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.     

Oral and maxillofacial surgery in patients with chronic orofacial pain.

PURPOSE: In this investigation, we evaluated a population of patients with chronic orofacial pain who sought treatment at a pain center in an academic institution. These patients were evaluated with respect to 1) the frequency and types of previous oral and maxillofacial surgery procedures, 2) the frequency of previous significant misdiagnoses, and 3) the number of patients who subsequently required surgical treatment as recommended by an interdisciplinary orofacial pain team. The major goal of this investigation was to determine the role of oral and maxillofacial surgery in patients with chronic orofacial pain. Patients and Methods: The study population included patients seen at the Center for Oral, Facial and Head Pain at New York Presbyterian Hospital from January 1999 through April 2001. (120 patients; female-to-male ratio, 3:1; mean age, 49 years; average pain duration, 81 months; average number of previous specialists, 6). The patient population was evaluated by an interdisciplinary orofacial pain team and the following characteristics of this population were profiled: 1) the frequency and types of previous surgical procedures, 2) diagnoses, 3) the frequency of previous misdiagnoses, and 4) treatment recommendations made by the center team. RESULTS: There was a history of previous oral and maxillofacial surgical procedures in 38 of 120 patients (32%). Procedures performed before our evaluation included endodontics (30%), extractions (27%), apicoectomies (12%), temporomandibular joint (TMJ) surgery (6%), neurolysis (5%), orthognathic surgery (3%), and debridement of bone cavities (2%). Surgical intervention clearly exacerbated pain in 21 of 38 patients (55%) who had undergone surgery. Diagnoses included myofascial pain (50%), atypical facial neuralgia (40%), depression (30%), TMJ synovitis (14%), TMJ osteoarthritis (12%), trigeminal neuralgia (10%), and TMJ fibrosis (2%). Treatment recommendations included medications (91%), physical therapy (36%), psychiatric management (30%), trigger injections (15%), oral appliances (13%), biofeedback (13%), acupuncture (8%), surgery (4%), and Botox injections (1%) (Allergan Inc, Irvine, CA). Gross misdiagnosis leading to serious sequelae, with delay of necessary treatment, occurred in 6 of 120 patients (5%). CONCLUSIONS: Misdiagnosis and multiple failed treatments were common in these patients with chronic orofacial pain. These patients often have multiple diagnoses, requiring management by multiple disciplines. Surgery, when indicated, must be based on a specific diagnosis that is amenable to surgical therapy. However, surgical treatment was rarely indicated as a treatment for pain relief in these patients with chronic orofacial pain, and it exacerbated and perpetuated pain symptoms in some of them.     

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.     

Local and systemic effects of radiation on bone metabolism measured by quantitative SPECT.

Quantitative bone scintigraphy (QBS), which measures 99mTc-MDP uptake expressed as percent of injected dose per cc, indicates bone metabolism. It is measured in the bones of patients before and after radiation treatment and then compared to normal controls. QBS was performed in a group of 22 normal individuals and was measured twice, 2-10 mo (mean 4.9) apart. There was no significant difference between the two measurements. QBS was performed also in 28 patients before, immediately after and at certain time intervals after radiation therapy for cancer. Both the irradiated and the nonirradiated bones showed significant decreases in bone metabolism at 2-18 mo (mean 8.8) after irradiation. In addition, increases and decreases of 99mTc-MDP uptake were similar in the irradiated and in the nonirradiated bones, and there were significant correlations of the QBS values in the different bones of each individual patient. The etiology of the changes in bone metabolism in the nonirradiated bones is not yet fully understood, but it appears to be the result of a systemic effect of radiation.     

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.     

Effect of carbohydrate ingestion on exercise endurance and metabolism after a 1-day fast

Fasting before an exercise event has been demonstrated to decrease endurance. The purpose of this study was to investigate whether this decrement in performance after fasting could be reversed by ingestion of a carbohydrate solution before and during exercise. Nine fit male subjects ran to exhaustion at approximately 70% VO2max in two counterbalanced trials. The subjects were fasted for 21 h before both trials, and the trials were arranged so that the subjects ingested either a carbohydrate (CHO) or placebo (PL) solution. Although ratings of perceived exertion were significantly lower in the CHO trial, there were no differences in endurance time to exhaustion in the two trials (102 +/- 8 min in the PL trial and 106 +/- 8 min in the CHO trial). There were no differences between trials for the VO2, heart rate, and blood lactate concentrations. As expected, the blood glucose and insulin concentrations were higher in the CHO trial. The respiratory exchange ratio was significantly higher in the CHO trial at 40 min of exercise and tended to be higher at all other times, suggesting a greater reliance on carbohydrate and less on fat as an energy source. This seemed to be confirmed by the significantly lower plasma glycerol concentration, which suggested less fat mobilization in the CHO trial. Ingestion of a glucose polymer solution increased carbohydrate utilization in fasted subjects, but exercise performance was not improved.     

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.     

Environmental risk factors for Lyme disease identified with geographic information systems.

OBJECTIVES. A geographic information system was used to identify and locate residential environmental risk factors for Lyme disease. METHODS. Data were obtained for 53 environmental variables at the residences of Lyme disease case patients in Baltimore County from 1989 through 1990 and compared with data for randomly selected addresses. A risk model was generated combining the geographic information system with logistic regression analysis. The model was validated by comparing the distribution of cases in 1991 with another group of randomly selected addresses. RESULTS. In crude analyses, 11 environmental variables were associated with Lyme disease. In adjusted analyses, residence in forested areas (odds ratio [OR] = 3.7, 95% confidence interval [CI] = 1.2, 11.8), on specific soils (OR = 2.1, 95% CI = 1.0, 4.4), and in two regions of the county (OR = 3.5, 95% CI = 1.6, 7.4) (OR = 2.8, 95% CI = 1.0, 7.7) was associated with elevated risk of getting Lyme disease. Residence in highly developed regions was protective (OR = 0.3, 95% CI = 0.1, 1.0). The risk of Lyme disease in 1991 increased with risk categories defined from the 1989 through 1990 data. CONCLUSIONS. Combining a geographic information system with epidemiologic methods can be used to rapidly identify risk factors of zoonotic disease over large areas.     

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.