II.

The maintenance of cellular levels of free fatty acids and acyl-CoAs, the activated form of free fatty acids, is extremely important as imbalances in lipid metabolism have serious consequences for human health. Acyl-CoA thioesterases (ACOTs) hydrolyze acyl-CoAs to the free fatty acid and CoASH, and thereby have the potential to regulate intracellular levels of these compounds. We have previously identified and characterized a mouse ACOT gene cluster, comprised of six genes that apparently arose by gene duplications, encoding acylCoA thioesterases with localizations in cytosol (ACOT1), mitochondria (ACOT2) and peroxisomes (ACOT3-6). However, the corresponding human gene cluster contains only three genes, ACOT1, ACOT2 and ACOT4 coding for full-length thioesterase proteins, of which only one is peroxisomal (ACOT4). We therefore set out to characterize the human genes, and we here show that the human ACOT4 protein catalyzes the activities of three mouse peroxisomal ACOTs (ACOT3, 4, and 5), being active on succinyl-CoA and mediumto long-chain acyl-CoAs, while ACOT1 and ACOT2 carry out similar functions to the corresponding mouse genes. These data strongly suggest that the human ACOT4 gene has acquired the functions of three mouse genes by a functional convergent evolution that also provides an explanation for the unexpectedly low number of human genes.

Dicarboxylic acids are formed by -oxidation of fatty acids in the endoplasmic reticulum and degraded as the CoA ester via ␤-oxidation in peroxisomes. Both synthesis and degradation of dicarboxylic acids occur mainly in kidney and liver, and the chain-shortened dicarboxylic acids are excreted in the urine as the free acids, implying that acyl-CoA thioesterases (ACOTs), which hydrolyze CoA esters to the free acid and CoASH, are needed for the release of the free acids. Recent studies show that peroxisomes contain several acyl-CoA thioesterases with different functions. We have now expressed a peroxisomal acyl-CoA thioesterase with a previously unknown function, ACOT4, which we show is active on dicarboxylyl-CoA esters. We also expressed ACOT8, another peroxisomal acyl-CoA thioesterase that was previously shown to hydrolyze a large variety of CoA esters. Acot4 and Acot8 are both strongly expressed in kidney and liver and are also target genes for the peroxisome proliferator-activated receptor ␣. Enzyme activity measurements with expressed ACOT4 and ACOT8 show that both enzymes hydrolyze CoA esters of dicarboxylic acids with high activity but with strikingly different specificities. Whereas ACOT4 mainly hydrolyzes succinyl-CoA, ACOT8 preferentially hydrolyzes longer dicarboxylyl-CoA esters (glutaryl-CoA, adipyl-CoA, suberylCoA, sebacyl-CoA, and dodecanedioyl-CoA). The identification of a highly specific succinyl-CoA thioesterase in peroxisomes strongly suggests that peroxisomal ␤-oxidation of dicarboxylic acids leads to formation of succinate, at least under certain conditions, and that ACOT4 and ACOT8 are responsible for the termination of ␤-oxidation of dicarboxylic acids of medium-chain length with the concomitant release of the corresponding free acids.

The aim was to investigate the efficacy of behavioural interventions as treatment of dental anxiety/phobia in adults, by conducting a systematic review of randomized controlled trials (RCTs). The inclusion criteria were defined according to the Patients, Interventions, Controls, Outcome (PICO) methodology. The study samples had documented dental anxiety, measured using validated scales [the Dental Anxiety Scale (DAS) or the Dental Fear Survey (DFS)], or fulfilled the psychiatric criteria for dental phobia. Behavioural interventions included were based on cognitive behavioural therapy (CBT)/behavioural therapy (BT), and control conditions were defined as information, sedation, general anaesthesia, and placebo/no treatment. The outcome variables were level of dental anxiety, acceptance of conventional dental treatment, dental treatability ratings, quality of life and oral health‐related quality of life, and complications. This systematic review identified 10 RCT publications. Cognitive behavioural therapy/behavioural therapy resulted in a significant reduction in dental anxiety, as measured using the DAS (mean difference = −2.7), but the results were based on low quality of evidence. There was also some support that CBT/BT improves the patients' acceptance of dental treatment more than general anaesthesia does (low quality of evidence). Thus, there is evidence that behavioural interventions can help adults with dental anxiety/phobia; however, it is clear that more well‐designed studies on the subject are needed.