The adolescent behavioral repertoire as a context for drug exposure: behavioral autarcesis at play

AIMS: The aim of this study is to investigate suspected behavioral autarcesis. Autarcesis refers to a mechanism of non-specific shielding from or immunity to infection or disease. Here, suspecting that some facets of the adolescent behavioral repertoire (ABR) might shield youths from early drug involvement, we studied recent-onset occurrence of first chances to try a drug and first actual drug use, expressed as a function of five observed ABR dimensions: religious, socializing, sports-related, gender socialization, and home-based activities. DESIGN AND PARTICIPANTS: Nationally representative samples of school-attending youths were drawn in Panama, the five Spanish heritage countries of Central America and the Dominican Republic (n = 12797). MEASUREMENTS: Drug involvement and ABR were assessed via anonymous self-administered questionnaires. FINDINGS: A religious activity dimension and a separate sports dimension were associated inversely with recent onset of adolescent drug experiences, and a socializing activity dimension was related to an increased occurrence of these experiences. For example, for each unit increase of the religious activity dimension of the ABR, there was an associated reduced occurrence of the first chance to try tobacco (OR = 0.75, 95% CI: 0.63-0.90, P = 0.002). Adolescents at higher levels of sports activities and home-based activities were less likely to experience recent-onset actual use of marijuana (OR = 0.45, 95% CI: 0.30-0.67, P < 0.001; OR = 0.56, 95% CI: 0.32-0.99, P = 0.048, respectively). CONCLUSIONS: The study evidence lends some support for behavioral autarcesis. Manipulation of selected ABR dimensions might help prevent or reduce adolescent drug involvement, enhancing autarcesis as a protective mechanism.     

Alteration in dendritic morphology of pyramidal neurons from the prefrontal cortex of rats with renovascular hypertension

We have studied, in the rat, the dendritic morphological changes of the pyramidal neurons of the medial part of the prefrontal cortex induced by the chronic effect of high blood pressure. Renovascular hypertension was induced using a silver clip on the renal artery by surgery. The morphology of the pyramidal neurons from the medial part of the prefrontal cortex was investigated in these animals. The blood pressure was measured to confirm the increase in the arterial blood pressure. After 16 weeks of increase in the arterial blood pressure, the animals were sacrificed by overdoses of sodium pentobarbital and perfused intracardially with a 0.9% saline solution. The brains were removed, processed by the Golgi-Cox stain method and analyzed by the Sholl method. The dendritic morphology clearly showed that the hypertensive animals had an increase (32%) in the dendritic length of the pyramidal cells with a decrease (50%) in the density of dendritic spines when compared with sham animals. The branch-order analysis showed that the animals with hypertension exhibit more dendritic arborization at the level of the first to fourth branch order. This result suggests that renovascular hypertension may in part affect the dendritic morphology in this limbic structure, which may implicate cognitive impairment in hypertensive patients.     

Corneal aberrations after astigmatic keratotomy combined with laser in situ keratomileusis

PURPOSE: To evaluate the optical aberrations in the cornea before and after astigmatic keratotomy (AK) combined with laser in situ keratomileusis (LASIK) in a group of patients with high myopic astigmatism. SETTING: Refractive Surgery Unit, NISA Hospital Virgen del Consuelo, Valencia, Spain. METHODS: Twelve patients (24 eyes) with high myopic astigmatism (from 3.50 to 6.00 diopters) participated in the study. Astigmatic keratotomy was performed as the first step to reduce astigmatism; after 2 months, the residual refractive error was corrected with LASIK. Videokeratography measurements were conducted before and after each procedure. Topography maps were used to calculate the wavefront corneal aberrations for a 6.0 mm pupil diameter. RESULTS: Total, coma-like, and spherical-like aberrations increased significantly from preoperatively to post LASIK (x6.34, x2.52, and x10.50, respectively; P<.01). Astigmatic keratotomy significantly increased coma-like (x4.04; P<.01) and spherical-like (x5.66; P<.01) aberrations. After LASIK, the coma-like aberration was significantly reduced (x0.62; P =.008) and the spherical-like aberration was significantly increased (x1.86; P<.01). CONCLUSION: Astigmatic keratotomy increased higher-order corneal aberrations, both coma-like and spherical-like, whereas LASIK performed after AK increased the spherical-like aberration and reduced the coma-like aberration.     

Ulcerative keratitis caused by Serratia marcescens after laser in situ keratomileusis

We report 2 cases of severe corneal infections caused by Serratia marcescens after laser in situ keratomileusis (LASIK). Twenty-four hours after LASIK, 2 patients developed infectious keratitis, 1 bilaterally. In each eye, the corneal flap was edematous, ulcerated, and detached from the stromal bed. Treatment included removal of the necrotic flap and aggressive antibiotic therapy. Cultures from corneal exudates were positive for S marcescens. After 1 year, both patients had a loss of best corrected visual acuity (BCVA) ranging from 20/40 to 20/22 because of irregular astigmatism. Overrefraction with a hard contact lens resulted in a BCVA of 20/20 in the 3 affected eyes. Slitlamp examination showed trace subepithelial haze without severe corneal scarring. Videokeratography disclosed areas of paracentral inferior steepening resembling keratoconus. Refraction and videokeratography remained stable after 6 months of follow-up. Ulcerative keratitis caused by S marcescens is a potential complication of LASIK. Bilateral involvement may occur if bilateral simultaneous surgery is performed.     

Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain

Rationale The principal use of antidepressants is in the treatment of depression and affective disorders. Antidepressants have also been used as an adjuvant to analgesics in pain treatment. However, in chronic treatment, their antinociceptive and antidepressive effects coexist simultaneously. Antidepressants can interact with the opioid system, which is also involved in regulating nociceptive processing and affective state. Chronic antidepressants could act by increasing mu-opioid receptor expression in many brain areas involved in the regulation of nociception and affective state.Objectives The aim of this study was to evaluate the antinociceptive and antidepressant-like effects and the possible variations in mu-opioid receptor expression induced by a chronic nefazodone treatment in brain areas related to pain and affective state.Methods Wistar rats were chronically treated with nefazodone (10 and 25 mg/kg IP, twice a day, for 14 days). Twelve hours after the last day 14 dose of nefazodone, a tail-flick test was performed. After the administration of a daily dose of nefazodone, Porsolts test was carried out 12 h after last dose. Two hours after completion of 14 days treatment, other animals were processed for mu-opioid receptor immunocytochemistry using polyclonal antisera raised in rabbits. Several brain regions were analyzed: the frontal and cingulate cortex, the dorsal raphe nucleus and the periaqueductal gray.Results Chronic nefazodone treatment induced a significant increase in tail-flick latency and a significant decrease in immobility time at total doses of 20 and 50 mg/kg per day (P<0.05). In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls.Conclusion Therefore, chronic nefazodone induces antinociceptive and antidepressant-like effects in rats and increases mu-opioid receptor expression in brain areas related to pain and affective state. These results suggest that antidepressants could be effective on somatic and affective dimensions of pain and this action could be related to its influence on the opioid system.     

Prognostic significance of p53 expression in oral squamous cell carcinoma without neck node metastases

Background. Aberrations of the p53 gene and overexpression of its protein are widely recognized markers of malignancy including oral squamous cell carcinomas. This study was performed to evaluate the relationship of immunoexpression of p53 protein in series of 91 squamous cell carcinomas of the oral cavity with clinicopathologic parameters and to investigate whether p53 immunoexpression might influence the clinical outcome of the disease. Methods. From a group of 287 consecutive patients, 91 surgically treated ones were randomly selected. P53 protein expression was investigated by means of immunohistochemistry. Clinical and histopathologic data were gathered, and the patient survival was analyzed. Results. Of the oral carcinomas, 52.7% (n = 48) overexpressed p53, using a threshold of 10% stained cell nuclei. There was a negative correlation of p53 immunoexpression with a histologic grade of differentiation (r = ?0.236, p = .06) but not with clinical variables. Overall survival rate was 59% at 5 years. In univariate analysis, tumor size, node status, and advanced clinical stage were significantly associated with shortened overall survival. In patients without neck node metastases, p53 showed a strong correlation with survival (p = .01). In multivariate analysis performed only on N0 patients, tumor extension and p53 immunoexpression were found to be the only independent prognostic parameters with relative risks of 1.9 and 4.3, respectively. Conclusions. A strong relationship was observed between p53 immunoexpression and poor prognosis in patients with oral squamous cell carcinomas without neck node metastases. © 2004 Wiley Periodicals, Inc. Head Neck 26: 22–30, 2004     

Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis

BACKGROUND: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. METHODS: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. RESULTS: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are 'responder' (or 'failure'). The definition of a 'failure' patient would be someone with progression of JSN>0.5mm over a period of 2-3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. CONCLUSION: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion.