Tricyclic antidepressant amitriptyline inhibits autophagic flux and prevents tube formation in vascular endothelial cells

Amitriptyline is a tricyclic antidepressant and an inhibitor of lysosomal acid sphingomyelinase (ASM). Amitriptyline is well known for its cardiovascular side effects and toxicity in psychiatric patients. However, the mechanisms underlying the cardiovascular side effects of amitriptyline remain largely undefined. This study aimed to determine the effects of amitriptyline on angiogenic capability of vascular endothelial cells in physiological settings and identify its mechanism of action. The ex vivo aortic ring angiogenesis and in vitro‐cultured endothelial cell tube formation assay were used to assess the effects of amitriptyline on endothelial angiogenic capability. It was demonstrated that amitriptyline impaired the angiogenesis of aortic rings, which was similar to that found in aortic rings with haploinsufficiency of the ASM gene. In cultured mouse microvascular endothelial cells (MVECs), amitriptyline impaired the proliferation and tube formation under basal condition, which were accompanied by attenuated angiogenic signalling pathways such as endothelial nitric oxide synthase, Akt and Erk1/2 pathways. Mechanistically, amitriptyline inhibited autophagic flux without affecting autophagosome biogenesis at basal condition. ASM gene silencing or autophagy inhibition mimics the inhibitory effects of amitriptyline on endothelial cell proliferation and tube formation. Collectively, our data suggest that amitriptyline inhibits endothelial cell proliferation and angiogenesis via blockade of ASM‐autophagic flux axis. It is implicated that the cardiovascular side effects of amitriptyline may be associated with its inhibitory action on physiological angiogenesis.     

Peer-Led and Professional-Led Group Interventions for People with Co-occurring Disorders: A Qualitative Study

This pilot study evaluated the experience of people with co-occurring disorders (mental illness and addiction) in relation to peer-led and professional-led group interventions. The study used a qualitative (phenomenological) approach to evaluate the experience of a convenience sample of 6 individuals with co-occurring disorders who participated in up to 8 sessions each of both peer-led and professional-led group interventions (with a similar rate of attendance in both groups). The semi-structured interview data were coded and thematically analyzed. We found 5 themes within and across the 2 interventions. In both groups, participants experienced a positive environment and personal growth, and learned, albeit different things. They were more comfortable in the peer-led group and acquired more knowledge and skills in the professional-led group. Offering both peer-led and professional-led group interventions to people with co-occurring disorders may be better than offering either alone     

Energy landscape analysis of native folding of the prion protein yields the diffusion constant, transition path time, and rates

Protein folding is described conceptually in terms of diffusion over a configurational free-energy landscape, typically reduced to a one-dimensional profile along a reaction coordinate. In principle, kinetic properties can be predicted directly from the landscape profile using Kramers theory for diffusive barrier crossing, including the folding rates and the transition time for crossing the barrier. Landscape theory has been widely applied to interpret the time scales for protein conformational dynamics, but protein folding rates and transition times have not been calculated directly from experimentally measured free-energy profiles. We characterized the energy landscape for native folding of the prion protein using force spectroscopy, measuring the change in extension of a single protein molecule at high resolution as it unfolded/refolded under tension. Key parameters describing the landscape profile were first recovered from the distributions of unfolding and refolding forces, allowing the diffusion constant for barrier crossing and the transition path time across the barrier to be calculated. The full landscape profile was then reconstructed from force-extension curves, revealing a double-well potential with an extended, partially unfolded transition state. The barrier height and position were consistent with the previous results. Finally, Kramers theory was used to predict the folding rates from the landscape profile, recovering the values observed experimentally both under tension and at zero force in ensemble experiments. These results demonstrate how advances in single-molecule theory and experiment are harnessing the power of landscape formalisms to describe quantitatively the mechanics of folding.     

Impression tray designs and techniques for complete dentures in cases of microstomia--a review

ObjectivesThe present paper aims to review the literature on various approaches in the tray designs and different techniques used to overcome difficulties in making impressions of patients with severely limited mouth opening published from 1984 to 2009.Study designA search in the National Library of Medicine's Pub Med database, Google search and Science Direct was performed to include all case reports and reviews on prosthodontic rehabilitation of patients with microstomia. A total of 17 articles were included for discussion in the review out of the 22 articles found to be giving new tray designs.ConclusionsDifferent tray designs and impression techniques which can be useful in management of difficult cases causing little discomfort to the patient and help in getting back such patients to a comfortable social living.     

Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers

Alzheimer’s disease (AD) is most commonly detected during old age, but the underlying neuropathologic changes likely appear decades earlier, especially among patients possessing genetic risk factors, such as the isoform E4 of the apolipoprotein E (ApoE4). In this study, we used magnetic resonance imaging (MRI) to assess default mode network (DMN) connectivity in 22 ApoE4 non-carriers and 14 matched ApoE4 carriers as well as white matter fractional anisotropy (FA) in 15 ApoE4 non-carriers and 11 demographically matched ApoE4 carriers. Cognitive tests were also administered. All of the participants were middle-aged adults. The analysis revealed no cognitive or white matter FA differences between carriers and non-carriers. However, in DMN regions previously implicated in AD, we did detect decreased functional connectivity. Our findings suggest that functional MRI abnormalities may be detectable well before cognitive decline or white matter changes among individuals at increased genetic risk for AD.     

Lessons Learned From Managing a Prospective, Private Practice Joint Replacement Registry: A 25-year Experience

Background

In 1984, we developed a private practice joint replacement registry (JRR) to prospectively follow patients undergoing THA and TKA to assess clinical and radiographic outcomes, complications, and implant survival. Little has been reported in the literature regarding management of this type of database, and it is unclear whether and how the information can be useful for addressing longer-term questions.

Questions/purposes

We answered the following questions: (1) What is the rate of followup for THA and TKA in our JRR? (2) What factors affect followup? (3) How successful is this JRR model in capturing data and what areas of improvement are identified? And (4) what costs are associated with maintaining this JRR?

Methods

We collected clinical data on all 12,047 patients having primary THA and TKA since 1984. Clinical and radiographic data were collected at routine followup intervals and entered into a prospective database. We searched this database to assess the rate of successful followup and data collection and to compare the effect of patient variables on followup. Costs related to database management were evaluated.

Results

Followup was poor at every time interval after surgery, with a tendency for worsening over time. Patients with a complication and those younger than 70 years tended to followup with greater frequency. There were difficulties with data capture and substantial expenses related to managing the database.

Conclusions

Our findings highlight the difficulties in managing a JRR. Followup is poor and data collection is often incomplete. Newer technologies that allow easier tracking of patients and facilitate data capture may streamline this process and control costs.

Electronic supplementary material

The online version of this article (doi:10.1007/s11999-012-2541-y) contains supplementary material, which is available to authorized users.