SummaryThyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.

Background/Aims: Tissue degradation in corneal thinning disorders, such as keratoconus (KC), involves the expression of inflammatory mediators. The purpose of this study was to determine the levels of proinflammatory cytokines and matrix metalloproteinase 9 (MMP-9) in tears from both eyes of unilateral keratoconus (KC) patients.Methods: Thirty patients diagnosed with asymmetric KC (30 KC eyes, and 30 subclinical KC eyes) and 20 normal control subjects (1 eye) were studied in a prospective, cross sectional study.Keratoconus screening programs were performed on these participants. Ten microliters of tears were collected from each eye. The concentrations of cytokines (interleukin-6[IL-6] and tumor necrosis factor α [TNF-α]), and MMP-9 were measured by ELISA. Results:Mean values for IL-6 levels were similar in KC and subclinical KC samples .1] ng/mL) vs. subclinical KC eye (7.0 [4.8-8.6] ng/mL) (p<0.0001). MMP-9 levels in the control group (6.1 [3.9 -8.3] ng/mL) and subclinical KC were similar (p= 0.203).Conclusions: IL-6 and TNF-α are overexpressed in the tears of subclinical and KC eyes. Increased MMP-9 levels were found only in the KC eye. These results indicate that the pathogenesis of KC may involve chronic inflammatory events.

Background and Purpose-Increased circulating endothelial progenitor cells (EPC) have been associated with a low cardiovascular risk and may be involved in endothelial cell regeneration. The present study was designed to evaluate the prognostic value of EPC in acute ischemic stroke. Methods-Forty-eight patients with a first-ever nonlacunar ischemic stroke were prospectively included in the study within 12 hours of symptoms onset. Stroke severity was evaluated by the National Institutes of Health Stroke Scale, and functional outcome was assessed at 3 months by the modified Rankin Scale (mRS). Infarct volume growth between admission and days 4 to 7 was measured on multiparametric MRI. EPC colonies were defined as early outgrowth colony-forming unit-endothelial cell (CFU-EC). The increment of CFU-EC was quantified during the first week and defined as the absolute difference between the number of CFU-EC at day 7 and admission. The influence of CFU-EC increase on good functional outcome (mRS Յ2) and infarct growth was analyzed by logistic regression and linear models. Results-Patients with good outcome (nϭ25) showed a higher CFU-EC increment during the first week (median [quartiles], 23 [11, 36] versus Ϫ3 [Ϫ7, 1], PϽ0.0001) compared with patients with poor outcome. CFU-EC increment Ն4 during the first week was associated with good functional outcome at 3 months (odds ratio, 30.7; 95% CI, 2.4 to 375.7; Pϭ0.004) after adjustment for baseline stroke severity, ischemic volume and thrombolytic treatment. For each unit increase in the CFU-EC the mean reduction in the growth of infarct volume was 0.39 (0.03 to 0.76) mL (Pϭ0.033). Conclusions-The increase of circulating EPC after acute ischemic stroke is associated with good functional outcome and reduced infarct growth. These findings suggest that EPC might participate in neurorepair after ischemic stroke. (Stroke.

Background and Purpose-Plasma levels of cellular fibronectin (c-Fn) Ն3.6 g/mL and of matrix metalloproteinase-9 (MMP-9) Ն140 ng/mL have been associated with parenchymal hematoma (PH) after treatment with tissue-type plasminogen activator (t-PA) in patients with acute ischemic stroke. In this prospective study, we sought to validate the predictive capacity of the preestablished cutoff values of these biomarkers for PH in a larger series of patients. Methods-We studied 134 patients treated with t-PA within 3 hours from symptom onset according to the SITS-MOST criteria (median time to infusion, 152 minutes; median National Institutes of Health Stroke Scale score, 14) in 4 university hospitals. Hemorrhagic transformation was classified according to the European-Australasian Acute Stroke Study II definitions on computed tomography scans performed 24 to 36 hours after treatment. Relevant hemorrhagic transformation was defined as hemorrhagic infarction type 2 or any PH. Serum c-Fn and MMP-9 levels were determined by an ELISA om blood samples obtained before treatment. Results-Cranial computed tomography showed hemorrhagic transformation in 27 patients (20%), hemorrhagic infarction in 15 (type 2 in 8 patients), and PH in 12 patients (symptomatic in 4). Serum c-Fn and MMP-9 concentrations at baseline were significantly higher in patients with relevant hemorrhagic transformation and PH than in those without (all PϽ0.001). The sensitivity, specificity, and positive and negative predictive values for PH by c-Fn levels Ն3.6 g/mL were 100%, 60%, 20%, and 100%, respectively, whereas corresponding values were 92%, 74%, 26%, and 99% for MMP-9 levels Ն140 ng/mL. When both biomarkers were at levels above the cutoff points, specificity increased to 87% and the positive predictive value increased to 41%. Conclusions-This prospective study confirmed the high sensitivity and negative predictive value, with retained good specificity, of c-Fn and MMP-9 for the prediction of PH in patients treated with t-PA. Development of faster analytic methods will prove the applicability of these biomarkers in routine clinical practice.