PTC, who presented with cervical LN disease and were managed with AS. Growth was defined as an increase ≥ 3mm in either diameter. Results: We included 32 patients: 27 (84.4%) women, age of 39 ± 14 years, all initially treated with total thyroidectomy, and 22 (69%) with therapeutic neck dissection. Cervical LN disease was diagnosed 1 year (0.3-12.6) after initial management, with a diameter of 9.0 mm (6.0-19.0). After a median AS of 4.3 years (0.6-14.1), 4 (12.5%) patients had LNgrowth: 2 (50%) of whom were surgically removed, 1 (25%) was effectively treated with radiotherapy, and 1 (25%) had a scheduled surgery. Tg increase was the only predictive factor of LN growth evaluated as both the delta Tg (p < 0.0366) and percentage of Tg change (p < 0.0140). None of the included patients died, had local complications due to LN growth or salvage therapy, or developed distant metastases during follow-up. Conclusion: In selected patients with PTC and suspicious cervical LNs diagnosed after initial treatment, AS is a feasible and safe strategy as it allows effective identification and treatment of the minority of patients who progress.


Assuntos
Linfonodos , Metástase Linfática , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Tireoidectomia , Conduta Expectante , Humanos , Feminino , Masculino , Adulto , Estudos Retrospectivos , Tireoidectomia/métodos , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/patologia , Linfonodos/patologia , Estudos de Viabilidade , Pescoço/cirurgia , Carcinoma Papilar/cirurgia , Carcinoma Papilar/patologia , Esvaziamento Cervical/métodos , Adulto Jovem
2.
Pediatr Emerg Care ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38718384

RESUMO

OBJECTIVE: Ketamine is a safe and widely used sedative and analgesic in children. The purpose of this study is to evaluate the response to sedoanalgesia for painful procedures in the pediatric emergency department. METHODS: A retrospective study was conducted in children younger than 16 years who underwent painful procedures with intravenous/intranasal ketamine between January 2016 and December 2022. We collected demographic variables, effectiveness, route of administration, indication, dose, sedation strategy, duration of procedure, and associated adverse effects. RESULTS: A total of 671 ketamine sedation procedures (411 males/260 females) were included, with a mean age of 7.2 years. Closed reduction was the most common painful procedure (53.8%), followed by burn healing (24.6%). Ketamine was administered intravenously in 93.4% of procedures and intranasally in 6.6%. The result of sedoanalgesia was satisfactory in 84.9% and unsatisfactory in 15.1%. The percentage of cases with unsatisfactory analgesia was higher with intranasal administration (36.4%; P < 0.001). In the intravenous group, the percentage of cases with unsatisfactory effectiveness (28.7%) was higher for patients younger than 2 years of age (P < 0.001). Arthrocentesis procedures were associated with the highest percentage of unsatisfactory sedoanalgesia failures among patients receiving intravenous ketamine (39.3%; P < 0.001). Intranasal ketamine patients who received a dose between 3.6 and 4 mg/kg had a significantly higher percentage of unsatisfactory sedoanalgesia (66.7%; P = 0.048). Patients receiving intravenous ketamine had significantly higher rates of unsatisfactory sedoanalgesia when the initial dose interval was 1.6 to 2 mg/kg (11.8%; P = 0.002) and when the final total dose was also 1.6 to 2 mg/kg (17.6%; P = 0.002). CONCLUSIONS: This study concludes that intravenous/intranasal ketamine can provide safe and successful analgesia in pediatric patients in the ED. At intravenous doses of 1-1.5 mg/kg, good effectiveness was achieved in almost 90% of cases. Arthrocentesis had the highest percentage of unsatisfactory results. Repeat dosing should be considered for procedures longer than 20 minutes.

3.
Molecules ; 29(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731446

RESUMO

Ilama leaves are an important source of secondary metabolites with promising anticancer properties. Cancer is a disease that affects a great number of people worldwide. This work aimed to investigate the in vivo, in vitro and in silico anticancer properties of three acyclic terpenoids (geranylgeraniol, phytol and farnesyl acetate) isolated from petroleum ether extract of ilama leaves. Their cytotoxic activity against U-937 cells was assessed using flow cytometry to determine the type of cell death and production of reactive oxygen species (ROS). Also, a morphological analysis of the lymph nodes and a molecular docking study using three proteins related with cancer as targets, namely, Bcl-2, Mcl-1 and VEGFR-2, were performed. The flow cytometry and histomorphological analysis revealed that geranylgeraniol, phytol and farnesyl acetate induced the death of U-937 cells by late apoptosis and necrosis. Geranylgeraniol and phytol induced a significant increase in ROS production. The molecular docking studies showed that geranylgeraniol had more affinity for Bcl-2 and VEGFR-2. In the case of farnesyl acetate, it showed the best affinity for Mcl-1. This study provides information that supports the anticancer potential of geranylgeraniol, phytol and farnesyl acetate as compounds for the treatment of cancer, particularly with the potential to treat non-Hodgkin's lymphoma.


Assuntos
Simulação de Acoplamento Molecular , Extratos Vegetais , Folhas de Planta , Plantas Medicinais , Espécies Reativas de Oxigênio , Humanos , Folhas de Planta/química , Plantas Medicinais/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , México , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Animais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Simulação por Computador , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células U937
4.
World Neurosurg ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38796143

RESUMO

BACKGROUND: Pediatric intracranial arteriovenous malformation (AVM) patients are commonly admitted to the emergency room (ER). Increasing patient utilization of the ER has been associated with healthcare disparities and a trend of decreased efficiency. Correspondingly, the aim of this study was to evaluate the trends of pediatric AVM ER admissions over recent years and identify factors associated with health care resource utilization and outcomes. METHODS: The 2016-2019 National Inpatient Sample (NIS) was queried for patients under the age of 18 admitted with AVM. Cases of admission through the ER were identified. Demographic and severity factors associated with ER admission were explored using comparative and regression statistics. RESULTS: Of 3,875 pediatric patients with AVM admitted between 2016-2019, 1,280 (33.0%) were admitted via the ER. Patients admitted via the ER were more likely to be in the lowest median income category (p < 0.001), on Medicaid insurance (p = 0.008), or in the South (p < 0.001) than patients admitted otherwise. There was increased severity and increased rates of intracranial hemorrhage (ICH) in patients admitted via the ER (p < 0.001). Finally, there were increasing trends in ER admission and ICH throughout the years. CONCLUSION: ER admission of pediatric AVM patients with ICH is increasing and is associated with a distinct socioeconomic profile and increased healthcare resource utilization. These findings may reflect decreased access to more advanced diagnostic modalities, primary care, and other important resources. Identifying populations with barriers to care is likely an important component to policy aimed at decreasing the risk of severe disease presentation.

5.
Mol Biol Rep ; 51(1): 681, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38796603

RESUMO

BACKGROUND: Silver nanoparticles (AgNPs) have been used in plant tissue culture as growth stimulants, promoting bud initiation, germination, and rooting. In prior studies, AgNPs were synthesized and characterized by green synthesis using extracts from Beta vulgaris var. cicla (BvAgNP), and their functionality as seed disinfectant and antimicrobial was verified. In this study, we evaluated the effect of BvAgNP on the growth and development of Mammillaria bombycina and Selenicereus undatus in vitro, as well as the expression of glyoxalase genes. METHODS: Explants from M. bombycina and S. undatus in vitro were treated with 25, 50, and 100 mg/L of BvAgNP. After 90 days, morphological characteristics were evaluated, and the expression of glyoxalase genes was analyzed by qPCR. RESULTS: All treatments inhibited rooting for M. bombycina and no bud initiation was observed. S. undatus, showed a maximum response in rooting and bud generation at 25 mg/L of BvAgNP. Scanning electron microscopy (SEM) results exhibited a higher number of vacuoles in stem cells treated with BvAgNP compared to the control for both species. Expression of glyoxalase genes in M. bombycina increased in all treatments, whereas it decreased for S. undatus, however, increasing in roots. CONCLUSIONS: This study presents the effects of BvAgNP on the growth and development of M. bombycina and S. undatus, with the aim of proposing treatments that promote in vitro rooting and bud initiation.


Assuntos
Lactoilglutationa Liase , Nanopartículas Metálicas , Prata , Nanopartículas Metálicas/química , Prata/farmacologia , Lactoilglutationa Liase/genética , Lactoilglutationa Liase/metabolismo , Beta vulgaris/crescimento & desenvolvimento , Beta vulgaris/efeitos dos fármacos , Beta vulgaris/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tioléster Hidrolases , Cactaceae
6.
Biomolecules ; 14(5)2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38786005

RESUMO

Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.


Assuntos
Fibroblastos , Glucosídeos , Mitocôndrias , Doenças Mitocondriais , Niacinamida , Estilbenos , Resposta a Proteínas não Dobradas , Humanos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Estilbenos/farmacologia , Glucosídeos/farmacologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Niacinamida/farmacologia , Mutação , Fenótipo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Neurônios/metabolismo , Neurônios/efeitos dos fármacos
7.
Ther Adv Respir Dis ; 18: 17534666241249841, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38817020

RESUMO

BACKGROUND: Ukraine remains a high World Health Organization priority country for drug-resistant tuberculosis (TB). Rifampicin-resistant TB (RR-TB) has a more protracted, more complicated, and more expensive treatment. In 2021, Ukraine reported 4025 RR-TB cases - 5.4 times more (751) than all 30 European Union/ European Economic Area countries together. OBJECTIVES: The objective of the study was to determine the diagnostic accuracy of line probe assay (LPA), AID Autoimmun Diagnostika GmbH, for detecting resistance to anti-TB drugs and its clinical application for selecting treatment regimens. DESIGN: A prospective observational cohort study. METHODS: From May 2019 to June 2020, we consecutively enrolled patients with active TB hospitalized at the Regional Phthisiopulmonology Center (Vinnytsia, Ukraine), aged between 18 and 82 years. The LPA was performed in the Genetic Research Laboratory at National Pirogov Memorial Medical University, Vinnytsia, Ukraine. RESULTS: A total of 84 clinical specimens and 97 culture isolates from 126 TB patients were tested during the study. Accuracy (95% confidence interval) of LPA for clinical samples in comparison with phenotypic drug susceptibility test (DST) was 80.1 (68.5-89.0) for isoniazid (H), 74.7 (62.4-84.6) for rifampicin (R), 74.4 (62.5-84.1) for ethambutol, 71.4 (41.9-91.6) for streptomycin, 84.6 (62.4-96.5) for prothionamide/ethionamide, and 84.6 (73.6-92.3) for levofloxacin (Lfx), respectively. We found a significantly higher sensitivity of LPA for H, R, and Lfx for the culture isolates compared to clinical specimens (p < 0.05). LPA detected different mutations in 6 out of 17 (35.5%) patients susceptible to R by Xpert. A shorter treatment regimen with an injectable agent demonstrated a low suitability rate of 5% (8/156) in a cohort of RR-TB patients from Ukraine. CONCLUSION: Initial LPA testing accurately identifies resistance to anti-TB drugs and facilitates the selection of an appropriate treatment regimen, minimizing exposure to empirical therapy.


Study about the impact of rapid resistance detection on the treatment of patients with tuberculosis in Ukraine written by healthcare and biomedical professionals to better understand how we can improve the results of treatment and to prevent spreading of resistant bacteriaWhy was the study done? Ukraine has over 4000 patients with tuberculosis (TB) resistant to at least one drug (rifampicin) - five times that of all 30 European Union/European Economic Area countries combined. Unfortunately, only about 60% of such patients have been successfully treated in 2019. At that time, the majority of people suffering from tuberculosis in Ukraine, after checking resistance to rifampicin, initially received standard combinations of the first-line or second-line anti-TB medicines before the result of traditionally used tests (usually few weeks later) became available to individualize the treatment. Alternatively, the sputum could be transported to some overloaded reference laboratories located hundreds of km away from the treatment places.What did the researchers do? The INNOVA4TB team implemented rapid diagnostics of drug resistance in routine practice, guiding key antibiotics use in TB patients. A total of 181 samples from 126 individuals were tested during 2019-2020.What did the researchers find? This new diagnostic technology accurately detected resistance to 9 anti-TB drugs in sputum samples. It could be helpful to select appropriate TB treatment regimens, reducing time for decision from 1 month up to 2 days. Recommended at the study time 9-month shorter standardized treatment regimen with injectable agent was suitable only for 5% of patients for whom it was indicated in Vinnytsia region of Ukraine.What do the findings mean? The study has demonstrated successful implementation of the new molecular diagnostic technology from scratch in a country with restricted resources and limited TB laboratory capacity. This test can facilitate optimal distribution of available wards among patients with different profiles of resistance and correct choice between treatment options.


Assuntos
Mycobacterium tuberculosis , Rifampina , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Estudos Prospectivos , Adulto , Ucrânia , Rifampina/farmacologia , Masculino , Pessoa de Meia-Idade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Feminino , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Adulto Jovem , Idoso , Adolescente , Antituberculosos/farmacologia , Antituberculosos/administração & dosagem , Testes de Sensibilidade Microbiana , Idoso de 80 Anos ou mais , Antibióticos Antituberculose/uso terapêutico , Antibióticos Antituberculose/farmacologia , Valor Preditivo dos Testes , Medicina de Precisão , Reprodutibilidade dos Testes
8.
World Neurosurg ; 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38677643

RESUMO

BACKGROUND: High volume (HV) has been associated with improved outcomes in various neurosurgical procedures. The objective of this study was to explore the regional distribution of HV spine centers for cervical spine fusion and compare characteristics and outcomes for patients treated at HV centers versus lower volume centers. METHODS: The National Inpatient Sample database 2016-2020 was queried for patients undergoing cervical spine fusion for degenerative pathology. HV was defined as case-loads greater than 2 standard deviations above the mean. Patient characteristics, procedures, and outcomes were compared. RESULTS: Of 3895 hospitals performing cervical spine fusion for degenerative pathology, 28 (0.76%) were HV. The Mid-Atlantic and West South Central regions had the highest number of HV hospitals. HV hospitals were more likely to perform open anterior fusion surgeries (P < 0.01). Patients treated at HV hospitals were less likely to have severe symptomatology or comorbidities (P < 0.01 for all). When controlling for severity and demographics on multivariate analysis, HV centers had higher odds of length of stay ≤1 day, favorable discharge, and decreased total charges. CONCLUSIONS: Patients who underwent cervical spine fusion surgery at HV hospitals were less complex and had increased odds of length of stay ≤1, favorable discharge, and total charges in the lower 25th percentile than patients treated at non-HV hospitals. Physician comfort, patient selection, institutional infrastructure, and geographic characteristics likely play a role.

9.
Chemotherapy ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38498996

RESUMO

Introduction Casiopeina III-ia (CasIII-ia) is a mixed chelate copper (II) compound capable of interacting with free radicals generated in the respiratory chain through redox reactions, producing toxic reactive oxygen species (ROS) that compromise the viability of cancer cells, bacteria and protozoa. Due to its remarkable effect on protozoa, this study evaluated the effect of CasIII-ia on Leishmania mexicana (L. mexicana) amastigotes and its potential use as a treatment for cutaneous leishmaniasis in the murine model. Methods We analyzed the leishmanicidal effect of CasIII-ia on L. mexicana amastigotes, and on their survival in bone marrow-derived macrophages. Furthermore, we evaluated the production of ROS in treated parasites and the efficacy of CasIII-ia in the treatment of mice infected with L. mexicana. Results Our results show that CasIII-ia reduces parasite viability in a dose-dependent manner that correlates with increased ROS production. A decrease in the size of footpad lesions and in parasite loads was observed in infected mice treated with the intraperitoneal administration of CasIII-ia. Conclusions We propose CasIII-ia as a potential drug for the treatment of cutaneous leishmaniasis.

10.
Front Neurol ; 15: 1292296, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38426179

RESUMO

Background: Patient disability, relapse rate, and age are used for family planning in multiple sclerosis (MS). However, the need for more accurate biomarkers is widely recognized. We aimed to explore the influence of age on neurofilament light chain (sNfL), which reflects acute inflammation; glial fibrillary acidic protein (GFAP), associated with disability progression independent of relapses; and anti-Müllerian hormone (AMH), reflecting ovarian reserve, to provide a tailored family planning strategy. Methods: This case-control study included 95 MS patients and 61 healthy control women (HCW). sNfL and GFAP levels were measured using a sensitive single-molecule array assay. AMH levels were measured by the automated Elecsys® Anti-Müllerian Hormone Assay. Results: We observed no significant differences in AMH values between MS patients and the control group within any of the age-matched categories. Age exhibited a negative correlation with AMH values in both groups, as expected. Nevertheless, our findings suggest a slight tendency toward reduced ovarian reserve in MS patients (rho MS patients = -0.67, p < 0.0001; rho HCW = -0.43, p = 0.0006). Interestingly, among the 76 MS participants under 40 years old, we identified ten individuals (13.1%) with AMH levels below 0.7 ng/ml, indicative of a low ovarian reserve, and an additional six individuals (7.8%) with AMH levels between 0.7 ng/ml and 0.9 ng/ml, suggesting a potential risk of premature ovarian failure. Conversely, sNfL and GFAP levels in the MS group exhibited high variability but showed no significant association with age intervals. Conclusion: We found no significant differences in AMH, sNfL or GFAP values between MS patients and the control group within any of the age-matched categories. The assessment of AMH, sNFL and GFAP levels at MS onset facilitates personalized therapeutic and family planning strategies for childbearing-age women.

11.
Front Neurol ; 15: 1360032, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38469589

RESUMO

Introduction: Spasticity is a common symptom in multiple sclerosis (MS) and it is often associated with other symptoms such as spasms/cramps and pain. The concept of Spasticity-Plus syndrome takes into account that spasticity is accompanied by one or more symptoms (spasms/cramps, pain, bladder dysfunction, sleep disorders, fatigue and/or tremor). As these symptoms share a common cannabinoid control, therapy acting on cannabinoid receptors may be useful. The main study objectives were to determine the number of MS patients who met Spasticity-Plus syndrome criteria and to identify the most common symptoms. Methods: Clinical records of MS patients treated with nabiximols in a tertiary hospital from 2002 to 2022 were reviewed retrospectively. Results: Of the 73 patients included in the study, 53.4% were women, and most had secondary progressive MS (64.4%). All patients met the criteria for Spasticity-Plus syndrome: 100% had spasticity and at least another symptom. Pain was the second most common symptom (91.8%), followed by spasms/cramps (79.4%), and fatigue (76.7%). Sleep disturbances (p < 0.0001) and tremor (p < 0.027) were more frequent in patients with relapsing-remitting MS than in patients with progressive MS. No statistically significant differences were found for spasticity, pain, spasms/cramps, and fatigue between MS phenotypes. Regarding symptoms clusters, 94.4% of the patients had three or more symptoms. Spasticity was more frequently associated with pain (91.8%) and spasms/cramps (79.4%). Conclusion: Spasticity-Plus syndrome was present in all the study population of patients with different MS phenotypes, and treated with nabiximols.

12.
PLoS One ; 19(2): e0296887, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38359037

RESUMO

Eosinophils are mainly associated with parasitic infections and allergic manifestations. They produce many biologically active substances that contribute to the destruction of pathogens through the degranulation of microbicidal components and inflammatory tissue effects. In leishmaniasis, eosinophils have been found within inflammatory infiltrate with protective immunity against the parasite. We analyzed the responses of eosinophils from patients with localized (LCL) and diffuse (DCL) cutaneous leishmaniasis, as well as from healthy subjects, when exposed to Leishmania mexicana. All DCL patients exhibited blood eosinophilia, along with elevated eosinophil counts in non-ulcerated nodules. In contrast, only LCL patients with prolonged disease progression showed eosinophils in their blood and cutaneous ulcers. Eosinophils from DCL patients secreted significantly higher levels of IL-6, IL-8, and IL-13, compared to eosinophils from LCL patients. Additionally, DCL patients displayed higher serum levels of anti-Leishmania IgG antibodies. We also demonstrated that eosinophils from both LCL and DCL patients responded to L. mexicana promastigotes with a robust oxidative burst, which was equally intense in both patient groups and significantly higher than in healthy subjects. Coincubation of eosinophils (from donors with eosinophilia) with L. mexicana promastigotes in vitro revealed various mechanisms of parasite damage associated with different patterns of granule exocytosis: 1) localized degranulation on the parasite surface, 2) the release of cytoplasmic membrane-bound "degranulation sacs" containing granules, 3) release of eosinophil extracellular traps containing DNA and granules with major basic protein. In conclusion, eosinophils damage L. mexicana parasites through the release of granules via diverse mechanisms. However, despite DCL patients having abundant eosinophils in their blood and tissues, their apparent inability to provide protection may be linked to the release of cytokines and chemokines that promote a Th2 immune response and disease progression in these patients.


Assuntos
Eosinofilia , Leishmania mexicana , Leishmaniose Cutânea , Leishmaniose Tegumentar Difusa , Parasitos , Animais , Humanos , Eosinófilos , Progressão da Doença
13.
ERJ Open Res ; 10(1)2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38410700

RESUMO

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

14.
CNS Drugs ; 38(3): 231-238, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38418770

RESUMO

BACKGROUND: Alemtuzumab is a high-efficacy treatment approved for relapsing-remitting multiple sclerosis (RRMS). Although clinical trials and observational studies are consistent in showing its efficacy and manageable safety profile, further studies under clinical practice conditions are needed to further support its clinical use. OBJECTIVE: The aim of this observational retrospective study was to evaluate the effectiveness and safety of alemtuzumab to add to the current real-world evidence on the drug. METHODS: A cohort of 115 adult patients with RRMS treated with alemtuzumab between 2014 and 2020 was retrospectively followed up in five centers in Spain. Analysis included annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW), 6-month confirmed disability improvement (CDI), radiological activity, no evidence of disease activity (NEDA-3), and safety signals. Given the different follow-up periods among participants, ARR was calculated using the person-years method. CDI was defined as a ≥ 1.0-point decrease in Expanded Disability Status Scale (EDSS) score assessed in patients with a baseline EDSS score ≥ 2.0 confirmed 6 months apart. CDW was defined as a ≥ 1.0-point increase in EDSS score assessed in patients with a baseline EDSS score ≥ 1.0 (≥ 1.5 if baseline EDSS = 0), confirmed 6 months apart. RESULTS: ARR decreased from 1.9 (95% confidence interval 1.60-2.33) in the year prior to alemtuzumab initiation to 0.28 (0.17-0.37) after 1 year of treatment (87% reduction), and to 0.22 (0.13-0.35) after the second year. Over the entire follow-up period, ARR was 0.24 (0.18-0.30). At year 1, 75% of patients showed no signs of magnetic resonance imaging (MRI) activity and 70% at year 5. One percent of patients experienced 6-month CDW at year 1, 2.6% at year 2, 7.4% at year 3, and no patients over years 4 and 5. A total of 7.7% of patients achieved 6-month CDI in year 1, 3.6% in year 2, and maintained it at years 3 and 4. Most patients achieved annual NEDA-3: year 1, 72%; year 2, 79%; year 3, 80%; year 4, 89%; year 5, 75%. Infusion-related reactions were observed in 95% of patients and infections in 74%. Thyroid disorders occurred in 30% of patients, and only three patients developed immune thrombocytopenia. No cases of progressive multifocal leukoencephalopathy were reported. CONCLUSIONS: This study shows that alemtuzumab reduced the relapse rate and disability worsening in real-world clinical practice, with many patients achieving and sustaining NEDA-3 over time. The safety profile of alemtuzumab was consistent with previous findings, and no new or unexpected safety signals were observed. As this was an observational and retrospective study, the main limitation of not having all variables comprehensively available for all patients should be considered when interpreting results.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Adulto , Humanos , Alemtuzumab/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Estudos Retrospectivos , Esclerose Múltipla/tratamento farmacológico , Recidiva
15.
Cureus ; 16(1): e51525, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38304662

RESUMO

BACKGROUND: Pediatric non-accidental trauma often necessitates the involvement of protective services. However, the subjectivity and lack of standardization of referral infrastructure may result in some discrepancies between referral patterns and instances of child abuse. METHODS: An institutional retrospective chart review was conducted between 2015 and 2021, in which all cases of patients under the age of 14 who suffered a burn injury and received a child protective service (CPS) consult were reviewed. Baseline demographics and characteristics were defined. Multivariate analysis was utilized to identify predictors of CPS involvement, while the regression analysis was employed to parse associations between burn injuries and CPS involvement. RESULTS: Between July 2015 and December 2021, 340 patients (median age two years, IQR: 1-6 years) under the age of 14 who experienced a burn injury were evaluated. Forty-four (12.9%) of the patients' cases received a CPS referral, of which three (0.9%) resulted in a CPS intervention. The most common mechanism of burn within the cohort was scald (241 patients, 70.9%). The median total body surface area (TBSA) was 3.0% (IQR: 1.0%-6.0%), and 76 (22.4%) suffered a high TBSA (>75th percentile). Caucasian race (p < 0.001) and scald mechanisms (p = 0.014) were associated with higher TBSA. When considering how such injuries translated to CPS referrals, increasing age was found to be associated with a decreased likelihood of CPS involvement. Meanwhile, the Black race (p = 0.027) and increasing area deprivation index (ADI) (p = 0.038) were associated with CPS involvement. Those with CPS involvement experienced a greater length of hospital stay (p = 0.001). Black race and intensive care unit level of care were found to be positive predictors of CPS involvement. In total, three (6.82%) of the 44 cases with CPS involvement were found to be substantiated. The three children who required CPS intervention were discharged to foster care settings. CONCLUSION: Hospitalized pediatric burn injuries must be investigated due to concern of child abuse, yet external factors such as race and socioeconomic status may play a role in the involvement of CPS. Such referrals may not always be substantiated and could lead to further injurious sequelae for children and their families.

16.
Am J Physiol Endocrinol Metab ; 326(4): E428-E442, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38324258

RESUMO

Glucagon rapidly and profoundly stimulates hepatic glucose production (HGP), but for reasons that are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a sixfold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group, glucose remained at basal, whereas in the other, glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) and largely sustained increase in hepatic cAMP over 4 h, a continued elevation in glucose-6-phosphate (G6P), and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis increased rapidly, peaking at 15 min due to activation of the cAMP/PKA pathway, then slowly returned to baseline over the next 3 h in line with allosteric inhibition by glucose and G6P. Glucagon's stimulatory effect on HGP was sustained relative to the hyperglycemic control group due to continued PKA activation. Hepatic gluconeogenic flux did not increase due to the lack of glucagon's effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, as well as downregulation of genes involved in extracellular matrix assembly and development.NEW & NOTEWORTHY Glucagon rapidly stimulates hepatic glucose production, but these effects are transient. This study links the molecular and metabolic flux changes that occur in the liver over time in response to a rise in glucagon, demonstrating the strength of the dog as a translational model to couple findings in small animals and humans. In addition, this study clarifies why the rapid effects of glucagon on liver glycogen metabolism are not sustained.


Assuntos
Glucagon , Insulina , Humanos , Cães , Animais , Glucagon/metabolismo , Insulina/metabolismo , Transcriptoma , Glucose/metabolismo , Fígado/metabolismo , Gluconeogênese/genética , Glicemia/metabolismo
17.
Nat Cancer ; 5(3): 448-462, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38267628

RESUMO

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.


Assuntos
Neoplasias Pancreáticas , Animais , Camundongos , Neoplasias Pancreáticas/metabolismo , Linfócitos T CD8-Positivos/patologia , Tolerância Imunológica , Terapia de Imunossupressão , Senescência Celular , Microambiente Tumoral
18.
Mikrochim Acta ; 191(2): 82, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38191940

RESUMO

A novel approach is presented that combines filtration and the direct immunomagnetic separation of the retained bacteria Legionella in filters, for further electrochemical immunosensing. This strategy allows for the separation and preconcentration of the water-borne pathogen from high-volume samples, up to 1000 mL. The limit of detection of the electrochemical immunosensor resulted in 100 CFU mL-1 and improved up to 0.1 CFU mL-1 when the preconcentration strategy was applied in 1 L of sample (103-fold improvement). Remarkably, the immunosensor achieves the limit of detection in less than 2.5 h and simplified the analytical procedure. This represents the lowest concentration reported to date for electrochemical immunosensing of Legionella cells without the need for pre-enrichment or DNA amplification. Furthermore, the study successfully demonstrates the extraction of bacteria retained on different filtering materials using immunomagnetic separation, highlighting the high efficiency of the magnetic particles to pull out the bacteria directly from solid materials. This promising feature expands the applicability of the method beyond water systems for detecting bacteria retained in air filters of air conditioning units by directly performing the immunomagnetic separation in the filters.


Assuntos
Técnicas Biossensoriais , Legionella , Separação Imunomagnética , Imunoensaio , Bactérias , Água
19.
Sci Rep ; 14(1): 1137, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38212416

RESUMO

The study of specific T-cell responses against SARS-CoV-2 is important for understanding long-term immunity and infection management. The aim of this study was to assess the dual IFN-γ and IL-2 detection, using a SARS-CoV-2 specific fluorescence ELISPOT, in patients undergoing acute disease, during convalescence, and after vaccination. We also evaluated humoral response and compared with T-cells with the aim of correlating both types of responses, and increase the number of specific response detection. Blood samples were drawn from acute COVID-19 patients and convalescent individuals classified according to disease severity; and from unvaccinated and vaccinated uninfected individuals. IgGs against Spike and nucleocapsid, IgMs against nucleocapsid, and neutralizing antibodies were also analyzed. Our results show that IFN-γ in combination with IL-2 increases response detection in acute and convalescent individuals (p = 0.023). In addition, IFN-γ detection can be a useful biomarker for monitoring severe acute patients, as our results indicate that those individuals with a poor outcome have lower levels of this cytokine. In some cases, the lack of cellular immunity is compensated by antibodies, confirming the role of both types of immune responses in infection, and confirming that their dual detection can increase the number of specific response detections. In summary, IFN-γ/IL-2 dual detection is promising for characterizing and assessing the immunization status, and helping in the patient management.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Interleucina-2 , Imunidade Celular , Anticorpos Neutralizantes , Anticorpos Antivirais , Imunidade Humoral
20.
Heliyon ; 10(1): e23969, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38259962

RESUMO

Surface treatments help to protect the built heritage against damage (environmental, accidental, etc.), reducing repair and restitution costs and increasing the useful life of building materials. The use of nanomaterials is currently the most important field of research in surface treatment technology for the preservation of building materials and, more specifically, to improve their durability and prevent their deterioration, extending their useful life. This paper studies the influence of a graphene oxide (GO) suspension as a surface treatment on the properties of concrete. The results indicate that, at best, surface treatment with GO can decrease both the water absorption and capillary absorption of concrete by about 15 %. The increase in the amount of GO deposited as a surface treatment leads to a further reduction in concrete water absorption. It is shown that, at best, GO coating also reduces water penetration at low and high pressures by approximately 20 % and 60 %, respectively. In addition, scanning electron microscopy analysis shows that GO surface treatment facilitates the hydration process and densifies the concrete microstructure. A simple aqueous suspension of GO is revealed as a tool with a high potential to protect concrete surfaces in a fast and cost-effective way, thanks to the easy application by spraying and the small amount of material needed to obtain great results.

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