Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation

Hematologic stem cell rescue after high-dose cytotoxic therapy is extensively used for the treatment of many hematopoietic and solid cancers. Gene marking studies suggest that occult tumor cells within the autograft may contribute to clinical relapse. To date purging of autografts contaminated with cancer cells has been unsuccessful. The selective oncolytic property of reovirus against myriad malignant histologies in in vitro, in vivo, and ex vivo systems has been previously demonstrated. In the present study we have shown that reovirus can successfully purge cancer cells within autografts. Human monocytic and myeloma cell lines as well as enriched ex vivo lymphoma, myeloma, and Waldenstr?m macroglobulinemia patient tumor specimens were used in an experimental purging model. Viability of the cell lines or purified ex vivo tumor cells of diffuse large B-cell lymphoma, chronic lymphocytic leukemia, Waldenstr?m macroglobulinemia, and small lymphocytic lymphoma was significantly reduced after reovirus treatment. Further, [35S]-methionine labeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of cellular proteins demonstrated reovirus protein synthesis and disruption of host cell protein synthesis as early as 24 hours. Admixtures of apheresis product with the abovementioned tumor cells and cell lines treated with reovirus showed complete purging of disease. In contrast, reovirus purging of enriched ex vivo multiple myeloma, Burkitt lymphoma, and follicular lymphoma was incomplete. The oncolytic action of reovirus did not affect CD34+ stem cells or their long-term colony-forming assays even after granulocyte colony-stimulating factor (G-CSF) stimulation. Our results indicate the ex vivo use of an unattenuated oncolytic virus as an attractive purging strategy for autologous stem cell transplantations.     

p53 Is required for 1,25-dihydroxyvitamin D3-induced G0 arrest but is not required for G1 accumulation or apoptosis of LNCaP prostate cancer cells

1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is an effective agent for inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell lines. However, the extent of growth inhibition in these cell lines differs because LNCaP cells are much more responsive than PC-3 cells. Previous studies in LNCaP cells have shown that 1,25-(OH)(2)D(3) treatment results in G(0)/G(1) cell cycle accumulation, loss of Ki67 expression, and induction of apoptosis. One difference between the two cell lines is that PC-3 cells lack functional p53, a protein that plays roles both in cell cycle regulation and induction of apoptosis. In this study, the role of p53 in 1,25-(OH)(2)D(3) action was examined using the p53-negative PC-3 cells and a line of LNCaP cells, called LN-56, in which p53 function was shut off using a dominant negative p53 fragment. We found that treatment with 1,25-(OH)(2)D(3) extensively inhibits growth of LN-56 prostate cancer cells lacking p53, but in contrast to the parental LNCaP cells, the LN-56 cells recover rapidly. Moreover, in prostate cancer cells, the synergism between 1,25-(OH)(2)D(3) and 9-cis retinoic acid appears to be dependent on the presence of functional p53; however, 1,25-(OH)(2)D(3)-mediated induction of G(1) cell cycle accumulation and induction of apoptosis is not.     

Which SSRI? A meta-analysis of pharmacotherapy trials in pediatric obsessive-compulsive disorder

OBJECTIVE: The authors conducted a meta-analysis of published randomized, controlled medication trials in children and adolescents with obsessive-compulsive disorder (OCD) to assess evidence for differential efficacy based on type of drug, study design, and outcome measure. METHOD: A systematic literature search was performed for articles pertaining to the pharmacological treatment of pediatric and/or adolescent OCD. All baseline, posttreatment, and change scores with standard deviations reported in each study were included in the analyses. Effect sizes for dependent measures were expressed as standardized mean differences. The analysis included data on efficacy for four selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, fluvoxamine, and sertraline) and clomipramine, four study designs, four dependent outcome measures, and two types of outcome scores (change and posttreatment scores). Multivariate regression was performed to assess the degree to which the effect sizes varied with the methodological features of each study. RESULTS: Twelve studies with a total of 1,044 participants met all inclusion criteria for the analysis. The pooled standardized mean difference for the results of all studies was 0.46 and showed a highly significant difference between drug and placebo treatment. Only one of the four outcome measures evaluated was not sensitive to change with treatment. A multivariate regression analysis of drug effect with other variables controlled showed that clomipramine was significantly superior to each of the SSRIs but that the SSRIs were comparably effective. CONCLUSIONS: Although highly significant, the overall effect sizes for medication were modest. Similarities and differences between the variables studied that emerged in the meta-analysis may have implications for both clinical care and future research.     

Depression with atypical features in the National Comorbidity Survey: classification,description, and consequences

BACKGROUND: Atypical depression has been found to be distinct from other types of depression in terms of psychiatric symptom profile and treatment response. However, debate continues regarding its specific characteristics, impact, and diagnostic criteria. The current study was conducted to increase understanding of atypical depression diagnosed using only the reversed vegetative symptoms of hypersomnia and hyperphagia. METHODS: An atypical depression group (n = 304 [36.4% of the depressed sample; 39.0% when weighted to approximate the national population]) was identified within the US National Comorbidity Survey, which assessed psychiatric disorders among a nationally representative sample using the Composite International Diagnostic Interview. The atypical group was identified based on DSM-III-R criteria for a major depressive episode, in addition to atypical features of hypersomnia and hyperphagia. Comparison groups were those with nonatypical depression (n = 532) and individuals without a psychiatric disorder (n = 4071). RESULTS: Compared with nonatypical depression, atypical depression was associated with a greater percentage of women and an earlier age of onset. The atypical group also reported higher rates of most depressive symptoms, suicidal thoughts and attempts, psychiatric comorbidity (panic disorder, social phobia, and drug dependence), disability and restricted activity days, use of some health care services, paternal depression, and childhood neglect and sexual abuse (P<.05). Compared with people without psychiatric disorders, the atypical group reported higher rates of disability and restricted activity days, use of all mental health care services, parental depression, and childhood abuse (P<.001). CONCLUSIONS: This analysis of a nationally representative US sample suggests that overeating and oversleeping can be used to identify an atypical depression subgroup that is distinct from other depressed patients in terms of demographics, psychiatric comorbidities, and abuse history. Findings also suggest that atypical depression is associated with increased distress, suicidal ideation, and disability compared with nonatypical depression.     

Central projections of the saccular and utricular nerves in macaques

The central projections of the utricular and saccular nerve in macaques were examined using transganglionic labeling of vestibular afferent neurons. In these experiments, biotinylated dextran amine was injected directly into the saccular or utricular neuroepithelium of fascicularis (Macaca fascicularis) or rhesus (Macaca mulatta) monkeys. Two to 5 weeks later, the animals were killed and the peripheral vestibular sensory organs, brainstem, and cerebellum were collected for analysis. The principal brainstem areas of saccular nerve termination were lateral, particularly the spinal vestibular nucleus, the lateral portion of the superior vestibular nucleus, ventral nucleus y, the external cuneate nucleus, and cell group l. The principal cerebellar projection was to the uvula with a less dense projection to the nodulus. Principle brainstem areas of termination of the utricular nerve were the lateral/dorsal medial vestibular nucleus, ventral and lateral portions of the superior vestibular nucleus, and rostral portion of the spinal vestibular nucleus. In the cerebellum, a strong projection was observed to the nodulus and weak projections were present in the flocculus, ventral paraflocculus, bilateral fastigial nuclei, and uvula. Although there is extensive overlap of saccular and utricular projections, saccular inputs to the lateral portions of the vestibular nuclear complex suggest that saccular afferents contribute to the vestibulospinal system. In contrast, the utricular nerve projects more rostrally into areas of known concentration of vestibulo-ocular related cells. Although sparse, the projections of the utricle to the flocculus/ventral paraflocculus suggest a potential convergence with floccular projection inputs from the vestibular brainstem that have been implicated in vestibulo-ocular motor learning.     

Physician health,stress and gender at a university hospital

OBJECTIVE: To determine personal and work related factors contributing to physician health and stress in men and women physicians in a university hospital. METHOD: Mail survey of 161 hospital-based Canadian academic physicians (51 women, 110 men). RESULTS: Women compared to men, physicians were younger (M = 43 years, S.D. = 7.4 vs. M = 48 years, S.D. = 8.64; P = .001) and fewer had spouses (76% vs. 90%; P = .01) and children (76% vs. 91%; P = .02). A five-item scale measured somatic symptoms, the dependent variable. Among physicians of both gender, the somatic symptoms scale was significantly correlated with satisfaction with amount of time spent working and scales of mental health (five items), work satisfaction (five items), workload (five items), healthy lifestyle (five items), coping abilities (three items) and support-in-stress (two items). On stepwise regression analysis, for women physicians, 70% of the variance in somatic symptoms was explained by support from colleagues when stressed, and workload. For men, 42% of the variance was explained by healthy lifestyle, mental health, support from colleagues when stressed, and workload. Regardless of gender, the majority of physicians reported an excessive workload but the sources of support when stressed varied by gender. CONCLUSION: Different strategies are needed for women and men physicians to reduce their stress levels.