Physical Activity Compliance to American Cancer Society Recommendations Amongst Hematopoietic Stem Cell Transplant Survivors.

BACKGROUND AND OBJECTIVES: The aims of this study were to determine the extent to which hematopoietic cell transplantation (HCT) survivors adhere to the American Cancer Society recommendations for weekly physical activity and identify potential demographic and transplant characteristics associated with the lack of compliance. METHODS: This cross-sectional study included adults who had undergone HCT and were at least 1 year post transplantation. Physical activity was assessed using the screening tool of the Block 2014. The type of activity, frequency, and intensity were converted into the metabolic equivalent of task (MET) scores (0-499.0 MET min/week, inadequate activity; 500-1000 MET min/week, adequate activity; >1000 MET min/week, highly vigorous activity). RESULTS: Participants (n = 81) reported a median MET score of 153 min/week, and 83% failed to reach the physical activity guideline of >500 MET min/week. Only 17.3% met the ACS recommendations, with three reporting above 1000 MET min/week. Median daily moderate and vigorous physical activity minute totals were 18.0 and 5.9 min/d, with 85.2% and 60.5% of participants involved, respectively. The median total physical activity energy expenditure was 744 kcal/d. Only race was associated with MET score, with Whites reporting higher MET scores. CONCLUSION: Most HCT survivors assessed in this study did not meet the ACS physical activity recommendations. These findings reinforce the need to incorporate screening for physical activity into HCT survivorship care, offer counseling to those who do not meet the recommended levels, and encourage a physically active lifestyle among HCT survivors.

MUC1 regulates cyclin D1 gene expression through p120 catenin and ß-catenin.

MUC1 interacts with ß-catenin and p120 catenin to modulate WNT signaling. We investigated the effect of overexpressing MUC1 on the regulation of cyclin D1, a downstream target for the WNT/ß-catenin signaling pathway, in two human pancreatic cancer cell lines, Panc-1 and S2-013. We observed a significant enhancement in the activation of cyclin D1 promoter-reporter activity in poorly differentiated Panc1.MUC1F cells that overexpress recombinant MUC1 relative to Panc-1.NEO cells, which express very low levels of endogenous MUC1. In stark contrast, cyclin D1 promoter activity was not affected in moderately differentiated S2-013.MUC1F cells that overexpressed recombinant MUC1 relative to S2-013.NEO cells that expressed low levels of endogenous MUC1. The S2-013 cell line was recently shown to be deficient in p120 catenin. MUC1 is known to interact with P120 catenin. We show here that re-expression of different isoforms of p120 catenin restored cyclin D1 promoter activity. Further, MUC1 affected subcellular localization of p120 catenin in association with one of the main effectors of P120 catenin, the transcriptional repressor Kaiso, supporting the hypothesis that p120 catenin relieved transcriptional repression by Kaiso. Thus, full activation of cyclin D1 promoter activity requires ß-catenin activation of TCF-lef and stabilization of specific p120 catenin isoforms to relieve the repression of KAISO. Our data show MUC1 enhances the activities of both ß-catenin and p120 catenin.

Survival of Mycobacterium tuberculosis during experimental aerosolization and implications for aerosol challenge models.

AIMS: We undertook a series of experiments to investigate factors that contribute to variation in Mycobacterium tuberculosis viability and infectivity, during experimental aerosolization, with an aim to optimize a strategy to enable a more reproducible delivered dose within animal models of tuberculosis. METHODS AND RESULTS: The viability and infectivity of the challenge suspension was determined in relation to aerosolization time, concentration, method of preparation and M. tuberculosis strain. Challenge stocks generated from frozen aliquots of M. tuberculosis were shown to undergo a 1 log(10) CFU ml(-1) decrease in viability during the first 10 min of aerosolization. This correlated with a decrease in surface lung lesions developing in guinea pigs challenged during this time. The phenomenon of decreased viability in vitro was not observed when using freshly grown, nonfrozen cells of M. tuberculosis. The viability of aerosolized bacilli at the point of inhalation relative to the point of aerosolization always remained constant. CONCLUSION: Based on these findings, we have developed an improved strategy by which to reproducibly deliver aerosol infection doses to individually challenged animals and separately challenged groups of animals. SIGNIFICANCE AND IMPACT OF THE STUDY: Study of the aerobiological characteristics of micro-organisms is a critical step in the validation of methodology for aerosol infection animal models, particularly where large numbers of animals and nonhuman primates are used.

The impact of substance abuse on osteoporosis screening and risk of osteoporosis in women with psychotic disorders.

UNLABELLED: Review of the 1-year prevalence of screening for osteoporosis and of osteoporosis or idiopathic fracture in Maryland Medicaid administrative records found that screening rates did not differ among women in the control population, women with psychosis, and women with major mood disorders, but were reduced compared to controls in women with substance use disorder, with or without psychosis. Prevalence of osteoporosis was increased compared to controls in women with major mood disorders or women over 55 dually diagnosed with psychosis and substance use disorder. INTRODUCTION: Osteoporosis is a major public health concern. Substance abuse and psychosis may be risk factors, however, frequency of screening and disease risk in women with psychotic disorders and substance use disorder (SUD) remains unknown. METHODS: This study examined rates (FY 2005) of osteoporosis screening and disease risk in Medicaid enrolled women aged 50 to 64 (N = 18,953). Four diagnostic groups were characterized: (1) psychosis, (2) SUD, (3) major mood disorder, and (4) controls. The interaction of psychosis and SUD on screening and disease prevalence of osteoporosis was tested. RESULTS: The prevalence of osteoporosis across the entire population was 6.7%. Four percent of those without an osteoporosis diagnosis received osteoporosis screening with no notable differences between psychosis and controls. Those with SUD, however, had a significant reduction in screening compared to controls (OR = 0.61, 95% CI = 0.40-0.91, p = 0.016). Women with a major mood disorder were more likely to have osteoporosis in their administrative record (OR = 1.32, 95% CI = 1.03-1.70, p = 0.028) compared to controls. Those who were dually diagnosed (SUD and psychosis) in the oldest ages (55-64 years) had a markedly higher prevalence of osteoporosis compared to controls (OR = 6.4 CI = 1.51-27.6, p = 0.012), whereas this interaction (SUD and psychosis) was not significant in the entire population over age 49. CONCLUSIONS: Osteoporosis screening in the Medicaid population is significantly lower for women with SUD, after adjusting for age, race, and Medicaid enrollment category. The prevalence of osteoporosis appears markedly elevated in those with major mood disorders and those over age 55 dually diagnosed with schizophrenia and SUD.

Remission in schizophrenia: the relationship to baseline symptoms and changes in symptom domains during a one-year study.

The concepts of partial recovery and remission have become increasingly important for the evaluation of the effectiveness of schizophrenia therapeutics. The relationship of baseline symptoms and changes in symptoms to remission of psychosis was evaluated. Fifty-six outpatients with residual schizophrenia completed a double-blind trial of olanzapine versus haloperidol and were then enrolled into a one-year open-label trial of olanzapine. Out of these 56 subjects, 13 (23%) met remission criteria at the beginning of the open-label treatment and were excluded. During the one-year study, 7/43 (16%) subjects met remission criteria. These subjects had significantly lower baseline ratings for tardive dyskinesia (TD) than subjects who did not achieve remission (1.8 +/- 1.5 vs. 4.2 +/- 4.6, P = 0.03). As expected, remitted subjects had significantly greater improvements in Brief Psychiatric Rating Scale total scores, positive subscale scores and scale for the Assessment of Negative Symptoms total scores. Remitted subjects also experienced a significantly greater improvement in depressive symptoms (P = 0.001), activation (P = 0.005), and Clinical Global Impressions scores (P < 0.001), as well as greater improvements in extrapyramidal symptoms (P = 0.007) and TD (P < 0.001). These results suggest that the relationship of depressive symptoms and improved side effects to the construct of remission in schizophrenia may deserve special attention. Future studies should aim to relate remission criteria to functional outcomes, cognition, and other important symptom domains.

Characterization of a method for profiling gene expression in cells recovered from intact human prostate tissue using RNA linear amplification.

Coupling array technology to laser capture microdissection (LCM) has the potential to yield gene expression profiles of specific cell populations within tissue. However, remaining problems with linear amplification preclude accurate expression profiling when using the low nanogram amounts of RNA recovered after LCM of human tissue. We describe a novel robust method to reliably amplify RNA after LCM, allowing direct probing of 12K gene arrays. The fidelity of amplification was demonstrated by comparing the ability of amplified RNA (aRNA) versus that of native RNA to identify differentially expressed genes between two different cell lines, demonstrating a 99.3% concordance between observations. Array findings were validated by quantitative polymerase chain reaction analysis of a randomly selected subset of 32 genes. Using LCM to recover normal (N=5 subjects) or cancer (N=3) cell populations from intact human prostate tissue, three differentially expressed genes were identified. Independent investigators have previously identified differential expression of two of these three genes, hepsin and beta-microseminoprotein, in prostate cancer. Taken together, the current study demonstrates that accurate gene expression profiling can readily be performed on specific cell populations present within complex tissue. It also demonstrates that this approach efficiently identifies biologically relevant genes.

Measurement of antipsychotic-induced side effects: support for the validity of a self-report (LUNSERS) versus structured interview (UKU) approach to measurement.

A self-report measure of antipsychotic side effects (LUNSERS) was compared with that of an established semi-structured interview (UKU side effect rating scale). The validity and the ability of the LUNSERS to determine false positives by use of an internal 'red herring' subscale were assessed. 'Red herring' items are those which do not directly relate to known antipsychotic side effects. In an open study, 29 patients with schizophrenia and schizoaffective disorder from inpatient and outpatient settings within an Australian metropolitan mental health service were assessed for antipsychotic-induced side effects using both the LUNSERS and UKU. The LUNSERS and UKU were similar in their overall assessment of antipsychotic side effects (total score correlation of 0.58) and were correlated on a wide array of individual side effect items. Correlations between total scores and individual items were higher for those patients scoring low on the LUNSERS 'red herring' items compared with both those with high 'red herring' scores and the sample as a whole. Several LUNSERS items were identified as potentially problematic, requiring further explanation or supplementation with direct questioning. The 'red herring' scale appears to enable detection of patients that may be over-reporting symptomatology. The LUNSERS is a valuable self-report measure of antipsychotic side effects, particularly in cases where red herring scores are low.

Management of treatment resistance in schizophrenia.

A systematic approach to the evaluation and characterization of treatment resistance in schizophrenia has become increasingly important since the introduction of the second-generation antipsychotics. The need for accurate evaluation will increase further as other new antipsychotic medications are developed. Patients with schizophrenia may manifest poor response to therapy because of intolerance to medication, poor adherence, inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Criteria for treatment-resistance are presented to help in standardizing treatment and clinical trials. As clinicians face the decision of when to change or augment antipsychotic medications, a clear understanding of the appropriate length of a treatment trial and which target symptoms respond to antipsychotic therapy is critical for maximizing response in patients with treatment-resistant schizophrenia.

Comparison of discharge rates and drug costs for patients with schizophrenia treated with risperidone or olanzapine.

This study compared the discharge rates and drug costs of 789 patients with schizophrenia or schizoaffective disorder who began pharmacotherapy with olanzapine or risperidone between July 1997 and June 1998. Discharge rates 30 days after the start of treatment were 45 percent for the patients treated with risperidone and 32 percent for those treated with olanzapine (p=.001). Daily drug costs during the same period were $6.42 for risperidone and $12.29 for olanzapine (p<.001). For risperidone, lower dosages were associated with higher hospital discharge rates, whereas no significant association was observed for olanzapine. These data suggest that among inpatients with schizophrenia or schizoaffective disorder, use of risperidone results in a higher discharge rate and a lower drug cost than use of olanzapine.

Predictors of successful extubation in neurosurgical patients.

A respiratory therapist-driven weaning protocol incorporating daily screens, spontaneous breathing trials (SBT), and prompts to caregivers has been associated with superior outcomes in mechanically ventilated medical patients. To determine the effectiveness of this approach in neurosurgical (NSY) patients, we conducted a randomized controlled trial involving 100 patients over a 14-mo period. All had daily screens of weaning parameters. If these were passed, a 2-h SBT was performed in the Intervention group. Study physicians communicated positive SBT results, and the decision to extubate was made by the primary NSY team. Patients in the Intervention (n = 49) and Control (n = 51) groups had similar demographic characteristics, illness severity, and neurologic injuries. Among all patients, 87 (45 in the Control and 42 in the Intervention group) passed at least one daily screen. Forty (82%) patients in the Intervention group passed SBT, but a median of 2 d passed before attempted extubation, primarily because of concerns about the patient's sensorium (84%). Of 167 successful SBT, 126 (75%) did not lead to attempted extubation on the same day. The median time of mechanical ventilation was 6 d in both study groups, and there were no differences in outcomes. Overall complications included death (36%), reintubation (16%), and pneumonia (9%). Tracheostomies were created in 29% of patients. Multivariate analysis showed that Glasgow Coma Scale (GCS) score (p < 0.0001) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p < 0.0001) were associated with extubation success. The odds of successful extubation increased by 39% with each GCS score increment. A GCS score > or = 8 at extubation was associated with success in 75% of cases, versus 33% for a GCS score < 8 (p < 0.0001). Implementation of a weaning protocol based on traditional respiratory physiologic parameters had practical limitations in NSY patients, owing to concerns about neurologic impairment. Whether protocols combining respiratory parameters with neurologic measures lead to superior outcomes in this population requires further investigation.

Ziprasidone and the QTc interval: pharmacokinetic and pharmacodynamic considerations.

Many psychotropic medications might cause prolongation of the QTc interval; however, antipsychotics have recently come under increasing scrutiny in this regard. Ziprasidone, a newly marketed second-generation antipsychotic, was initially delayed in approval by the FDA due to its propensity to prolong the QTc interval in patients with schizophrenia. While ziprasidone does prolong the QTc interval, safety, concomitant medication, and overdose data present little reason to consider ziprasidone a major risk factor for Torsades de Pointes thus far. The paucity of data regarding this agent, however, and its use in those with additional risk factors for QTc-interval prolongation are striking. The risk for this phenomenon has not been studied in patients with concomitant disease states that might be associated with QTc-interval prolongation or in those taking metabolic inhibitors which might inhibit aldehyde oxidase. Little is known about a major metabolic route of ziprasidone, oxidation by aldehyde oxidase. Finally, experience with other agents associated with QTc-interval prolongation raises the possibility that both the type and number of individuals studied to date might not be sufficient to reveal problems with ziprasidone. This paper will review the literature concerning real and theoretical implications of pharmacokinetic and pharmacodynamic interactions with ziprasidone, particularly with regard to these effects on the QTc interval.

Treatment of the special patient with schizophrenia.

Special patient populations with schizophrenia have received little attention. These populations include adolescents, the elderly, substance abusers, and patients who are considered treatment-resistant. Interest in these populations is rapidly growing, especially with regard to their treatment with second-generation antipsychotics. This article describes the treatment of special patient populations and summarizes the research that has been done in this field.

A life cycle model of continuous clinical process innovation.

The changing healthcare environment has created a sense of urgency for continuous innovation in clinical care processes. Managers and clinicians are investing unprecedented funds and energy in the development of various clinical process innovations (CPI) such as clinical pathways, electronic workstations, and various forms of information technology. While increasing attention has been paid to the development of such initiatives, our understanding of how best to disseminate and ensure their use is limited. In this first of two articles dealing with the dissemination and use of CPI in integrated delivery systems, we present a "life cycle" model of the dissemination process and suggest opportunities for managing CPI. The management of CPI requires more than just an understanding of the factors that may facilitate or impede its implementation and use. Managers require an understanding of the actual process so that they can assess the specific implementation stage at which the organization is presently operating, and design appropriate interventions that can affect the process. A future article will identify the factors that facilitate and inhibit the process and suggest some intervention strategies.

DNA microarray analyses of genes regulated during the differentiation of embryonic stem cells.

Embryonic stem (ES) cells are derived from the inner cell mass of blastocysts, and in response to retinoic acid (RA) are induced to differentiate to form some of the first distinguishable cell types of early mammalian development. This makes ES cells an attractive model system for studying the initial developmental decisions that occur during embryogenesis and the molecular genetics and associated mechanisms underlying these decisions. Additionally, ES cells are of significant interest to those characterizing various gene functions utilizing transgenic and gene-targeting techniques. With the advent of DNA microarray technology, which allows for the study of expression patterns of a large number of genes simultaneously within a cell type, there is an efficient means of gaining critical insights to the expression, regulation, and function of genes involved in mammalian development for which information is not currently available. To this end, we have utilized Clontech's Atlas Mouse cDNA Expression Arrays to examine the expression of 588 known regulatory genes in D3 ES cells and their RA-induced differentiated progeny. We report that nearly 50% of the regulatory genes are expressed in D3 and/or D3-differentiated cells. Of these genes, the steady-state levels of 18 are down-regulated and 61 are up-regulated by a factor of 2.5-fold or greater. These changes in gene expression are highly reproducible and represent changes in the expression of a variety of molecular markers, including: transcription factors, growth factors and their receptors, cytoskeletal and extracellular matrix proteins, cell surface antigens, and intracellular signal transduction modulators and effectors.

Differential olanzapine plasma concentrations by sex in a fixed-dose study.

This study examined plasma concentrations of olanzapine by sex (20 males and seven females) in an 8-week fixed-dose study. Dosing was 12.5 mg/day for the first week, then 25 mg/day. Trough plasma concentrations were drawn at weeks 1, 3, 5 and 8. Women volunteers were found to have significantly higher plasma concentrations than men. This difference was first evident at study week 5. Women have higher plasma concentrations of olanzapine, possibly due to differences in metabolism of the CYP450 isoenzyme system.

A dose-outcome analysis of risperidone.

BACKGROUND: Although the establishment of appropriate dosage ranges for antipsychotics has important ramifications for both short-term treatment and long-term therapeutic outcomes, difficulties in dosing persist. Evidence exists that initial dosing recommendations for the titration of risperidone to 6 mg/day in 3 days are excessive. This study examines dosage trends of risperidone and further examines the relationship between dose and outcome by determination of discharge rates among individuals receiving varying doses of the drug. METHOD: Records of individuals receiving risperidone in Maryland state psychiatric facilities from March 1994 through February 1997 (N = 1056) were examined. Discharge rates and time to discharge were measured by Kaplan-Meier survival curve analysis. RESULTS: As risperidone use has risen each year since its introduction, mean doses in both inpatients and discharged patients have steadily declined. Additionally, risperidone doses for discharged patients were significantly lower than those for patients remaining in the hospital. Furthermore, patients receiving 2 and 4 mg/day were significantly more likely to be discharged than those receiving 6 mg/day (log-rank chi2 = 13.54, df = 2, p = .0011). This difference was seen in patients with similar diagnoses, ages, and racial status. CONCLUSION: Patients treated with doses less than the 6-mg/day initial dosing recommendations have better outcomes in terms of discharge. This finding should encourage clinicians to utilize adequate trials of risperidone aimed at stabilizing patients on doses in the 2- to 4-mg/day range before proceeding to higher doses.