Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation

The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.     

The combination of platelet-derived growth factor-BB and insulin-like growth factor-I stimulates bone repair in adult Yucatan miniature pigs

The combination of insulin-like growth factor-I and platelet-derived growth factor-BB has previously been shown to stimulate healing of soft tissue wounds and the formation of bone and ligament around teeth. The purpose of the present study was to evaluate the effects of platelet-derived growth factor-BB and insulin-like growth factor-I individually and in combination on the healing of osseous wounds. Four standardized cortical wounds were created in each tibia of 11 adult Yucatan miniature pigs. The wounds in one tibia per animal were treated with either purified recombinant human insulin-like growth factor-I, platelet-derived growth factor-BB, or both in a methylcellulose gel. The wounds in each contralateral tibia received placebo gel alone. Coded serial sections of each wound were evaluated by computer-aided histomorphometry 21 days after surgery. The area and perimeter of the newly formed mineralized callus, the thickness of the total callus, and the percentage of mineralized tissue within the callus were significantly increased compared with the values of matched controls only in wounds treated with a combination of insulin-like growth factor-I and platelet-derived growth factor-BB. No significant differences in the measured parameters of callus formation were found in wounds treated with either insulin-like growth factor-I or platelet-derived growth factor-BB alone. Cartilage was present only in sites treated with insulin-like growth factor-I alone. These results suggest that the combination of platelet-derived growth factor-BB and insulin-like growth factor-I stimulates bone formation in wounds in long bones of adult animals and that these growth factors act via different pathways during the repair process.     

Group coping skills training for anxiety and depression: its application with chronic patients

The literature on group coping skills training is reviewed and a model involving the use of a wide range of coping strategies with patients heterogeneous in terms of presenting problem is advocated. This study evaluates the effect of such an approach with a chronic inpatient and day-hospital patient population (n = 36) presenting with problems of anxiety and depression. Results suggest that the use of such groups can facilitate the transition from hospital to community. Further they are associated with symptomatic improvement that is of clinical significance in up to 50% of cases, which is largely maintained at 1 year follow-up and which is associated with a positive change in social functioning. In the light of this experience suggestions are made regarding the screening of patients and ways of enhancing group cohesion.     

Problems in the design of anticancer agents

Theoretically, two predominant paths for obtaining more selective anticancer agents may be envisaged. These are: (a) to make compounds which distribute only or preferentially in cancer cells; (b) to make compounds that are able selectively to kill or to differentiate cancer cells. Although in the last two decades research into new anticancer drugs has not produced satisfactory results, there is solid ground on which novel strategies can be developed, mainly based on a much greater biological knowledge of human tumours. This article does not review all the possible approaches that may be followed, but simply discusses some ideas and problems mainly taken from the current research of our laboratory.     

Patient teaching or patient counselling?

Careless or confused use of terms such as information giving, teaching and counselling may lead to inadequate understanding and practice. In view of the progress made in this area, designed to help patients cope with illness and treatment, this paper aims to clarify and identify similarities and differences between these activities and discuss their relevance for those in most need of these types of care. Having recognised the complexity and persistence of such needs, patients, their relatives and nurses should perhaps decide their respective roles and work towards improving the quality of and opportunities for such interventions.     

Psychological Assessment of the Headache Patient

Most clinicians agree that psychological factors are important considerations in the evaluation and treatment of headache patients. There has been a lack of systematic research, however, that has examined the relationship between these variables. Attention to such factors may become a greater concern as the frequency of a patient's headaches increases, there is increased disability secondary to headaches, and/or there is an inadequate response to usually effective treatment. In addition, there is no consensus as to the proper method to assess psychopathology in headache patients.     

585-nm Pulsed Dye Laser in the Treatment of Surgical Scars Starting on the Suture Removal Day

BACKGROUND: The optimal time frame to improve the quality and cosmetic appearance of scars by laser therapy has not been clearly elucidated by prior controlled clinical trials. OBJECTIVE: To determine the efficacy of the 585-nm pulsed dye laser (PDL) in the treatment of surgical scars starting on the day of suture removal. METHODS: Eleven patients (skin types I-IV) with 12 postoperative linear scars that were greater than 2 cm were treated three times on monthly intervals with the 585-nm PDL (450 micro s, 10-mm spot size, 3.5 J/cm2 with 10% overlap) on one scar half, whereas the other half received no treatment. Scars were later evaluated by a blinded examiner using the Vancouver Scar Scale (VSS) for pigmentation, vascularity, pliability, and height. Scars were then blindly examined for cosmetic appearance using a visual analog scale. RESULTS: One month after the last treatment, final scar analysis by the blinded examiner revealed a significant difference between treated and untreated sites, with the treated halves scoring better in all scar parameters in the VSS and in cosmetic appearance. The treated halves demonstrated an overall average improvement in the VSS between the first treatment score and the final score of 54% versus 10% in the controls (P=0.0002). The cosmetic appearance score (0=worst; 10=best) at final assessment was significantly better for the treated scars, scoring 7.3 versus the averaged control score of 5.2 (P=0.016). CONCLUSION: The 585-nm PDL is effective and safe in improving the quality and cosmetic appearance of surgical scars in skin types I-IV starting on the day of suture removal.     

Involving mental health service users in quality assurance

OBJECTIVE: This study compares the process and outcomes of two approaches to engaging mental health (MH) service users in the quality assurance (QA) process. BACKGROUND: QA plays a significant role in health and care services, including those delivered in the voluntary sector. The importance of actively, rather than passively, involving service users in evaluation and service development has been increasingly recognized during the last decade. DESIGN: This retrospective small-scale study uses document analysis to compare two QA reviews of a MH Day Centre, one that took place in 1998 as a traditional inspection-type event and one that took place in 2000 as a collaborative process with a user-led QA agenda. Setting and participants The project was undertaken with staff, volunteers and service users in a voluntary sector MH Day Centre. Intervention The study compares the management, style, evaluation tools and service user responses for the two reviews; it considers staff perspectives and discusses the implications of a collaborative, user-led QA process for service development. RESULTS: The first traditional top-down inspection-type QA event had less ownership from service users and staff and served the main purpose of demonstrating that services met organizational standards. The second review, undertaken collaboratively with a user-led agenda focused on different priorities, evolving a new approach to seeking users' views and achieving a higher response rate. CONCLUSIONS: Because both users and staff had participated in most aspects of the second review they were more willing to work together and action plan to improve the service. It is suggested that the process contributed to an evolving ethos of more effective quality improvement and user involvement within the organization.