Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing

The molecular circuitries controlling the process of skin wound healing have gained new significant insights in recent years. This knowledge is built on landmark studies on skin embryogenesis, maturation, and differentiation. Furthermore, the identification, characterization, and elucidation of the biological roles of adult skin epithelial stem cells and their influence in tissue homeostasis have provided the foundation for the overall understanding of the process of skin wound healing and tissue repair. Among numerous signaling pathways associated with epithelial functions, the PI3K/Akt/mTOR signaling route has gained substantial attention with the generation of animal models capable of dissecting individual components of the pathway, thereby providing a novel insight into the molecular framework underlying skin homeostasis and tissue regeneration. In this review, we focus on recent findings regarding the mechanisms involved in wound healing associated with the upregulation of the activity of the PI3K/Akt/mTOR circuitry. This review highlights critical findings on the molecular mechanisms controlling the activation of mTOR, a downstream component of the PI3K–PTEN pathway, which is directly involved in epithelial migration and proliferation. We discuss how this emerging information can be exploited for the development of novel pharmacological intervention strategies to accelerate the healing of critical size wounds.     

A Formative Evaluation of Two Evidence‐Based Psychotherapies for PTSD in VA Residential Treatment Programs

Between July 2008 and March 2011, 38 U.S. Department of Veterans Affairs (VA) residential treatment programs for posttraumatic stress disorder (PTSD) participated in a formative evaluation of their programmatic services, including evidenced‐based treatments (EBTs). Face‐to‐face qualitative interviews were conducted with over 250 staff by an independent psychologist along with onsite participant observations. This evaluation coincided with a national VA dissemination initiative to train providers in two EBTs for PTSD: prolonged exposure (PE) and cognitive processing therapy (CPT). A substantial proportion of eligible (based on professional background) residential treatment providers received training in PE (37.4%) or CPT (64.2%), with 9.5% completing case consultation or becoming national trainers in each therapy respectively. In semistructured interviews, providers reported that their clinical programs had adopted these EBTs at varying levels ranging from no adoption to every patient receiving the full protocol. Suggestions for improving the adoption of PE and CPT are noted, including distilling manualized treatments to essential common elements.     

Preferential recruitment of bone marrow-derived cells to rat palatal wounds but not to skin wounds

ObjectiveTo investigate the contribution of bone marrow-derived cells to oral mucosa wounds and skin wounds.BackgroundBone marrow-derived cells are known to contribute to wound healing, and are able to differentiate in many different tissue-specific cell types. As wound healing in oral mucosa generally proceeds faster and with less scarring than in skin, we compared the bone marrow contribution in these two tissues.DesignBone marrow cells from GFP-transgenic rats were transplanted to irradiated wild-type rats. After recovery, 4-mm wounds were made in the mucoperiosteum or the skin. Two weeks later, wound tissue with adjacent normal tissue was stained for GFP-positive cells, myofibroblasts (a-smooth muscle actin), activated fibroblasts (HSP47), and myeloid cells (CD68).ResultsThe fraction of GFP-positive cells in unwounded skin (19%) was larger than in unwounded mucoperiosteum (0.7%). Upon wounding, the fraction of GFP-positive cells in mucoperiosteum increased (8.1%), whilst it was unchanged in skin. About 7% of the myofibroblasts in both wounds were GFP-positive, 10% of the activated fibroblasts, and 25% of the myeloid cells.ConclusionsThe results indicate that bone marrow-derived cells are preferentially recruited to wounded oral mucosa but not to wounded skin. This might be related to the larger healing potential of oral mucosa.     

The oxytalan fibre network in the periodontium and its possible mechanical function

The biomechanical character of the periodontal ligament (PDL) is crucial in its response to functional and orthodontic forces. Collagen has been the primary subject of investigations in this field. Several studies, however, indicate that oxytalan fibres, which belong to the elastic fibre family, also contribute to the biomechanical character and behaviour of the PDL. In order to elucidate this, we have evaluated the available literature on the oxytalan fibre network within the PDL and supra-alveolar tissues with respect to development, morphology and distribution, and response to mechanical stimulation. To this end, we have combined the classical histological studies with more recent in vitro studies. Oxytalan fibres develop simultaneously with the root and the vascular system within the PDL. A close association between oxytalan fibres and the vascular system also remains later in life, suggesting a role in vascular support. Mechanical loading of the PDL, through orthodontic force application, appears to induce an increase in the number, size, and length of oxytalan fibres. In line with this, in vitro stretching of PDL fibroblasts (PDLFs) results in an increased production of fibrillin, a major structural component of the microfibrils that make up oxytalan fibres. The available data suggest a mechanical function for oxytalan, but to date experimental data are limited. Further research is required to clarify their exact mechanical function and possible role in orthodontic tooth movement.     

Local variations in turnover of periodontal collagen fibers in rats

Henneman S, Reijers RR, Maltha JC, Von den Hoff JW. Local variations in turnover of periodontal collagen fibers in rats. J Periodont Res 2012; 47: 383–388. © 2011 John Wiley & Sons A/S Background and Objective: The exact cause of orthodontic relapse is still unclear, although it is often suggested to be caused by periodontal collagen fibers. We hypothesize that long‐lived collagen fibers in the periodontium cause relapse. The aim was to determine the half‐life of periodontal collagen fibers around rat molars. Material and Methods: Thirty weanling rats were repeatedly injected with ³H‐proline, and autoradiography of histological sections was performed at 1, 4, 8, 15, 22, 29, 36, 57, 78 and 113 d after labeling. Grain densities determined in specific areas of the periodontium were used to calculate collagen half‐life. Results: The half‐life (t_½) was found to decrease from the supra‐alveolar region to the apical periodontal ligament region. It was longer in the supra‐alveolar region (1.39 ± 0.14 wk) compared with the deeper regions (p < 0.05). The t_½ of the upper periodontal ligament region (0.78 ± 0.20 wk) was longer than that of the inter‐radicular periodontal ligament region (0.42 ± 0.07 wk, p < 0.05). The t_½ of the apical periodontal ligament region was 0.61 ± 0.15 wk. Conclusion: The data indicate that long‐lived collagen fibers do not exist in the soft tissues of the periodontium, and are probably not responsible for relapse. The differences in collagen half‐life might be caused by local variations in compressive strain induced by normal function.     

Pain interference and incident mood,anxiety, and substance-use disorders: Findings from a representative sample of men and women in the general population

To examine gender differences in the longitudinal relationship between past-month pain interference and incident mood, anxiety, and substance-use disorders, chi-square tests and binomial logistic regression analyses were performed on data obtained from the National Epidemiologic Survey on Alcohol and Related Conditions from 34,465 adult respondents (47.9% men; 52.1% women) who completed waves 1 (2000–2001) and 2 (2004–2005) data collection. Models were adjusted for potentially confounding factors (i.e., age, race, marital status, educational level, employment, household income, number of stressful life events, number of general medical conditions, and wave-1 psychopathology). Respondents were categorized at wave 1 according to their past-month level of pain interference (i.e., no or low pain interference, moderate pain interference, severe pain interference). Moderate and severe pain interference (as compared to no or low pain interference) in male and female respondents was associated with the incidence of several psychiatric disorders. A stronger relationship was observed in male respondents as compared to female ones between past-month moderate pain interference and a new onset of any mood disorder (OR = 1.57, p = 0.03) and major depressive disorder (OR = 1.60, p = 0.03), and between past-month severe pain interference and a new onset of alcohol abuse or dependence (OR = 1.69, p = 0.045) and nicotine dependence (OR = 1.48, p = 0.04). These findings suggest that providers should consider screening patients with past-month moderate or severe pain interference for mood, anxiety, and substance-use problems and monitor the possible development of subsequent comorbid psychiatric disorders.