RESUMO
There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 µg/kg bolus + 1 µg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [-0.366, -0.028], Pr(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.
Assuntos
Animais Recém-Nascidos , Hipóxia-Isquemia Encefálica , Melatonina , Animais , Melatonina/farmacologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Suínos , Feminino , Masculino , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Modelos Animais de DoençasRESUMO
OBJECTIVES: To introduce and evaluate a simple method for assessing joint inflammation and structural damage on whole-body MRI (WBMRI) in juvenile idiopathic arthritis (JIA), which is usable in clinical practice. METHODS: The proposed system utilises post-contrast Dixon WBMRI scans. Joints are assessed for synovitis (grade 0-2) and structural damage (present/absent) at 81 sites. The synovitis grading is based on features including above-normal intensity synovial enhancement, synovial hypertrophy, joint effusion, subarticular bone marrow oedema and peri-articular soft tissue oedema.This system was evaluated in a prospective study of 60 young people (47 patients with JIA and 13 controls with non-inflammatory musculoskeletal pain) who underwent a WBMRI. Three readers (blinded to diagnosis) independently reviewed all images and re-reviewed 20 individual scans. The intra- and inter-reader overall agreement (OA) and the intra- and inter-reader Gwet's agreement coefficients 2 (GAC2) were measured for the detection of a) participants with ≥1 joint with inflammation or structural damage and b) joint inflammation or structural damage for each joint. RESULTS: The inter-reader OA for detecting patients with ≥1 joint with inflammation, defined as grade 2 synovitis (G2), and ≥1 joint with structural damage were 80% and 73%, respectively. The intra-reader OA for readers 1-3 were 80-90% and 75-90% respectively. The inter-reader OA and GAC2 for joint inflammation (G2) at each joint were both ≥85% for all joints but were lower if grade 1 synovitis was included as positive. CONCLUSION: The intra- and inter-reader agreements of this WBMRI assessment system are adequate for assessing objective joint inflammation and damage in JIA.
RESUMO
OBJECTIVES: To assess the frequency of joint inflammation detected by whole-body MRI (WBMRI) in young people (YP) with JIA and controls, and to determine the relationship between WBMRI-detected inflammation and clinical findings. METHODS: YP aged 14-24 years, with JIA (patients) or arthralgia without JIA (controls), recruited from one centre, underwent a WBMRI scan after formal clinical assessment. Consensus between at least two of the three independent radiologists was required to define inflammation and damage on WBMRI, according to predefined criteria. YP with JIA were deemed clinically active as per accepted definitions. The proportions of YP with positive WBMRI scans for joint inflammation (≥1 inflamed joint) as well as serum biomarkers were compared between active vs inactive JIA patients and controls. RESULTS: Forty-seven YP with JIA (25 active and 22 inactive patients) and 13 controls were included. WBMRI detected joint inflammation in 60% (28/47) patients with JIA vs 15% (2/13) controls (difference: 44%, 95% CI 20%, 68%). More active than inactive JIA patients had WBMRI-detected inflammation [76% (19/25) vs 41% (9/22), difference: 35% (95% CI 9%, 62%)], and this was associated with a specific biomarker signature. WBMRI identified inflammation in ≥ 1 clinically inactive joint in 23/47 (49%) patients (14/25 active vs 9/22 inactive JIA patients). CONCLUSIONS: WBMRI's validity in joint assessment was demonstrated by the higher frequency of inflammation in JIA patients vs controls, and in active vs inactive JIA patients. WBMRI found unsuspected joint inflammation in 49% YP with JIA, which needs further investigation of potential clinical implications.