Typical but not "atypical" antipsychotic effects on startle gating deficits in prepubertal rats

RATIONALE: Dopamine (DA) agonists and NMDA antagonists disrupt sensorimotor gating in rats, as measured by a loss of prepulse inhibition of the startle reflex. These effects are used in predictive models for antipsychotic efficacy: clinically "typical" and "atypical" antipsychotics restore PPI in adult rats treated with DA agonists such as apomorphine (APO), while clinically "atypical" antipsychotics restore PPI in rats treated with NMDA antagonists such as phencyclidine (PCP). We previously reported that the PPI disruptive effects of both APO and PCP are evident in 16- to 18-day-old rat pups, suggesting that the brain substrates for these effects are functional very early in development. OBJECTIVE: In the present study we assessed the developmental patterns of antipsychotic effects in these measures. METHODS: The PPI-disruptive effects of APO and PCP, and their antagonism by the typical antipsychotic haloperidol, and the atypical antipsychotic quetiapine, were assessed across development in Sprague-Dawley rats. RESULTS: Similar to the pattern seen in adults, both haloperidol and quetiapine opposed APO-induced PPI deficits in 16- to 19-day-old rat pups. However, the "atypical" antipsychotic quetiapine did not oppose PCP-induced PPI deficits in pups or prepubertal (45 day) adolescents, but did oppose these PCP effects in postpubertal rats. CONCLUSIONS: While brain substrates mediating the PPI-disruptive effects of DA agonists and NMDA antagonists are functional early in development, some physiological event associated with puberty is a necessary condition for the "atypical antipsychotic profile" in this predictive model.     

Children's perceptions of strategies for resolving community health problems

We examine children's perceptions of the strategies they would use to resolve community health problems. Qualitative analysis using a grounded theory approach showed that 9- to 10-year-old children could conceptualize a range of solutions to hypothetical community health problems. Children's responses reflected an egocentric perspective, one that was centered on self and peers acting on short-term solutions to the immediate problem. Less frequently, children conceptualized broader structural interventions aimed at removing the problem altogether. Children could name resource persons including their friends, family, school personnel and other people in the community. However, outside of their family and peers, their knowledge was non-specific, i.e. it is doubtful that they would actually be able to access the resources. In light of our findings we discuss several important implications for future research. We note that children are interested in changing community conditions that affect their heath. However, their recognition of their marginalized position in adult society and their perception that adults do not take them seriously may be significant barriers to their participation. We suggest that society must rethink the position and roles that are assigned to children so that their valuable potential is not lost.     

Psoriasis disease severity measures: comparing efficacy of treatments for severe psoriasis

Measurement of psoriasis disease severity and effectiveness of treatment involves both objective and subjective assessments.1 Comparing the efficacy of different treatments is complicated by the use of different metrics for measuring outcomes.2 Because these measures are not used routinely in clinical practice, interpreting these data, in particular assessing the degree of clinically meaningful improvement, is difficult. The drug approval process and product labeling reflect historical changes in standards of efficacy measurement.3 This paper reviews the metrics used to evaluate psoriasis treatment and compares available information on approved treatments for severe psoriasis. It further attempts to elucidate the value of these metrics and provide some guidance in properly evaluating the relative efficacy of current proven therapy with new treatments. While clinical trials are somewhat artificial, they provide proof that a drug is more effective than placebo. Efficacy in clinical practice, however, may be very different from the clinical trial setting. Comparison of efficacy under the current circumstances of varying evaluative metrics scales is possible with proper knowledge of the functionality of these methods.     

Prostate specific antigen bounce phenomenon after external beam radiation for clinically localized prostate cancer

PURPOSE: We characterize the prostate-specific antigen (PSA) bounce in patients who underwent external beam radiation therapy for prostate cancer and correlate the PSA bounce with the development of biochemical disease progression. MATERIALS AND METHODS: In this study 964 patients received full dose radiation therapy alone. Followup PSA values were obtained 3 months after completion of radiotherapy and every 3 to 6 months thereafter. Median followup of the entire study group was 48 months. All time intervals were calculated from the completion date of radiation therapy. PSA bounce was defined as an initial increase in serum PSA of at least 0.5 ng./ml., followed by a decrease to pre-bounce baseline serum PSA values no more than 60 months after external beam radiation therapy. RESULTS: Of the 964 patients 119 (12%) had a PSA bounce. PSA bounce was unrelated to age, race, pretreatment PSA, Gleason score, clinical T stage or radiation dose. Mean time to PSA bounce was 9 months from the time of therapy. The respective 1 and 5-year biochemical disease-free survival rates were 100% and 82.1% for patients with PSA bounce and 93.9% and 57.7% for those without PSA bounce (p = 0.0001). CONCLUSIONS: Of men with prostate cancer treated with external beam radiation therapy 12% experienced a transient increase in PSA (PSA bounce) followed by a return to pre-bounce levels after radiation. The PSA bounce phenomenon was not predictive of time to biochemical recurrence.     

Quality of life in social anxiety disorder compared with panic disorder and the general population

OBJECTIVE: Quality of life in a treatment-seeking cohort of patients with social anxiety disorder was compared with that of patients with panic disorder who were matched for age, comorbid illnesses, and gender and with population-based norms. METHODS: The study participants were 33 patients with social anxiety disorder and 33 patients with panic disorder who had participated in clinical trials and who had completed the Medical Outcomes Study Short-Form-36 (SF-36) as part of a baseline evaluation. The patients did not have significant comorbid psychiatric disorders. Paired t tests were used to compare baseline scores on subscales of the SF-36 between the two cohorts. One-sample t tests were used to compare scores on subscales of the SF-36 with expectation scores based on 2,474 persons from the general population. RESULTS: Compared with the general population, the patients with social anxiety disorder had significantly greater impairment as measured by the SF-36 social functioning and mental health subscales. Subscale scores also indicated poorer emotional role functioning, but the difference was not significant. However, they were significantly less impaired than the patients with panic disorder in terms of physical functioning, physical role, and mental health. CONCLUSIONS: Patients with social anxiety disorder who do not have significant comorbid depression or anxiety are substantially impaired in quality of life, but to a lesser extent than patients with panic disorder, who suffer from both mental and physical impairments in quality of life.     

DNA topoisomerase IIalpha predicts progression-free and overall survival in pediatric malignant non-brainstem gliomas

Malignant non-brainstem glioma (MNBG) is a rare pediatric brain tumor. The prognosis for children harboring this lesion remains largely unpredictable. Assessment of histologic features alone only provides a marginal insight into the biologic behavior of these lesions. Hence, the identification of novel molecular markers capable of characterizing these lesions more accurately with respect to their biologic aggressiveness is definitely needed. Our current study examined the expression of nuclear DNA topoisomerase IIalpha (TIIalpha), a novel marker of cell cycle turnover and a determinant of tumor cell resistance to chemotherapy, in a series of 17 archival pediatric MNBGs. TIIalpha expression was found to extend over a wide range in the study cohort (3.9-69.1%). A cutoff labeling index of 12% was found to define 2 prognostic subgroups (TIIalpha <12 vs. >or=12) with profoundly different 5-year progression-free survival (60% vs. 8%; p = 0.0108, log-rank test) and overall survival (100% vs. 8%; p = 0.0038) rates. TIIalpha expression was significantly linked to MIB-1 antibody labeling of the Ki-67 nuclear antigen (R = 0.919, p < 0.001). A high TIIalpha labeling index remained associated with short progression-free survival (p = 0.022) and overall survival (p = 0.022) in multivariate analysis (Cox regression). In conclusion, considering that TIIalpha expression was not related to histopathologic grade, biological characteristics as assessed by TIIalpha labeling may complement the information obtained by tumor morphology as a means of improving the accuracy of patient prognosis prediction.     

Increased emotional distress in daughters of breast cancer patients is associated with decreased natural cytotoxic activity,elevated levels of stress hormones and decreased secretion of Th1 cytokines

DBCP who are aware of their increased risk of developing breast cancer may suffer from high emotional distress. Chronic stress may interfere with NCA and low NCA is associated with increased cancer risk. We studied 80 DBCP and 47 age- and education-matched healthy females (controls). Heparinized venous blood (30 ml) was drawn from all subjects between 8 and 9 A.M., and each participant answered a set of psychologic questionnaires. In addition, the first-morning urine sample was collected. DBCP scored significantly higher in emotional distress compared to controls. Levels of stress hormones in DBCP were higher and in vitro secretion of IL-2, IL-12 and IFN-gamma lower compared to controls. NCA against NK-resistant (MCF-7, COLO-205, U937) and NK-sensitive (K562) cell lines was significantly lower in DBCP and much less augmented by in vitro preincubation with IL-2 or IL-12 compared to controls. NCA and in vitro Th1 cytokine secretion were inversely correlated with the degree of emotional distress and the level of stress hormones in blood or urine. High emotional distress and elevated levels of stress hormones are associated with impaired immune surveillance functions in DBCP. This may contribute to the increased risk of DBCP to develop breast cancer. An interventional trial to enhance coping and reduce stress levels may help to decrease the risk for breast cancer onset in DBCP.     

Challenges in developing a molecular characterization of cancer

DNA microarrays are widely used to measure gene expression across thousands of genes in parallel. Recently, considerable efforts have been made to utilize this technology to improve our understanding of cancer and to identify novel diagnostic markers and therapeutic targets. Here, we detail some of the challenges in developing a molecular characterization of cancer and in translating these new discoveries towards clinical utility.