Common and rare alleles of the serotonin transporter gene,SLC6A4, associated with Tourette's disorder

To evaluate the hypothesis that functionally over‐expressing alleles of the serotonin transporter (SERT) gene (solute carrier family 6, member 4, SLC6A4) are present in Tourette's disorder (TD), just as we previously observed in obsessive compulsive disorder (OCD), we evaluated TD probands (N = 151) and controls (N = 858). We genotyped the refined SERT‐linked polymorphic region 5‐HTTLPR/rs25531 and the associated rs25532 variant in the SLC6A4 promoter plus the rare coding variant SERT isoleucine‐to‐valine at position 425 (I425V). The higher expressing 5‐HTTLPR/rs25531 L_A allele was more prevalent in TD probands than in controls (χ² = 5.75; P = 0.017; odds ratio [OR], 1.35); and, in a secondary analysis, surprisingly, it was significantly more frequent in probands who had TD alone than in those who had TD plus OCD (Fisher's exact test; P = 0.0006; OR, 2.29). Likewise, the higher expressing L_AC haplotype (5‐HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14). Furthermore, the rare gain‐of‐function SERT I425V variant was observed in 3 male siblings with TD and/or OCD and in their father. Thus, the cumulative count of SERT I425V becomes 1.57% in OCD/TD spectrum conditions versus 0.15% in controls, with a recalculated, family‐adjusted significance of χ² = 15.03 (P < 0.0001; OR, 9.0; total worldwide genotyped, 2914). This report provides a unique combination of common and rare variants in one gene in TD, all of which are associated with SERT gain of function. Thus, altered SERT activity represents a potential contributor to serotonergic abnormalities in TD. The present results call for replication in a similarly intensively evaluated sample. © 2013 Movement Disorder Society     

Differential and synergistic effects of selective norepinephrine and serotonin reuptake inhibitors in rodent models of pain

There is increasing recognition that norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors (NRIs and SRIs) are efficacious in treating some types of pain. To date, studies have not systematically evaluated the relative activity at the NE and/or 5-HT transporter required for maximal efficacy in rodent pain models. Known selective NE and 5-HT reuptake inhibitors reboxetine, desipramine, fluoxetine, and paroxetine were evaluated in both in vitro and in vivo assays. Using the spinal nerve ligation model of neuropathic pain, the compounds differentially reversed tactile allodynia. Evaluation of a broader spectrum of reuptake inhibitors in the para-phenylquinone (PPQ)-induced abdominal constriction model, a model of acute visceral pain, demonstrated that both the SRIs and the NRIs significantly blocked abdominal constrictions. However, the magnitude of this effect was greater following treatment with compounds having greater affinity for NRI compared with SRI affinity. In addition, isobolographic analyses indicated significant synergistic effects for all combinations of desipramine and fluoxetine in the PPQ model of visceral pain. Collectively, the present results support the hypothesis that compounds with greater NRI activity should be more effective for the treatment of pain than compounds having only SRI activity, and this hypothesis is also supported by clinical data. These studies also suggest that the potency and effectiveness of NRIs might be enhanced by the presence of 5-HT activity.     

Influenza and Other Respiratory Viruses: Impact of nonpharmaceutical interventions on laboratory detections of influenza A and B in Canada

BackgroundThe first coronavirus disease 2019 (COVID-19) case was reported in Canada on January 25, 2020. In response to the imminent outbreak, many provincial and territorial health authorities implemented nonpharmaceutical public health measures to curb the spread of disease. “Social distancing” measures included restrictions on group gatherings; cancellation of sports, cultural and religious events and gatherings; recommended physical distancing between people; school and daycare closures; reductions in non-essential services; and closures of businesses.ObjectivesTo evaluate the impact of the combined nonpharmaceutical interventions imposed in March 2020 on influenza A and B epidemiology by comparing national laboratory surveillance data from the intervention period with 9-year historical influenza season control data.MethodsWe obtained epidemiologic data on laboratory influenza A and B detections and test volumes from the Canadian national influenza surveillance system for the epidemiologic period December 29, 2019 (epidemiologic week 1) through May 2, 2020 (epidemiologic week 18). COVID-19-related social distancing measures were implemented in Canada from epidemiologic week 10 of this period. We compared influenza A and B laboratory detections and test volumes and trends in detection during the 2019–20 influenza season with those of the previous nine influenza seasons for evidence of changes in epidemiologic trends.ResultsWhile influenza detections the week prior to the implementation of social distancing measures did not differ statistically from the previous nine seasons, a steep decline in positivity occurred between epidemiologic weeks 10 and 14 (March 8–April 4, 2020). Both the percent positive on week 14 (p≤0.001) and rate of decline between weeks 10 and 14 (p=0.003) were significantly different from mean historical data.ConclusionThe data show a dramatic decrease in influenza A and B laboratory detections concurrent with social distancing measures and nonpharmaceutical interventions in Canada. The impact of these measures on influenza transmission may be generalizable to other respiratory viral illnesses during the study period, including COVID-19.     

Aneurysmal remodeling in the circle of Willis after carotid occlusion in an experimental model

Carotid occlusions are associated with de novo intracranial aneurysm formation in clinical case reports, but this phenomenon is not widely studied. We performed bilateral carotid ligation (n=9) in rabbits to simulate carotid occlusion, and sham surgery (n=3) for control. Upon euthanasia (n=3 at 5 days, n=6 at 6 months post ligation, and n=3 at 5 days after sham operation), vascular corrosion casts of the circle of Willis (CoW) were created. Using scanning electron microscopy, we quantified gross morphologic, macroscopic, and microscopic changes on the endocasts and compared findings with histologic data. At 5 days, CoW arteries of ligated animals increased caliber. The posterior communicating artery (PCom) increased length and tortuosity, and the ophthalmic artery (OA) origin presented preaneurysmal bulges. At 6 months, calibers were unchanged from 5 days, PComs further increased tortuosity while presenting segmental dilations, and the OA origin and basilar terminus presented preaneurysmal bulges. This exploratory study provides evidence that flow increase after carotid occlusion produces both compensatory arterial augmentation and pathologic remodeling such as tortuosity and saccular/fusiform aneurysm. Our findings may have considerable clinical implications, as these lesser-known consequences should be considered when managing patients with carotid artery disease or choosing carotid ligation as a therapeutic option.