Members of the synaptobrevin/vesicle-associated membrane protein (VAMP) family in Drosophila are functionally interchangeable in vivo for neurotransmitter release and cell viability

Synaptobrevins or VAMPs are vesicle-associated membrane proteins, often called v-SNARES, that are important for vesicle transport and fusion at the plasma membrane. Drosophila has two characterized members of this gene family: synaptobrevin (syb) and neuronal synaptobrevin (n-syb). Mutant phenotypes and gene-expression patterns indicate that n-Syb is exclusively neuronal and required only for synaptic vesicle secretion, whereas Syb is ubiquitous and, as shown here, essential for cell viability. When the eye precursor cells were made homozygous for syb(-), the eye failed to develop. In contrast, n-syb(-) eye clones developed appropriately but failed to activate downstream neurons. To determine whether the two proteins are structurally specialized to accomplish these distinct in vivo functions, we have driven the expression of each gene in the absence of the other to look for phenotypic rescue. We find that expression of n-syb during eye development can rescue the cell lethality of the syb mutations, as can rat VAMP2 and cellubrevin. Expression of syb can restore synaptic transmission to n-syb mutants as assayed both by electroretinogram and recordings of excitatory junctional currents at the neuromuscular junction. Therefore, we find that Syb, which usually is not involved in synaptic function, can mediate Ca(2+)-triggered synaptic activity and that no particular specialization of the v-SNARE is required to differentiate synaptic exocytosis from other forms.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Significance of silent myocardial ischemia during exercise testing in patients with coronary artery disease

To evaluate the significance of ischemic ST-segment depression without associated chest pain during exercise testing, data were analyzed from 2,982 patients from the Coronary Artery Surgery Study (CASS) registry who underwent coronary arteriography and exercise testing and were followed up for 7 years. Patients with proved coronary artery disease (CAD) (at least 70% diameter narrowing) were grouped according to whether they had at least 1 mm of ST-segment depression or anginal chest pain during exercise testing. Four hundred twenty-four had ischemic ST depression without angina (group 1); 232 had angina but no ischemic ST depression (group 2); 456 had both ischemic ST depression and angina (group 3); and 471 had neither ischemic ST depression nor angina (group 4). Sixty-three percent of patients in group 1 and 55% in group 2 had multivessel CAD (difference not significant). The 7-year survival rates were similar for patients in groups 1 (76%), 2 (77%), and 3 (78%), but were significantly better for patients in group 4 (88%, p less than 0.001). Among group 1 patients, survival was related to severity of CAD (p less than 0.001). The 7-year survival rate in group 1 was significantly worse than that in a separate group of 282 patients with ischemic ST depression without angina during exercise testing who had no CAD (95% survival, p less than 0.001). Thus, in patients with silent myocardial ischemia during exercise testing, the extent of CAD and the 7-year survival rate are similar to those of patients with angina during exercise testing. Prognosis is determined primarily by the severity of CAD. In patients without CAD, the survival rate is excellent.     

Postoperative Atrial Fibrillation or Flutter Following Transcatheter or Surgical Aortic Valve Replacement: PARTNER 3 Trial

ObjectivesThe aim of this study was to assess the incidence and prognostic impact of early and late postoperative atrial fibrillation or flutter (POAF) in patients with severe aortic stenosis (AS) treated with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR).BackgroundThere is an ongoing controversy regarding the incidence, recurrence rate, and prognostic impact of early (in-hospital) POAF and late (postdischarge) POAF in patients with AS undergoing TAVR or SAVR.MethodsIn the PARTNER (Placement of Aortic Transcatheter Valve) 3 trial, patients with severe AS at low surgical risk were randomized to TAVR or SAVR. Analyses were performed in the as-treated population excluding patients with preexistent atrial fibrillation or flutter.ResultsAmong 781 patients included in the analysis, early POAF occurred in 152 (19.5%) (18 of 415 [4.3%] and 134 of 366 [36.6%] following TAVR and SAVR, respectively). Following discharge, 58 new or recurrent late POAF events occurred within 1 year following the index procedure in 55 of 781 patients (7.0%). Early POAF was not an independent predictor of late POAF following discharge (odds ratio: 1.04; 95% CI: 0.52-2.08; P = 0.90). Following adjustment, early POAF was not an independent predictor of the composite outcome of death, stroke, or rehospitalization (hazard ratio: 1.10; 95% CI: 0.64-1.92; P = 0.72), whereas late POAF was associated with an increased adjusted risk for the composite outcome (hazard ratio: 8.90; 95% CI: 5.02-15.74; P < 0.0001), irrespective of treatment modality.ConclusionsIn the PARTNER 3 trial, early POAF was more frequent following SAVR compared with TAVR. Late POAF, but not early POAF, was significantly associated with worse outcomes at 2 years, irrespective of treatment modality.     

Examining Potential Substance Use Disorders Among Former Interscholastic Athletes

Background: Despite numerous studies examining the association between competitive sports participation and substance use behaviors among adolescents and young adults, the use of standardized measures to assess potential substance use disorders has been largely neglected. The objective of this study was to examine if past involvement in interscholastic sports (competitive school-sponsored sports) was associated with potential substance use disorders in young adulthood. Methods: Data for this study were taken from the Student Life Survey (SLS). A total of 3442 young adults participated in the SLS during the spring semester in 2013, with 74% of males and 71% of females indicating participation in interscholastic sport during high school. Results: Respondents who participated in interscholastic sports during high school had higher odds of positive screens for potential alcohol use disorders when compared with their peers who did not participate in interscholastic sports. No association was detected between interscholastic sports participation and potential drug abuse disorders. Moreover, previous involvement in certain types of sports was found to be associated with positive screens for potential alcohol use disorders (i.e., crew and football) and positive screens for potential drug abuse disorders (i.e., lacrosse) among the sample of young adults. Conclusions: School and community sport organizations should be aware of the potential link between sports participation and potential substance use disorders, and may consider brief substance use screeners during yearly physicals to monitor potential substance use problems among athletes.     

Hepatitis B immunisation among invasive cardiologists: poor compliance with United Kingdom guidelines.

OBJECTIVES--To assess the compliance of invasive cardiologists in the United Kingdom with recently accepted national guidelines on the protection of health care workers and patients from hepatitis B. To determine levels of awareness of the infectivity and prevalence of the virus and current attitudes towards screening of patients before cardiac catheterisation and surgery. DESIGN--Anonymous postal survey by questionnaire from the University Hospital of Wales, Cardiff. The questionnaire established the respondent's position, knowledge of hepatitis B, current immunological state, and policy towards the routine screening of patients for hepatitis B carriage. PARTICIPANTS--All British cardiologists of consultant or senior registrar grade involved in invasive procedures. RESULTS--The response rate was 78% (211/271). 20% of respondents had never been vaccinated against hepatitis B and about a third of those vaccinated had not complied correctly with the recommended immunisation regimen. There was little uniformity in practices for screening patients for hepatitis B carriage before invasive procedures, and the level of knowledge concerning the prevalence of hepatitis B and the risks of inoculation was poor. CONCLUSIONS--Invasive cardiologists are at high risk of inoculation with hepatitis B. Nationally agreed guidelines are designed to protect both medical staff and patients against the risk of infection but currently they are ill heeded.     

Shared decision-making in ongoing outpatient psychiatric treatment

Objective

Research on patient involvement in decision-making in psychiatry has focused on first encounters. This study investigated what decisions are made, level of patient involvement and factors influencing patient involvement in ongoing outpatient visits.

Methods

72 visits conducted by 20 psychiatrists were video recorded. Patients had a diagnosis of depression or schizophrenia.

Results

On average, there was one medication related and one other decision per visit. Some psychiatrists involved patients more in decisions, as did female psychiatrists. Involvement was lower when patients had more negative symptoms.

Conclusion

Involvement in decision-making appears to be influenced by the individual psychiatrist and specific symptoms but not visit length.

Practice implications

It is noteworthy that patient involvement is not influenced by length of the visit given that this would be a barrier in busy clinical practice. The next step would be to identify the communication patterns of psychiatrists who involve patients more in decision-making.