Biomedical subjects

David J Harrison

Publications and source records attributed to David J Harrison.

At least 19 recordsLinked to original sources

PubMed2006

Effect of initial ziprasidone dose on length of therapy in schizophrenia.

OBJECTIVE: To examine the effects of initial ziprasidone dose on discontinuation rates, using retrospective integrated medical and pharmacy claims data. METHODS: Patients > or = 18 years with a diagnosis of schizophrenia or schizoaffective disorder and a ziprasidone claim between March 2001 and February 2003 who were continuously enrolled for at least six months before and three months after initiation of ziprasidone were included. They were stratified by initial daily dose (> or = 40 and < 80 mg [low] vs. > or = 80 and < 120 mg [medium] vs. 120-160 mg [high]). The six-month risk of discontinuation was examined using Cox proportional hazards models controlling for gender, psychiatric comorbidities, and pre-ziprasidone utilization of antipsychotics (atypical, conventional, none). RESULTS: The mean age of the sample (n=1058) was 38 years; 42% were male. The six-month risk of discontinuation was significantly lower in patients in the high-dose group as compared to the low-dose group (HR=0.737 for high-dose vs. low-dose, 95% CI=0.581, 0.935; P=0.012) and trended towards significance when comparing high-dose and medium-dose groups (HR=0.857 for high-dose vs. medium-dose, 95% CI=0.694, 1.059; P=0.153). CONCLUSIONS: Patients initiating ziprasidone therapy with an initial dose of at least 120 mg/day had better medication adherence compared to those initiating at lower doses. These findings confirm results seen in clinical trials suggesting improved efficacy and tolerability at higher ziprasidone doses.

Adult↗

PubMed2006

Effect of initial ziprasidone dose on treatment persistence in schizophrenia.

OBJECTIVE: To determine the relationship between ziprasidone initial dose and treatment persistence among patients diagnosed with schizophrenia. METHOD: Adult Medicaid recipients (N=1096) diagnosed with schizophrenia who had ziprasidone prescription claims between July 1, 2001 and September 30, 2003, were categorized by initial dose: low (20-60 mg per day, n=464), medium (61-119 mg per day, n=320) and high dose (120-160 mg per day, n=312). Treatment persistence up to 365 days was measured using refill patterns, allowing 15-day gaps between expected refill dates. Multivariate survival analysis explored the simultaneous impact of age, gender, race, previous hospitalization, and concomitant medication usage, in addition to initial dose of ziprasidone. Sensitivity analysis tested the robustness of results with different definitions for persistence and allowable gaps between refills. RESULTS: Discontinuation rates across the observation period (maximum, 12 months per individual) were lower for patients initiated with high-dose than low-dose ziprasidone (P=0.001). Other factors significantly associated with greater discontinuation of medication were monotherapy (versus combination therapy) and hospitalization within the 6 months prior to the index date of therapy. Black race was associated with greater discontinuation, although this was not consistent across sensitivity analyses. CONCLUSIONS: Patients with schizophrenia started on high doses of ziprasidone have lower discontinuation rates in a retrospective Medicaid database than patients started on low doses. These results were robust across various sensitivity analyses.

Adult↗

PubMed2006

Growth factor attenuation of IFNgamma-mediated hepatocyte apoptosis requires p21waf-1.

Interferon gamma (IFNgamma) is an important mediator of inflammatory liver damage as part of a complex cytokine network. In vitro, IFNgamma induces hepatocyte apoptosis. We hypothesized that the hepatocyte response to IFN signalling is context-dependent, and that specific growth factors, via phosphatidylinositol 3 kinase (PI(3)K) and protein kinase B/Akt signalling pathways, confer a cytoprotective effect. We established an in vitro model of IFNgamma-mediated primary hepatocyte injury. We show that epidermal growth factor (EGF) and hepatocyte growth factor (HGF) attenuate the IFNgamma-induced hepatocyte apoptosis. IRF-1, but not p53, is required for IFNgamma-mediated apoptosis. The loss of p21(waf-1) not only sensitizes the hepatocyte to IFNgamma-mediated injury but is required for survival factor mediated cytoprotection. We show that the PI(3)K inhibitor, LY294002, partially inhibits the apoptotic response of the hepatocyte to IFNgamma. In summary, we present evidence that a component of pro-apoptotic IFNgamma signalling in the primary hepatocyte occurs via the PI(3)K pathway. We show that the hepatocyte response to IFNgamma is modulated by external survival factors and that this survival signalling requires p21(waf-1).

Animals↗

PubMed2005

The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice.

Ras proteins function as molecular switches in signal transduction pathways, and, here, we examined the effects of the K-ras4A and 4B splice variants on cell function by comparing wild-type embryonic stem (ES) cells with K-ras(tmDelta4A/tmDelta4A) (exon 4A knock-out) ES cells which express K-ras4B only and K-ras(-/-) (exons 1-3 knock-out) ES cells which express neither splice variant, and intestinal epithelium from wild-type and K-ras(tmDelta4A/tmDelta4A) mice. RT-qPCR analysis found that K-ras4B expression was reduced in K-ras(tmDelta4A/tmDelta4A) ES cells but unaffected in small intestine. K-Ras deficiency did not affect ES cell growth, and K-Ras4A deficiency did not affect intestinal epithelial proliferation. K-ras(tmDelta4A/tmDelta4A) and K-ras(-/-) ES cells showed a reduced capacity for differentiation following LIF withdrawal, and K-ras(-/-) cells were least differentiated. K-Ras4A deficiency inhibited etoposide-induced apoptosis in ES cells and intestinal epithelial cells. However, K-ras(tmDelta4A/tmDelta4A) ES cells were more resistant to etoposide-induced apoptosis than K-ras(-/-) cells. The results indicate that (1) K-Ras4A promotes apoptosis while K-Ras4B inhibits it, and (2) K-Ras4B, and possibly K-Ras4A, promotes differentiation. The findings raise the possibility that alteration of the K-Ras4A/4B isoform ratio modulates tumorigenesis by differentially affecting stem cell survival and/or differentiation. However, K-Ras4A deficiency did not affect life expectancy or spontaneous overall tumor incidence in aging mice.

Aging↗

PubMed2005

p53 deficiency exacerbates pleiotropic mitotic defects, changes in nuclearity and polyploidy in transdifferentiating pancreatic acinar cells.

In a primary culture model for pancreatic acinar-ductal transdifferentiation, cells exhibited increased proliferation, changes in nuclearity and polyploidy. We identify the 'nucleus to centrosome' ratio of the progenitor cell, the dissemination of centrosomes at spindle poles and cytokinesis failure as critical determinants of mitosis outcome and centrosome inheritance. Abortive cytokinesis of mononuclear cells contributes to the binuclear cell pool, whereas enclosure of entire mitotic formations, within a single nuclear envelope, perpetuates polyploidization. Binuclear cell nuclei combine their genomes on a single metaphase plate, doubling descendant ploidy. Moreover, approximately 42% of binuclear and tetraploid cells assemble aberrant spindles with up to 8 centrosomes/poles. These phenotypes were exacerbated in p53-deficient cultures exhibiting increased S-phase entry, giant nuclei, multinucleation, multipolar mitoses and centrosome hyperamplification. The tendency of p53-proficient cells to spontaneously evade the tetraploidy checkpoint degenerates to uncontrolled polyploid progression in p53-deficient cultures, explaining why p53 abrogation alone rapidly descends to aneuploidy in this system. We detected constitutively nuclear mdm2, which may circumvent endogenous cell-cycle checkpoints, and pronounced accumulation of p21 and p27 in multinuclear cells and giant nuclei, consistent with roles in polyploidization. This in vitro model may recapitulate the processes underlying genomic instability in pancreatic tumours in vivo, and attests to the existence of a p53-dependent polyploidy checkpoint acting to limit the degree of polyploidization.

Animals↗

PubMed2005

ERbeta isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates.

Colorectal carcinoma shows several sex-related differences with regard to incidence, response to chemotherapy and microsatellite instability. These differences may relate to differential expression of ERbeta1 (wild-type) as well as the truncated ERbeta2 and ERbeta5 splice variant isoforms, which have recently been detected in normal and malignant colorectal epithelium. This hypothesis was tested through the study of ERbeta isoform protein and/or mRNA expression amongst 91 primary colorectal carcinoma cases and 20 colorectal carcinoma cell lines. Study of the latter showed an absolute correlation between mRNA and protein expressions for ERbeta1 and ERbeta2. ERbeta1 and ERbeta2 protein expression was lost in 22% and 49%, respectively, of the primary colorectal carcinomas. By contrast, ERbeta5 expression was found in all primary colorectal carcinomas and all colorectal carcinoma cell lines studied. Lower ERbeta1 protein expression was associated with poorer differentiation, higher pT stage and absence of microsatellite instability. Higher ERbeta2 protein expression was associated with right-sided location and presence of lymph node metastases. Protein expression of ERbeta1 correlated positively with expression of the oestrogen-responsive protein trefoil factor 1 (TFF1). There was no correlation between ERbeta protein isoform expression and response to 5-fluorouracil therapy, tumour proliferation, or thymidylate synthase expression. These data suggest that ERbeta1 and/or ERbeta2 isoform expression may have prognostic value and may explain sex-related differences in microsatellite instability and colorectal carcinoma. The opposing associations shown by ERbeta1 and/or ERbeta2 in relation to colorectal carcinoma are in keeping with differential activities shown by the two isoforms.

Adult↗

PubMed2005

Relationship between preventative physical health care and mental health in individuals with schizophrenia: a survey of caregivers.

The relationship between preventative physical health care and mental health in individuals with schizophrenia was assessed retrospectively by questionnaires completed by 504 caregivers. Psychiatric symptom severity and quality-of-life data on 332 respondents were evaluable. Suboptimal preventative physical health care was defined as absence of > or =2 examinations within a specified time: physical and dental within 12 months, eye within 24 months. Findings revealed similar use of mental health care services for all individuals, but those in the suboptimal physical health care group (n = 93 [28%]) had a lower quality of life (p < .011), more negative symptoms (p < .009), less paid employment (p < .001), and more alcohol/drug abuse (p = .02). These findings suggest that mental health care providers should play a more active role in monitoring the basic physical health care of patients with schizophrenia.

Adult↗

PubMed2005

Integrin characterization in pulmonary bronchioles.

Integrins are a family of cell surface glycoproteins that act as receptors for ECM proteins or for membrane bound counter-receptors on other cells. The integrin receptor family of vertebrates includes at least 16 distinct alpha subunits and at least 8 beta subunits which can associate to form more than 20 distinct integrins. So far, there are no published reports describing integrin characterization in mouse lung tissue and mouse Clara cells. This paper described the characterization of six integrins, mainly alpha(5), alpha(v), alpha(6), beta(1), beta(3), and beta(4), in mouse pulmonary bronchioles and also in Clara cell cultures. alpha(5), alpha(v), alpha(6), beta(1), and beta(4) integrins were present in Clara cells both in tissue sections and cultures. beta(3) integrin was found to be absent in mouse Clara cells.

Animals↗

PubMed2005

Hematopoietic stem cell trafficking in liver injury.

Bone marrow (BM) hematopoietic stem cells (HSCs) have been shown to facilitate regeneration in multiple nonhematopoietic tissues by either generating epithelial cells or altering the inflammatory response. Depending on injury type, the predominant mechanism of epithelial lineage regeneration occurs by spontaneous cell fusion or transdifferentiation. Irrespective of the mechanism, mobilization from the BM is a prerequisite. Mechanisms by which HSCs mobilize into damaged organs are currently under scrutiny. Murine and human studies have shown that the chemokine SDF-1 and its receptor CXCR4 participate in the mobilization of HSCs from BM and in the migration of HSCs to injured liver. SDF-1 is a potent HSC chemoattractant and is produced by the liver. Production is increased during liver injury leading to increased HSC migration to the liver, a finding diminished by neutralizing anti-CXCR4 antibodies. Additional factors have been implicated in the control of hepatic migration of HSCs such as IL-8, hepatocyte growth factor, and MMP-9. Matriceal remodeling is an essential component in HSC engraftment, and MMP-9 expression is increased in liver injury. This review focuses on the complex interaction of chemokines, adhesion molecules, and extracellular matrix factors required for successful migration and engraftment of HSCs into the liver.

Animals↗

PubMed2005

Improved retention of zymogen granules in cultured murine pancreatic acinar cells and induction of acinar-ductal transdifferentiation in vitro.

OBJECTIVES: To establish a primary culture model for murine pancreatic acinar cells and to investigate the effects of different culture conditions on the phenotype and plasticity of these cells in extended culture. METHODS: Acinar cells, cultured in Chee (CME) or Waymouth/Ham F-12 (WHME) media, exhibited 2 markedly dissimilar phenotypes. We employed 5'-bromo-2'-deoxyuridine (BrdU) incorporation, immunocytochemistry, and electron microscopy to investigate differences in cell cycle status and phenotype. RESULTS: CME-cultured cells grew as discrete epithelial islands and retained zymogen granules and endoplasmic reticulum stacks, yet expressed cytokeratin 7, suggesting that they comprise an intermediate between the acinar and ductal cell types. Observed by time-lapse videomicroscopy, cells transferred to WHME formed a confluent monolayer, flattened and dedifferentiated to a duct-like phenotype typified by loss of secretory apparatus, variable beta-catenin expression, an elongated teardrop shape, increased cell size, and nuclear pleomorphism. Transition between phenotypes did not involve apoptosis as assessed by morphologic criteria in Feulgen-stained cultures. The flattened cells exhibited increased BrdU incorporation and mitotic index, suggesting that dedifferentiation precedes the capacity for increased cell cycle entry, while the appearance of meganuclei is consistent with amplified DNA content. We also demonstrate greatly improved gene delivery to cultured acinar cells by adenovirus-mediated transduction compared with lipid-mediated transfection. CONCLUSIONS: This in vitro model confirms the plasticity of acinar cells and may serve to delineate the changes underlying acinar cell dedifferentiation and acquisition of a duct-like pluripotent phenotype.

Adenoviridae↗

PubMed2005

Pharmacoeconomic analysis of sertraline treatment of depression in patients with unstable angina or a recent myocardial infarction.

BACKGROUND: The prevalence of major depressive disorder in patients with acute coronary syndromes (ACSs) is high and associated with worse cardiovascular outcomes and higher health care costs. Sertraline is the only treatment for major depressive disorder studied in a placebo-controlled trial of patients with ACS and found to be safe and effective. The cost implications of providing antidepressant treatment in this population have not yet been examined. The objective was to evaluate from a payer perspective the potential reduction in costs and psychiatric and cardiovascular events and procedures following sertraline versus placebo treatment of major depressive disorder in patients hospitalized for ACS. METHOD: Data were analyzed from a randomized, double-blind, placebo-controlled 24-week trial (Sertraline Antidepressant Heart Attack Randomized Trial) of sertraline treatment for major depressive disorder in patients hospitalized for ACS. Main outcome measures included frequency and costs (derived from Medicare diagnosis-related group fee schedules) of psychiatric and cardiovascular events occurring during the treatment period. RESULTS: There was a trend toward significantly fewer psychiatric or cardiovascular hospitalizations in the sertraline compared with the placebo group (55/186 vs. 76/183; p = .054). The mean per patient cost associated with psychiatric and medical events over the course of treatment was 2733 US dollars for sertraline and 3326 US dollars for placebo, but the difference was not statistically significant (p = .32). After including the costs of the sertra-line (360 US dollars over 24 weeks), there was no increase in treatment costs for sertraline compared with placebo. CONCLUSION: Sertraline treatment of major depressive disorder following hospitalization for a recent myocardial infarction or unstable angina appears to be a cost-effective strategy.

Angina, Unstable↗

PubMed2005

Impact of atypical antipsychotics on outcomes of care in schizophrenia.

OBJECTIVE: To compare persistence, compliance, and psychiatric treatment costs in patients who were initiated on atypical antipsychotics. METHODS: Medical and pharmacy claims data were used to compare persistence (days of therapy between first and last prescriptions, allowing therapy gaps < 90 days); compliance (ratio of days of medication supplied to total days on therapy); treatment costs in adults with schizophrenia having claims for atypical antipsychotics from March 2001 to August 2003; and enrollment for > or =6 months before and > or =12 months after therapy initiation. Psychiatric treatment costs for 1 year were examined before and after therapy initiation. Differences in costs were tested by univariate analyses. RESULTS: Persistence was approximately 30 days longer for patients receiving ziprasidone (n = 217; 228 days) than risperidone (n = 831; 193 days) or olanzapine (n = 762; 201 days). Compliance was significantly (P<.05) higher among patients receiving ziprasidone (87%) compared with other treatments (78%-80%). Ziprasidone patients had significantly larger decreases (- USD 6866) in mean annual psychiatric-related costs following therapy initiation than those on risperidone (- USD 3353; P = .0116) or olanzapine (- USD 4764; P = .0021). The primary driver of cost savings was reduced hospitalization after treatment initiation. CONCLUSION: Patients initiated on ziprasidone had longer persistence, better compliance, and greater decreases in psychiatric-related costs than those initiated on other atypicals.

Adult↗

PubMed2004

Functional Smoothened is required for expression of GLI3 in colorectal carcinoma cells.

We investigated a role for Hedgehog signalling in colon cancer by studying transcription of members of the pathway in human colorectal carcinoma cell lines. We determined the methylation status and screened the gene encoding the Hedgehog receptor-associated protein Smoothened (SMO) for putative mutations. In three cell lines lacking SMO expression the SMO promoter was fully methylated and the transcription factor GLI3 was not expressed. Two additional cell lines both having one methylated SMO allele and expressing mutant SMO did not express GLI3. Our results suggest that expression of wild-type SMO is required for expression of GLI3 by a mechanism that is independent of conventional Hedgehog signalling.

Base Sequence↗

PubMed2004

Additive effect of p53, p21 and Rb deletion in triple knockout primary hepatocytes.

Using Cre-Lox technology to inducibly delete Rb from wild-type, p21- and/or p53-deficient primary hepatocytes, we investigated the role of p53, p21 and pRb in the regulation of liver cell proliferation, polyploidization and death. These cellular decisions are critical to maintaining liver cell replacement in disease, and in determining the likelihood of carcinogenesis in chronic liver injury. Clearly, the present study shows a complex interplay between p53, p21 and pRb, which regulates the likelihood of hepatocytes stimulated from quiescence, to proliferate, undergo polyploidy or die. It reveals that these proteins act both in concert and independently, demonstrating that a small set of key cellular players is common to diverse cell decisions of fundamental importance to disease.

Animals↗

PubMed2004

Expression of Sonic hedgehog pathway genes is altered in colonic neoplasia.

The Hedgehog (Hh) signalling pathway is crucial for normal development and patterning of numerous human organs including the gut. Hh proteins are also expressed during gastric gland development and gastric epithelial differentiation in adults. Recently, dysregulation of these developmentally important genes has been implicated in cancer, leading to the present study of the expression of Hh signalling proteins in colon cancer. In this study, normal colon and colonic lesions (hyperplastic polyp, adenoma, and colonic adenocarcinoma) were examined by immunohistochemistry using antibodies against Hh signalling molecules: the secreted protein Sonic hedgehog (SHH), its receptor Patched (PTCH), and the PTCH-associated transmembrane protein Smoothened (SMOH). The study shows that Hh signalling pathway members are expressed in normal colonic epithelium. SHH was expressed at the top of the crypts and in a few basally located cells, while PTCH was detected in the neuroendocrine cells and SMOH at the brush border of superficial epithelium. RT-PCR analysis of laser-microdissected crypts from normal human colon confirmed that mRNAs encoding these proteins were expressed in colonic epithelium. Expression of SHH, PTCH, and SMOH was up-regulated in hyperplastic polyps, adenomas, and adenocarcinomas of the colon, and SHH expression correlated with increased expression of the proliferation marker Ki-67 in all lesions examined. To address whether the Hh signalling pathway is functional in the gut, the effect of Shh on epithelial cells in vitro was explored by treating primary murine colonocytes with either Shh peptide or neutralizing anti-Shh antibody. The proportion of cells in the S-phase was assessed by bromodeoxyuridine (BrdU) incorporation. It was found that exogenous Shh promotes cell proliferation in colonocytes, while anti-Shh inhibits proliferation, suggesting that Shh is required during proliferation of epithelial cells in vitro. It is suggested that SHH is required during epithelial proliferation in the colon and that there is a possible role for Hh signalling in epithelial colon tumour progression in vivo.

Adenocarcinoma↗

PubMed2004

p21(Waf1/Cip1) regulates proliferation and apoptosis in airway epithelial cells and alternative forms have altered binding activities.

p21(Waf1/Cip1) plays central roles in proliferation, differentiation, and apoptosis. Alterations in the expression and subcellular localisation of p21 occur during several lung diseases but the roles of p21 in the lung epithelium are unknown. The effects of p21 on proliferation and apoptosis in mouse airway epithelial cells (AECs) were examined using p21-null mice. AECs isolated from p21-null mice had increased proliferation and apoptotic rates compared to AECs from wild-type mice. Alterations in the subcellular localization of the cell cycle regulatory proteins p27, PCNA, and p53 were also evident in p21(-/-) cells. The nuclear and cytoplasmic forms of p21 present in AECs were also examined. Full-length p21 (20 kDa) was detected in nuclear fractions but a C-terminal truncated form (17 kDa) of p21 was present in cytoplasmic fractions. The binding activities of truncated p21 were altered compared to full-length p21. Although the latter was complexed with PCNA, Cdk2, Cdk4, Cdk6, cyclin D3, and cyclin E, truncated p21 was bound only to Cdk4 and cyclin D3. In conclusion, p21 regulates proliferation and protects against apoptosis in AECs. In addition, different forms of p21 are present in AECs and the subcellular localization of these forms reflects differences in p21 activity.

Animals↗

PubMed2004

Potential of hematopoietic stem cell therapy in hepatology: a critical review.

Adult stem cell plasticity raised expectations regarding novel cellular therapies of regenerative medicine after findings of unexpected plasticity were reported. In this review, reports of hematopoietic stem cells (HSCs) contributing to hepatocytic lineages are critically discussed with reference to rodent and human models. In particular, the role of liver injury and the potential contribution HSCs make to hepatic regeneration in both injury and physiological maintenance is reviewed. The relative contributions of genomic plasticity and cell fusion are studied across different model systems, highlighting possible factors that may explain differences between often conflicting reports. Insights from experimental studies will be described that shed light on the mechanisms underlying the migration, engraftment, and transdifferentiation of HSCs in liver injury. Although it appears that under differing circumstances, macrophage fusion, HSC fusion, and HSC transdifferentiation can all contribute to hepatic epithelial lineages, a much greater understanding of the factors that regulate the long-term efficacy of such cells is needed before this phenomenon can be used clinically.

Animals↗

PubMed2004

Induction of p21 and nuclear accumulation of TAp73alpha and c-abl during apoptosis of cisplatin-treated primary pancreatic acinar cells.

To understand the role of endogenous p53 and related proteins in pancreatic injury responses, we established primary pancreatic acinar cultures from wild-type and p53-deficient mice and investigated the relationship between apoptosis, proliferation and underlying molecular events in cells exposed to the DNA cross-linking agent cisplatin. This treatment led to a time-dependent elevation in p53 levels, accompanied by phosphorylation at key serine residues. Despite this apparent activation of p53, acinar cells entered growth arrest unaffected by p53 deficiency. Moreover, p53-null cells exhibited only a temporal delay in engaging apoptosis, compared to wild-type counterparts. Whilst p53-proficient cells rapidly accumulated nuclear p21, the kinetics of p21 accumulation in p53-null cells were delayed, correlating with the execution of p53-independent apoptosis. During the course of treatment, c-abl and TAp73alpha, a p53 homologue, accumulated in acinar cell nuclei, irrespective of genotype, indicating that they are induced upon DNA damage and that they may act in parallel or in concert with p53 for the eradication of damaged acinar cells. We also report the nuclear accumulation of c-abl and TAp73alpha in cells, treated with the nuclear export inhibitor leptomycin B, suggesting that these proteins undergo constant nucleocytoplasmic shuttling in normal culture conditions, possibly reflecting a role for TAp73alpha-mediated transactivation or repression in the regulation of in vitro acinar cell growth.

Animals↗