The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3,5-triiodothyronine (T3), the disruption of which (Dio2 ؊/؊ ) results in brown adipose tissue (BAT)-specific hypothyroidism in an otherwise euthyroid animal. In the present studies, cold exposure increased Dio2 ؊/؊ BAT sympathetic stimulation ϳ10-fold (normal ϳ4-fold); as a result, lipolysis, as well as the mRNA levels of uncoupling protein 1, guanosine monophosphate reductase, and peroxisome proliferator-activated receptor ␥ coactivator 1, increased well above the levels detected in the coldexposed wild-type animals. The sustained Dio2 ؊/؊ BAT adrenergic hyperresponse suppressed the three-to fourfold stimulation of BAT lipogenesis normally seen after 24 -48 h in the cold. Pharmacological suppression of lipogenesis with ␤␤-methyl-substituted ␣--dicarboxylic acids of C14 -C18 in wild-type animals also impaired adaptive thermogenesis in the BAT. These data constitute the first evidence that reduced adrenergic responsiveness does not limit cold-induced adaptive thermogenesis. Instead, the resulting compensatory hyperadrenergic stimulation prevents the otherwise normal stimulation in BAT lipogenesis during cold exposure, rapidly exhausting the availability of fatty acids. The latter is the preponderant determinant of the impaired adaptive thermogenesis and hypothermia in cold-exposed Dio2 ؊/؊ mice. A dequate quantities of thyroid hormone are required for the maintenance of basal energy expenditure (1,2) and are also critical for adjustments in energy homeostasis during acute exposure to cold, without which survival is not possible (3). These adjustments in nonshivering adaptive thermogenesis are initiated by an increase in the activity of the sympathetic nervous system (SNS). In human newborns and other small mammals, brown adipose tissue (BAT) is the main site of the sympathetic-mediated adaptive thermogenesis. During cold exposure, there is an acute ϳ50-fold increase in type 2 iodothyronine deiodinase (D2) activity in BAT that accelerates thyroxine (T4) to 3,3Ј,5-triiodothyronine (T3) conversion (4). This increases thyroid hormone receptor (TR) saturation and leads to intracellular thyrotoxicosis specifically in this tissue (5), which in turn increases adrenergic responsiveness (6 -8) in a feed-forward mechanism that allows BAT to produce heat in a sustainable manner.The current paradigm of thyroid-adrenergic synergism is based on the principle that hypothyroidism causes a generalized decrease in adrenergic responsiveness and, therefore, frustrates the homeostatic role of the SNS, including the stimulation of BAT (9,10). However, these studies are largely based on the hypothyroid animal as a model, which has serious limitations for this purpose. The reduced obligatory energy expenditure caused by systemic hypothyroidism leads to a generalized and gradual increase in sympathetic activity that, in the BAT, activates adaptive energy expenditure to sustain normal core temperature, even at room temperature (11). However, chronic norepi...

No abstract

FDG-PET demonstrated 95.9% accuracy in restaging for patients with HL with CRu/PR after first-line therapy. Given the observed probabilities, FDG-PET is highly cost effective and would reduce costs for the public health care program in Brazil.

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0–tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 (ClinicalTrials.gov identifier). Date of registration: July 9, 2019