Effects of social defeat stress and fluoxetine treatment on neurogenesis and behavior in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc

Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behavior and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress‐induced behavioral symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression‐like effects, including social avoidance and anxiety‐like behavior. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety‐like behavior. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioral benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.     

How do macro-level structural determinants affect inequalities in mental health? – a systematic review of the literature

Background

In Europe and elsewhere there is rising concern about inequality in health and increased prevalence of mental ill-health. Structural determinants such as welfare state arrangements may impact on levels of mental health and social inequalities. This systematic review aims to assess the current evidence on whether structural determinants are associated with inequalities in mental health outcomes.

Methods

We conducted a systematic review of quantitative studies published between 1996 and 2017 based on search results from the following databases Medline, Embase, PsychInfo, Web of Science, Sociological Abstracts and Eric. Studies were included if they focused on inequalities (measured by socio-economic position and gender), structural determinants (i.e. public policies affecting the whole population) and showed a change or comparison in mental health status in one (or more) of the Organisation for Economic Cooperation and Development (OECD) countries. All studies were assessed for inclusion and study quality by two independent reviewers. Data were extracted and synthesised using narrative analysis.

Results

Twenty-one articles (17 studies) met the inclusion criteria. Studies were heterogeneous with regards to methodology, mental health outcomes and policy settings. More comprehensive and gender inclusive welfare states (e.g. Nordic welfare states) had better mental health outcomes, especially for women, and less gender-related inequality. Nordic welfare regimes may also decrease inequalities between lone and couple mothers. A strong welfare state does not buffer against socio-economic inequalities in mental health outcomes. Austerity measures tended to worsen mental health and increase inequalities. Area-based initiatives and educational policy are understudied.

Conclusion

Although the literature on structural determinants and inequalities in mental health is limited, our review shows some evidence supporting the causal effects of structural determinants on mental health inequalities. The lack of evidence should not be interpreted as lack of effect. Future studies should apply innovative methods to overcome the inherent methodological challenges in this area, as structural determinants potentially affect both levels of mental health and social inequalities.

     

Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial

BACKGROUND: Growth factors are generally accepted to be essential mediators of tissue repair via well-established mechanisms of action that include stimulatory effects on angiogenesis and cellular proliferation, ingrowth, differentiation, and matrix biosynthesis. The aim of this study was to evaluate in a large-scale, prospective, blinded, and randomized controlled clinical trial the safety and effectiveness of purified recombinant human platelet-derived growth factor (rhPDGF-BB) mixed with a synthetic beta-tricalcium phosphate (beta-TCP) matrix for the treatment of advanced periodontal osseous defects at 6 months of healing. METHODS: Eleven clinical centers enrolled 180 subjects, each requiring surgical treatment of a 4 mm or greater intrabony periodontal defect and meeting all inclusion and exclusion criteria. Subjects were randomized into one of three treatment groups: 1) beta-TCP + 0.3 mg/ml rhPDGF-BB in buffer; 2) beta-TCP + 1.0 mg/ml rhPDGF-BB in buffer; and 3) beta-TCP + buffer (active control). Safety data were assessed by the frequency and severity of adverse events. Effectiveness measurements included clinical attachment levels (CAL) and gingival recession (GR) measured clinically and linear bone growth (LBG) and percent bone fill (% BF) as assessed radiographically by an independent centralized radiology review center. The area under the curve (AUC), an assessment of the rate of healing, was also calculated for CAL measurements. The surgeons, clinical and radiographic evaluators, patients, and study sponsor were all masked with respect to treatment groups. RESULTS: CAL gain was significantly greater at 3 months for group 1 (rhPDGF 0.3 mg/ml) compared to group 3 (beta-TCP + buffer) (3.8 versus 3.3 mm; P = 0.032), although by 6 months, this finding was not statistically significant (P = 0.11). This early acceleration of CAL gain led to group 1 exhibiting a significantly greater rate of CAL gain between baseline and 6 months than group 3 as assessed by the AUC (68.4- versus 60.1-mm weeks; P = 0.033). rhPDGF (0.3 mg/ml)-treated sites also had significantly greater linear bone gain (2.6 versus 0.9 mm, respectively; P < 0.001) and percent defect fill (57% versus 18%, respectively; P < 0.001) than the sites receiving the bone substitute with buffer at 6 months. There was less GR at 3 months in group 1 compared to group 3 (P = 0.04); at 6 months, GR for group 1 remained unchanged, whereas there was a slight gain in gingival height for group 3 resulting in comparable GR. There were no serious adverse events attributable to any of the treatments. CONCLUSIONS: To our knowledge, this study is the largest prospective, randomized, triple-blinded, and controlled pivotal clinical trial reported to date assessing a putative periodontal regenerative and wound healing therapy. The study demonstrated that the use of rhPDGF-BB was safe and effective in the treatment of periodontal osseous defects. Treatment with rhPDGF-BB stimulated a significant increase in the rate of CAL gain, reduced gingival recession at 3 months post-surgery, and improved bone fill as compared to a beta-TCP bone substitute at 6 months.     

Histologic and radiographic evidence of vertical ridge augmentation utilizing distraction osteogenesis: 10 consecutively placed distractors

BACKGROUND: Vertical ridge augmentation for dental implant placement is one of the greatest challenges facing the surgeon. Inadequate vertical bone compromises the implant positioning and resulting restoration. The cleansibility, esthetics, and mechanical properties of the restoration can all be compromised. While the technique of distraction osteogenesis has been successfully employed for long bone applications for over 40 years, it has only recently been introduced as a technique for vertical ridge augmentation prior to dental implant reconstruction. METHODS: In this study, the placement of 10 consecutive distractors in 7 patients was evaluated. The surgical technique, latency period, distraction rate, and consolidation period are reviewed. RESULTS: The technique of distraction osteogenesis resulted in an average vertical augmentation of 7 mm, with a range of 5 to 9 mm. There were no complications affecting the outcome of the distraction procedure. No failures have occurred to date in the 16 implants that were placed and loaded following distraction. CONCLUSIONS: In summary, clinical, histologic, and radiographic evidence of consistent vertical bone augmentation was found with this technique of distraction osteogenesis for vertical ridge augmentation.     

Bone augmentation techniques

BACKGROUND: The advent of osseointegration and advances in biomaterials and techniques have contributed to increased application of dental implants in the restoration of partial and completely edentulous patients. Often, in these patients, soft and hard tissue defects result from a variety of causes, such as infection, trauma, and tooth loss. These create an anatomically less favorable foundation for ideal implant placement. For prosthetic-driven dental implant therapy, reconstruction of the alveolar bone through a variety of regenerative surgical procedures has become predictable; it may be necessary prior to implant placement or simultaneously at the time of implant surgery to provide a restoration with a good long-term prognosis. Regenerative procedures are used for socket preservation, sinus augmentation, and horizontal and vertical ridge augmentation. METHODS: A broad overview of the published findings in the English literature related to various bone augmentation techniques is outlined. A comprehensive computer-based search was performed using various databases that include Medline and PubMed. A total of 267 papers were considered, with non-peer-reviewed articles eliminated as much as possible. RESULTS: The techniques for reconstruction of bony defects that are reviewed in this paper include the use of particulate bone grafts and bone graft substitutes, barrier membranes for guided bone regeneration, autogenous and allogenic block grafts, and the application of distraction osteogenesis. CONCLUSIONS: Many different techniques exist for effective bone augmentation. The approach is largely dependent on the extent of the defect and specific procedures to be performed for the implant reconstruction. It is most appropriate to use an evidenced-based approach when a treatment plan is being developed for bone augmentation cases.