PPARgamma activators such as rosiglitazone (RSG) stimulate adipocyte differentiation and increase subcutaneous adipose tissue mass. However, in addition to preadipocyte differentiation, adipose ...tissue expansion requires neovascularization to support increased adipocyte numbers. Paradoxically, endothelial cell growth and differentiation is potently inhibited by RSG in vitro, raising the question of how this drug can induce an increase in adipose tissue mass while inhibiting angiogenesis. We find that adipose tissue from mice treated with RSG have increased capillary density. To determine whether adipose tissue angiogenesis was stimulated by RSG, we developed a novel assay to study angiogenic sprout formation ex vivo. Angiogenic sprout formation from equally sized adipose tissue fragments, but not from aorta rings, was greatly increased by obesity and by TZD treatment in vivo. To define the mechanism involved in RSG-stimulated angiogenesis in adipose tissue, the expression of proangiogenic factors by adipocytes was examined. Expression of VEGFA and VEGFB, as well as of the angiopoietin-like factor-4 (ANGPTL4), was stimulated by in vivo treatment with RSG. To define the potential role of these factors, we analyzed their effects on endothelial cell growth and differentiation in vitro. We found that ANGPTL4 stimulates endothelial cell growth and tubule formation, albeit more weakly than VEGF. However, ANGPTL4 mitigates the growth inhibitory actions of RSG on endothelial cells in the presence or absence of VEGF. Thus, the interplay between VEGF and ANGPTL4 could lead to a net expansion of the adipose tissue capillary network, required for adipose tissue growth, in response to PPARgamma activators.
Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of ...definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10
−8
); the top signal was found in rs7868992 on chromosome 9q32 within
COL27A1
(p=1.85 × 10
−6
). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10
−7
for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.
Fluoxetine (Prozac®) is a potent serotonin (5‐HT) reuptake inhibitor which has rapidly gained popularity as a first‐line antidepressant due to its favourable side‐effect profile. However, it has ...recently been reported to worsen drug‐induced parkinsonism when used in conjunction with neuroleptics (Bouchard et al., 1989; Tate, 1989; Brod, 1989). Since fluoxetine inhibits hepatic microsomal enzymes, a pharmacokinetic interaction cannot be ruled out in such cases — the drug is known to interact with other psychotropic drugs such as MAO inhibitors (Sternbach, 1988; Feighner et al., 1990) and tricyclic antidepressants (Bell and Cole, 1988; Vaughan, 1988; Goodnick, 1989; Schraml et al., 1989; Kahn, 1990) via this mechanism among others. So far, fluoxetine has not been reported to worsen symptoms in patients with Parkinson's disease (PD) who have never received neuroleptics. Bouchard et al. (1989) observed that other selective 5‐HT reuptake inhibitors might exacerbate PD, and Meltzer et al. (1979) described a bipolar patient who developed an acute dystonic reaction, with parkinsonian rigidity and increased serum prolactin when treated with fluoxetine for psychotic depression. Fluoxetine has been implicated in the development of neuroleptic malignant syndrome (Halman and Goldbloom, 1990) and akathisia (Lipinski et al., 1989; Baldwin et al., 1991), which may also be linked to central dopaminergic blockade. A recent review of extrapyramidal tract disorders in association with fluoxetine and fluvoxamine, another selective 5‐HT uptake blocker, noted the absence of unambiguous cases and the lack of objective documentation of psychopathological and neurological changes, even though evidence for a causal relationship was compelling (Baldwin et al., 1991).
1. Supersensitivity psychosis (SSP) has emerged as a potential side-effect of long term neuroleptic therapy similar to tardive dyskinesia. 2. Five schizophrenic patients with SSP and considered to be ...drug-resistant were treated with antiepileptic drugs. All 5 improved initially, and in three the improvement was maintained at follow-up. 3. The proposed mechanism of action of the antiepileptic drugs is through correcting a pharmacological kindling effect in the limbic system which results from chronic neuroleptic therapy.
1.
1. The role of serotonin in the aetiology of obsessive-compulsive disorder (OCD) has been established through considerable indirect evidence (Landry and Chouinard, 1990). The strongest evidence ...comes from the fact that drugs known to be serotonin-selective reuptake inhibitors (SSRIs) have been found to be useful in the pharmacotherapy of OCD (Landry and Chouinard, 1990).
2.
2. The authors investigated a new treatment approach by adding an adrenal steroid suppressant to a SSRI, fluoxetine, in the case of a severe obsessive-compulsive patient who was drug-resistant to clomipramine and SSRIs.
3.
3. We found that the combination of aminoglutethimide 250 mg qid and fluoxetine 40 mg die significantly improved the patient's condition. Moreover, during a four and a haff year period, each time we tried to decrease either fluoxetine or the steroid suppressant, the patient started to relapse, suggesting that the adrenal steroid suppressant had a potentiating effect on the SSRI.
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