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1.
Acta Neuropathol ; 147(1): 52, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467937

RESUMO

Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Dopa Descarboxilase/genética , Proteômica , Biomarcadores/líquido cefalorraquidiano , Plasma/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Descarboxilases de Aminoácido-L-Aromático
2.
BMC Neurol ; 24(1): 92, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468258

RESUMO

BACKGROUND: Human prion diseases (HPDs) are fatal neurodegenerative disorders characterized by abnormal prion proteins (PrPSc). However, the detection of prion seeding activity in patients with high sensitivity remains challenging. Even though real-time quaking-induced conversion (RT-QuIC) assay is suitable for detecting prion seeding activity in a variety of specimens, it shows lower accuracy when whole blood, blood plasma, and blood-contaminated tissue samples are used. In this study, we developed a novel technology for the in vitro amplification of abnormal prion proteins in HPD to the end of enabling their detection with high sensitivity known as the enhanced quaking-induced conversion (eQuIC) assay. METHODS: Three antibodies were used to develop the novel eQUIC method. Thereafter, SD50 seed activity was analyzed using brain tissue samples from patients with prion disease using the conventional RT-QUIC assay and the novel eQUIC assay. In addition, blood samples from six patients with solitary prion disease were analyzed using the novel eQuIC assay. RESULTS: The eQuIC assay, involving the use of three types of human monoclonal antibodies, showed approximately 1000-fold higher sensitivity than the original RT-QuIC assay. However, when this assay was used to analyze blood samples from six patients with sporadic human prion disease, no prion activity was detected. CONCLUSION: The detection of prion seeding activity in blood samples from patients with sporadic prion disease remains challenging. Thus, the development of alternative methods other than RT-QuIC and eQuIC will be necessary for future research.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Proteínas Priônicas , Doenças Priônicas/diagnóstico , Doenças Priônicas/metabolismo , Encéfalo/metabolismo , Plasma/metabolismo , Síndrome de Creutzfeldt-Jakob/diagnóstico
3.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473799

RESUMO

Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that ultra-high dose rates (UHDRs) induce a sparing effect in normal tissue without modifying the therapeutic effect on the tumor, successful clinical translation of FLASH-RT depends on a better understanding of the biological mechanisms underpinning the sparing effect. Suitable in vitro studies are required to fully understand the radiobiological mechanisms associated with UHDRs. From a technical point of view, it is also crucial to develop optimal technologies in terms of beam irradiation parameters for producing FLASH conditions. This review provides an overview of the research progress of FLASH RT and discusses the potential challenges to be faced before its clinical application. We critically summarize the preclinical evidence and in vitro studies on DNA damage following UHDR irradiation. We also highlight the ongoing developments of technologies for delivering FLASH-compliant beams, with a focus on laser-driven plasma accelerators suitable for performing basic radiobiological research on the UHDR effects.


Assuntos
Dano ao DNA , Motivação , Humanos , Cabeça , Plasma , Radiobiologia
4.
Int J Mol Sci ; 25(5)2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38473836

RESUMO

Immunoadsorption (IA) has proven to be clinically effective in the treatment of steroid-refractory multiple sclerosis (MS) relapses, but its mechanism of action remains unclear. We used miniaturized adsorber devices with a tryptophan-immobilized polyvinyl alcohol (PVA) gel sorbent to mimic the IA treatment of patients with MS in vitro. The plasma was screened before and after adsorption with regard to disease-specific mediators, and the effect of the IA treatment on the migration of neutrophils and the integrity of the endothelial cell barrier was tested in cell-based models. The in vitro IA treatment with miniaturized adsorbers resulted in reduced plasma levels of cytokines and chemokines. We also found a reduced migration of neutrophils towards patient plasma treated with the adsorbers. Furthermore, the IA-treated plasma had a positive effect on the endothelial cell barrier's integrity in the cell culture model. Our findings suggest that IA results in a reduced infiltration of cells into the central nervous system by reducing leukocyte transmigration and preventing blood-brain barrier breakdown. This novel approach of performing in vitro blood purification therapies on actual patient samples with miniaturized adsorbers and testing their effects in cell-based assays that investigate specific hypotheses of the pathophysiology provides a promising platform for elucidating the mechanisms of action of those therapies in various diseases.


Assuntos
Esclerose Múltipla , Humanos , Projetos Piloto , Plasma , Neutrófilos , Leucócitos
5.
Tex Heart Inst J ; 51(1)2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38494437

RESUMO

OBJECTIVE: This study sought to identify periprocedural risk predictors that affect long-term prognosis in patients with chronic obstructive pulmonary disease (COPD) undergoing isolated coronary artery bypass grafting (CABG). METHODS: All consecutive 4,871 patients undergoing isolated CABG between May 2005 and June 2021 were included. Patients with and without COPD were compared for baseline demographics and preoperative characteristics. A propensity-matched analysis was used to compare the 2 groups. The primary outcome was long-term incidence of all-cause death. RESULTS: After matching, 767 patients each were included in the COPD and non-COPD groups; mean age was 71.6 and 71.4 years (P = .7), respectively; 29.3% and 32% (P = .2) were women, respectively. Intraoperatively, median (IQR) operating room time was higher in the COPD group than in the non-COPD group (5.9 [5.2-7.0] hours vs 5.8 [5.1-6.7] hours, respectively; P = .01). Postoperatively, intensive care unit stay (P = .03), hospital length of stay (P = .0004), and fresh frozen plasma transfusion units (P = .012) were higher in the COPD group than in the non-COPD group. Thirty-day mortality was not different between groups (1.3% in the COPD group vs 1% in the non-COPD group; P = .4). Median follow-up time was 4.0 years. The rate of all-cause death was higher in the COPD group than in the non-COPD group (138 patients [18.3%] vs 109 patients [14.5%], respectively; P = .042). Periprocedural risk predictors for all-cause death in patients with COPD were atrial fibrillation, diabetes, male sex, dialysis, ejection fraction less than 50%, peripheral vascular disease, and Society of Thoracic Surgeons Predicted Risk of Mortality score greater than 4%. CONCLUSION: Patients with COPD undergoing isolated CABG had a significantly higher incidence of all-cause death than those without COPD. Herein, risk predictors are provided for all-cause death in patients undergoing isolated CABG.


Assuntos
Doença da Artéria Coronariana , Doença Pulmonar Obstrutiva Crônica , Humanos , Masculino , Feminino , Resultado do Tratamento , Transfusão de Componentes Sanguíneos , Plasma , Ponte de Artéria Coronária/efeitos adversos , Prognóstico , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Fatores de Risco , Estudos Retrospectivos
6.
Sci Rep ; 14(1): 6326, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491119

RESUMO

Propofol's pharmacokinetics have been extensively studied using human blood samples and applied to target-controlled infusion systems; however, information on its concentration in the brain remains scarce. Therefore, this study aimed to simultaneously measure propofol plasma and brain concentrations in patients who underwent awake craniotomy and establish new pharmacokinetic model. Fifty-seven patients with brain tumors or brain lesions who underwent awake craniotomy were sequentially assigned to model-building and validating groups. Plasma and brain (lobectomy or uncapping margins) samples were collected at five time-points. The concentration of propofol was measured using high-performance liquid chromatography. Population pharmacokinetic analysis was conducted through a nonlinear mixed-effects modeling program using a first-order conditional estimation method with interactions. Propofol's brain concentrations were higher than its plasma concentrations. The measured brain concentrations were higher than the effect site concentrations using the previous models. Extended models were constructed based on measured concentrations by incorporating the brain/plasma partition coefficient (Kp value). Extended models showed good predictive accuracy for brain concentrations in the validating group. The Kp value functioned as a factor explaining retention in the brain. Our new pharmacokinetic models and Kp value can predict propofol's brain and plasma concentrations, contributing to safer and more stable anesthesia.


Assuntos
Propofol , Humanos , Encéfalo/cirurgia , Plasma , Anestésicos Intravenosos , Infusões Intravenosas
7.
Metabolomics ; 20(2): 43, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38491253

RESUMO

INTRODUCTION: Pre-analytical factors like sex, age, and blood processing methods introduce variability and bias, compromising data integrity, and thus deserve close attention. OBJECTIVES: This study aimed to explore the influence of participant characteristics (age and sex) and blood processing methods on the metabolic profile. METHOD: A Thermo UPLC-TSQ-Quantiva-QQQ Mass Spectrometer was used to analyze 175 metabolites across 9 classes in 208 paired serum and lithium heparin plasma samples from 51 females and 53 males. RESULTS: Comparing paired serum and plasma samples from the same cohort, out of the 13 metabolites that showed significant changes, 4 compounds related to amino acids and derivatives had lower levels in plasma, and 5 other compounds had higher levels in plasma. Sex-based analysis revealed 12 significantly different metabolites, among which most amino acids and derivatives and nitrogen-containing compounds were higher in males, and other compounds were elevated in females. Interestingly, the volcano plot also confirms the similar patterns of amino acids and derivatives higher in males. The age-based analysis suggested that metabolites may undergo substantial alterations during the 25-35-year age range, indicating a potential metabolic turning point associated with the age group. Moreover, a more distinct difference between the 25-35 and above 35 age groups compared to the below 25 and 25-35 age groups was observed, with the most significant compound decreased in the above 35 age groups. CONCLUSION: These findings may contribute to the development of comprehensive metabolomics analyses with confounding factor-based adjustment and enhance the reliability and interpretability of future large-scale investigations.


Assuntos
Metabolômica , Plasma , Masculino , Adulto , Feminino , Humanos , Metabolômica/métodos , Reprodutibilidade dos Testes , Plasma/química , Soro , Aminoácidos/análise
8.
Nat Commun ; 15(1): 2615, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38521766

RESUMO

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Neuropatologia , Plasma , Emaranhados Neurofibrilares , Autopsia , Proteínas tau , Biomarcadores , Peptídeos beta-Amiloides
9.
Front Immunol ; 15: 1364473, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487531

RESUMO

Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Proteômica , Neoplasias Pulmonares/tratamento farmacológico , Imunoterapia , Inibidores de Checkpoint Imunológico , Plasma
10.
J Extracell Vesicles ; 13(3): e12419, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38443328

RESUMO

Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication in cancer, from development to metastasis. EV-based liquid biopsy is a promising strategy for cancer diagnosis as EVs can be found in cancer patients' body fluids. In this study, the lipid composition of breast cancer-derived EVs was studied as well as the potential of blood plasma EVs for the identification of lipid biomarkers for breast cancer detection. Initially, an untargeted lipidomic analysis was carried out for a panel of cancerous and non-cancerous mammary epithelial cells and their secreted EVs. We found that breast cancer-derived EVs are enriched in sphingolipids and glycerophospholipids compared to their parental cells. The initial in vitro study showed that EVs and their parental cells can be correctly classified (100% accuracy) between cancerous and non-cancerous, as well as into their respective breast cancer subtypes, based on their lipid composition. Subsequently, an untargeted lipidomic analysis was carried out for blood plasma EVs from women diagnosed with breast cancer (primary or progressive metastatic breast cancer) as well as healthy women. Correspondingly, when blood plasma EVs were analysed, breast cancer patients and healthy women were correctly classified with an overall accuracy of 93.1%, based on the EVs' lipid composition. Similarly, the analysis of patients with primary breast cancer and healthy women showed an overall accuracy of 95% for their correct classification. Furthermore, primary and metastatic breast cancers were correctly classified with an overall accuracy of 89.5%. This reveals that the blood plasma EVs' lipids may be a promising source of biomarkers for detection of breast cancer. Additionally, this study demonstrates the usefulness of untargeted lipidomics in the study of EV lipid composition and EV-associated biomarker discovery studies. This is a proof-of-concept study and a starting point for further analysis on the identification of EV-based biomarkers for breast cancer.


Assuntos
Neoplasias da Mama , Vesículas Extracelulares , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Plasma , Biomarcadores , Glicerofosfolipídeos
11.
N Engl J Med ; 390(11): e27, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38466610
13.
Pharm. pract. (Granada, Internet) ; 22(1): 1-14, Ene-Mar, 2024. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-231360

RESUMO

Objectives: This study aimed to compare and correlate plasma and salivary levels of cardiometabolic risk biomarkers’ of pharmacotherapy (appraised using colorimetric assays), adiposity, and atherogenicity indices. Methods: 61 Nascent MetS subjects vs. 30 lean normoglycemic and healthy controls were recruited in Family Medicine outpatient clinics/Jordan University Hospital (a referral medical center). Fasting blood and saliva specimens were collected. Clinical and anthropometric variables were determined along with atherogenecity and adiposity indices. Results: Among nascent MetS (metabolic syndrome) recruits, almost half were normoglycemic, 43% were prediabetic and 8% were diabetic. Pronouncedly Glycemic (FPG and Alc) and lipid parameters (TG, HDL-C and non-HDL-C), adiposity indices (BMI, WHR, WtHR, Conicity-index, BAI, LAP, VAI) and atherogenicity indices (AIP, TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C and TG/HDL-C) were higher in the nascent MetS group (P<0.05 vs. controls). Markedly among the plasma cardiometabolic risk biomarkers (P<0.05 vs. controls) in the nascent MetS group, adipolin, cathepsin S, ghrelin, irisin, LBP, leptin, and osteocalcin were higher but plasma FGF1 levels were oddly lower. Significantly (P<0.05 vs. controls) nascent MetS –linked salivary levels of adipolin and LBP were higher as opposed to the lower cathepsin S. Only osteocalcin, amongst 9 metabolic risk biomarkers studied, had remarkably significant correlation between plasma and saliva levels, in both total sample and MetS patients (P<0.05). Markedly in the nascent MetS only group, both plasma and salivary osteocalcin correlated with FPG and A1c (P<0.05); salivary osteocalcin correlated with BMI and LAP (P<0.05). Likewise, in the total sample plasma osteocalcin correlated significantly with BMI, BAI, WHt R, SBP, DBP, TG, LAP, VAI, TG/HDL-C and AIP (P<0.05), while salivary osteocalcin had substantial correlations only with FPG and A1c (P<0.05). Conclusion: Association of nascent MetS-related plasma and salivary osteocalcin levels and clinical characteristics and indices propagate salivary osteocalcin as a non-invasive marker for clinical control of MetS-/preDM.(AU)


Assuntos
Humanos , Masculino , Feminino , Síndrome Metabólica/genética , Osteocalcina/administração & dosagem , Saliva/microbiologia , Estado Pré-Diabético/diagnóstico , Plasma , Biomarcadores , Tratamento Farmacológico , Fator 1 de Crescimento de Fibroblastos , Adiposidade , Lipopolissacarídeos , Leptina , Osteocalcina
14.
Pharm. pract. (Granada, Internet) ; 22(1): 1-16, Ene-Mar, 2024. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-231361

RESUMO

Background/methods: The impact of clinical pharmacist on undiagnosed pregnancy hyperglycemia (PHG) in mid- and late- pregnancy as a major preventable cause of maternal and neonatal (M/N) complications is investigated. This longitudinal randomized controlled study of changes in plasma levels of predictive/prognostic/diagnostic biomarkers of oxytocin, thrombospondin, MCP1, IL6, MIF, insulin and LAR and undesirable M/N pregnancy outcomes in women with/out PHG (pregnancy normoglycemia; PNG) following the implementation of clinical pharmacist interventions were investigated. Results: A total of 68 PHG (36 intervention vs. 32 non-intervention) vs. 21 PNG participants were enrolled at 20–28 weeks and followed up till delivery. BMI of intervention PHG (unlike non-intervention) was greater (p=0.036) compared to PNG’s. LAR and insulin, oxytocin, thrombospondin1, adiponectin and MCP1 plasma levels and their differences between 2nd and 3rd pregnancy trimesters lacked discrepancies in participants. Both PHG groups in mid pregnancy had substantially greater HbA1c %, FPG and IL6 levels vs. PNG, while PHG non-intervention’ leptin was greater than PNG’s. In late pregnancy, greater SBP, IL6 and MIF levels between either PHG groups vs. PNG’s were observed. Unlike PHG non-intervention and PNG; IL6 level in PHG intervention group decreased (-2.54±6.61; vs. non-intervention PHG’s 4.26±5.28; p<0.001 and vs. PNG’s 2.30±4.27; p=0.023). None of the assessed M/N outcomes was found of differential significance between any of the three study groups. Conclusions: Proinflammatory IL6 as a robust and generalizable cardiometabolic risk-based and related pharmacotherapy biomarker in mid and late hyperglycemic pregnancy with likely implications of novel therapeutic targets was delineated by clinical pharmacist interventions.(AU)


Assuntos
Humanos , Feminino , Gravidez , Farmacêuticos , Plasma/efeitos dos fármacos , Complicações na Gravidez , Hiperglicemia , Trombospondinas/administração & dosagem , Ocitocina , Farmacocinética , Estudos Longitudinais , Biomarcadores Farmacológicos
15.
Clin Biochem ; 125: 110719, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38316335

RESUMO

BACKGROUND: Increased cerebrospinal fluid (CSF) ß2-microglobulin (ß2-MG) values are attributed to immune activation, lymphoid cell turnover and release of tissue destruction in the central nervous system (CNS). We investigated plasma and CSF ß2-MG levels in adult patients with viral encephalitis/meningitis and their correlations with clinical parameters. METHOD: CSF samples from 26 patients with viral encephalitis/meningitis were collected. Moreover, 24 CSF samples from patients with non-inflammatory neurological disorders (NIND) as controls were collected. Plasma samples from 22 enrolled patients and 20 healthy individuals were collected. The ß2-MG levels were measured by immunoturbidimetry on an automatic biochemical analyzer. Clinical data were extracted from an electronic patient documentation system. RESULT: CSF levels of ß2-MG, adenosine deaminase (ADA), white blood cell (WBC), lactate dehydrogenase (LDH), protein and lactate were significantly increased in patients with viral encephalitis/meningitis respectively (p < 0.001, p < 0.001, p < 0.001, p = 0.001, p < 0.001, p = 0.013). In contrast, no statistically significant difference was found in plasma levels of ß2-MG. Furthermore, CSF levels of ß2-MG were weakly correlated with WBC (r = 0.426, p = 0.030), lymphocyte percentage (r = 0.599, p = 0.018), ADA (r = 0.545, p = 0.004) and LDH (r = 0.414, p = 0.036), but not with lactate (r = 0.381, p = 0.055), protein (r = 0.179, p = 0.381) and plasma levels of ß2-MG (r = -0.156, p = 0.537) in viral encephalitis/meningitis patients. CONCLUSION: CSF ß2-MG may be a potential inflammatory marker for viral encephalitis/meningitis in adult patients diagnosed with viral encephalitis/meningitis.


Assuntos
Encefalite Viral , Encefalite , Meningite , Adulto , Humanos , Meningite/líquido cefalorraquidiano , Meningite/diagnóstico , Ácido Láctico , Plasma , Líquido Cefalorraquidiano
16.
J Antimicrob Chemother ; 79(3): 669-677, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38323369

RESUMO

BACKGROUND: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. OBJECTIVES: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients. PATIENTS AND METHODS: Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe. RESULTS: The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L. CONCLUSIONS: Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.


Assuntos
Encéfalo , Estado Terminal , Isocianatos , Humanos , Linezolida , Antibacterianos/uso terapêutico , Plasma
17.
J Gynecol Obstet Hum Reprod ; 53(3): 102744, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38346495

RESUMO

OBJECTIVE: NOD-like receptor pyrin domain-containing 3 (NLRP3) is a cytosolic multi-protein complex that induces inflammation and is negatively regulated by progesterone. Previous researches have reported abnormal induction of reactive oxygen species (ROS) and progesterone resistance in endometriosis (EM). Since progesterone regulates ROS level and, consequently, inflammation, our objective is to investigate whether dienogest (DNG) regulates NLRP3 and whether the regulation of NLRP3 inflammasome by DNG in the blood plasma of patients with EM can affect oxidant and antioxidant markers. METHODS: Plasma samples were obtained from control and EM patients experiencing pain symptoms to measure the level of NLRP3, oxidants, and antioxidants. Subsequently, these patients were given oral DNG 2 mg/day for six months for drug treatment. After six months, plasma samples were collected from the patients for re-examination. RESULTS: The findings indicate that DNG reduced NLRP3 concentration and oxidant production while increasing antioxidant production in blood plasma. By reducing NLRP3, DNG was able to alleviate inflammation and pain caused by inflammation in EM patients. CONCLUSION: In conclusion, the use of DNG in EM patients resulted in a decrease in NLRP3 concentration in the patient's plasma. Furthermore, this effect was enhanced by balancing oxidant/antioxidant levels, which may contribute to reducing inflammation associated with EM.


Assuntos
Antioxidantes , Endometriose , Nandrolona/análogos & derivados , Feminino , Humanos , Oxidantes , Endometriose/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Progesterona , Espécies Reativas de Oxigênio , Dor , Inflamação , Plasma
18.
Clin Transl Sci ; 17(2): e13724, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38407540

RESUMO

LYS006 is a novel, highly potent and selective, new-generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil-driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006-treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re-distribution from target expressing cells resulted in a long terminal half-life and a long-lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well-tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose-limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil-driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.


Assuntos
Epóxido Hidrolases , Plasma , Humanos , Neutrófilos , Pele
19.
Amino Acids ; 56(1): 4, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300362

RESUMO

This study investigated the effect of high-intensity interval exercise on total and individual amino acid concentrations in red blood cells (RBCs) and plasma. Seven males (31 ± 13 yr) provided venous blood samples at rest, immediately and 15 min and 30 min following an 8-min high-intensity exercise bout. The exercise bout was 16 × 15 s cycle efforts at 0.4N/kg of body mass and 90 rpm, interspersed with 15 s passive recovery. Total and individual amino acid concentrations of RBC and plasma and blood cell parameters were analysed. No significant differences for total amino acid concentrations between RBC and plasma were found. Individual amino acid analyses showed significant interaction effects for alanine and α-aminoadipic acid (P < 0.05), with plasma alanine significantly increased from baseline across the recovery period (P < 0.001). Blood fraction (group) effects showed greater concentrations of glycine, serine, asparagine, aspartic acid, glutamic acid, α-aminoadipic acid and ornithine in RBC, while greater concentrations of alanine, α-aminobutyric acid, valine, leucine, isoleucine, threonine, proline, phenylalanine, glutamine, tryptophan and cystine were found in plasma (P < 0.05). Comparable levels of histidine, lysine and tyrosine were observed between blood fractions. Significant differences in the variation of total amino acids in RBC were reported with higher variance at rest compared to following exercise (P = 0.01). Haemoglobin, pack cell volume and white blood cell count significantly increased immediately following exercise (P < 0.05) but returned to baseline after 15 min recovery. These results support the notion of individualised amino acid transportation roles for RBC and plasma during exercise.


Assuntos
Aminoácidos , Eritrócitos , Masculino , Humanos , Plasma , Alanina , Ácido Glutâmico
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 312: 124060, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38402704

RESUMO

A green, rapid and sensitive fluorimetric method to quantify levodropropizine (LVP) in human plasma was exploited for the first time. The proposed method adopts LVP's intrinsic fluorescence in distilled water at a detecting emission of 345 nm following excitation at 240 nm. LVP displayed linearity across concentrations ranging from 50 to 1000 ng mL-1, with a detection limit of 0.77 ng mL-1 and a quantification limit of 2.33 ng mL-1. Thorough validation confirmed its reliability, successfully determining LVP in tablets with an average recovery of 98.64 ± 1.07 %. Furthermore, the method's applicability extended to estimate the studied drug in spiked human plasma with excellent obtained percentage recoveries (98.68 ± 1.28-100.14 ± 1.23).


Assuntos
Plasma , Propilenoglicóis , Humanos , Espectrometria de Fluorescência/métodos , Reprodutibilidade dos Testes , Fluorometria , Comprimidos
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