Ruling Out Myocardial Infarction with Troponin T and Creatine Kinase MB Mass: Diagnostic and Prognostic Aspects

Objective - To investigate the time window for ruling out myocardial infarction (MI) with troponin T (TnT) and creatine kinase isoenzyme MB mass (CK-MBm) and the prognosis of patients with ruled-out MI diagnosis. Design - The study was based on 397 patients admitted with a suspected acute coronary syndrome but with relief of symptoms within 24 h. Results - MI diagnosis was confirmed with elevated TnT (> 0.10 µg/l) in 108 patients, in 91% within 12-24 h from the onset of symptoms, and in 99% within 12 h from admission. In 94 of these patients CK-MBm became elevated (> 5.0 µg/l), in 95% within 10-12 h from the onset of symptoms, and in 99% within 6 h from admission. Among patients with ruled-out MI diagnosis, the 1-year incidence of recurrent coronary events was 29% in those with positive history of coronary heart disease (CHD) but only 7% in those without prior CHD ( p < 0.001). Conclusion - Using TnT or CK-MBm, MI can be ruled out within 12 h from admission in the majority of patients. Among patients with ruled-out MI diagnosis, positive history of CHD is an important determinant of prognosis.     

Automated GMP production and long-term experience in radiosynthesis of CB1 tracer [18F]FMPEP-d2

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB₁ receptor imaging tracer (3R,5R)-5-(3-([¹⁸F]fluoromethoxy-d₂)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([¹⁸F]FMPEP-d₂), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic ¹⁸F-fluorination of an alkylating agent and its GC purification, the subsequent ¹⁸F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the ¹⁸F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the ¹⁸F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013–2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.     

Automated production of [18F]FTHA according to GMP

14‐(R,S)‐[¹⁸F]fluoro‐6‐thia‐heptadecanoic acid is a tracer for fatty acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in‐house for multistep nucleophilic ¹⁸F‐fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14‐(R,S)‐[¹⁸F]fluoro‐6‐thia‐heptadecanoic acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer‐ascorbic acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14‐(R,S)‐[¹⁸F]fluoro‐6‐thia‐heptadecanoic acid, decay‐corrected to the end of bombardment, was 13% ± 6.3%. The total amount of formulated end product was 1.7 ± 0.8 GBq at end of synthesis.     

Serum α- and γ-tocopherol concentrations and risk of advanced beta cell autoimmunity in children with HLA-conferred susceptibility to type 1 diabetes mellitus

Aims/hypothesis The aim of our study was to assess the associations of serum α- and γ-tocopherol concentrations with the risk of advanced beta cell autoimmunity in children with HLA-conferred genetic susceptibility to type 1 diabetes mellitus. Methods A case–control study with 108 cases with advanced beta cell autoimmunity and 216 matched control participants nested within the birth cohort of the Type 1 Diabetes Prediction and Prevention Project. A serum sample for vitamin E analyses was collected from all the children in the cohort at the age of 1 year and thereafter at 12 month intervals. For each case–control group, all the repeated serum samples up to the age of seroconversion to autoantibody positivity in the case were analysed. A conditional logistic regression model was used to determine potential associations between seroconversion and serum tocopherol concentrations. Results Serum α- or γ-tocopherol concentrations were not significantly associated with the risk of advanced beta cell autoimmunity. The odds ratio (95% CI) for μmol/l increase in serum concentration of the first-year sample was 0.97 (0.92–1.03) for α-tocopherol and 1.10 (0.70–1.74) for γ-tocopherol. However, there was an interaction between high values of γ-tocopherol at the age of 1 year and the time of seroconversion (p = 0.024). Conclusions/interpretation It seems unlikely that high concentrations of α- or γ-tocopherol protect against advanced beta cell autoimmunity in young children.     

Brown adipose tissue function is accompanied by cerebral activation in lean but not in obese humans

Brown adipose tissue (BAT) is able to generate heat and dissipate energy in response to cold exposure in mammals. It has recently been acknowledged that adult humans also have functional BAT, whose metabolic activity is reduced in obesity. In healthy humans, the cerebral mechanisms that putatively control BAT function are unclear. By using positron emission tomography (PET), we showed that cold-induced BAT activation is associated with glucose metabolism in the cerebellum, thalamus, and cingulate, temporoparietal, lateral frontal, and occipital cortices in lean participants, whereas no such associations were found under warm control conditions. The cold-induced increase in cerebral glucose metabolism was more robust in lean than obese participants. Cerebral glucose metabolism was not associated with skeletal muscle or white adipose tissue glucose uptake under warm or cold conditions. In conclusion, BAT metabolism was accompanied by the activation of specific cerebral regions, and this shows an uncharacterized role that the brain plays in the regulation of BAT function. In obese participants, the cold-induced response in cerebral activity was attenuated that provides a clue for obesity-induced impairment in BAT metabolism.