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J J Anderson

Publications and source records attributed to J J Anderson.

At least 19 recordsLinked to original sources
PubMed2003

Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) produces anxiolytic or antidepressant effects in several rodent models through incompletely described mechanisms. Anxiolytics and antidepressants share several neuroendocrine features, including acute activation of the hypothalamic-pituitary-adrenal (HPA)-axis, desensitization of neuroendocrine responses with repeated dosing, and desensitization of the HPA axis to 5-HT1A agonist stimulation. We characterized these neuroendocrine parameters in rats treated systemically with MPEP and compared them to those induced by the anxiolytic buspirone. Acutely, MPEP dose-dependently (0.1-10 mg/kg i.p.) increased plasma corticosterone concentrations. These responses were blocked by 50% with the 5-HT1A antagonist WAY100635. The corticosterone responses to both 3 mg/kg MPEP and buspirone were decreased by 80% after 5 days of twice-daily injections. Repeated injection with MPEP decreased HPA-axis sensitivity to buspirone challenge by 75%. This desensitization was not associated with changes in mGluR5 or 5-HT1A receptor binding properties, expression of G-protein subunits coupled to these receptors, or in 5-HT-stimulated binding of [(3)H]-GTPgammaS to membranes. We conclude that MPEP acutely disinhibits the HPA axis, in part through uncharacterized changes in serotonergic signaling. Desensitization of 5-HT1A responses after repeated MPEP administration may indicate that, like other anxiolytics and antidepressants, plasticity in 5-HT signal transduction pathways has occurred.

Animals↗
PubMed2003

Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268.

Previous studies have shown that the metabotropic glutamate receptor (mGluR)2/3 agonist LY354740 attenuated glutamate release in medial prefrontal cortex (mPFC) induced by the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine. In the present study we examined the effects of the more potent mGluR2/3 selective agonist LY379268 on ketamine-evoked glutamate and dopamine (DA) release in mPFC of male rats. Subjects were implanted with a unilateral microdialysis probe in the mPFC and were tested 12-24 h after implantation. Ketamine (18 mg/kg, s.c.) evoked a significant release of glutamate and DA, although the glutamate response was slower in onset compared with DA. Pretreatment with either systemic (3 mg/kg s.c.) or local (1 microM, in the probe) LY379268 blocked ketamine-evoked glutamate, but not DA, release. When applied directly to the mPFC via the dialysis probe, ketamine (1 mM in the probe) had no effect on glutamate release but did significantly enhance the release of DA. Application of NMDA (500 microM in the probe), on the other hand, decreased DA while increasing glutamate release. The effect of NMDA on evoking glutamate release was blocked by systemic but not local administration of LY379268. These findings indicate that systemic ketamine increases both glutamate and DA release in mPFC and that the effect on glutamate can be blocked by stimulating mPFC group II mGluR receptors. Local ketamine, on the other hand, does not increase glutamate but does increase DA release. This suggests that ketamine acts outside of the mPFC to enhance glutamate, but within the mPFC to enhance DA release. The origin of the ketamine effect on mPFC glutamate is currently not known.

Amino Acids↗
PubMed2003

Type 1 growth factor receptor expression in node positive breast cancer: adverse prognostic significance of c-erbB-4.

BACKGROUND: There is a clear need to define biological markers that will predict the response to treatment in breast cancer, and several recent studies suggest that the expression of type 1 growth factor receptors may prove important in this regard. The type 1 growth factor receptors are a family of transmembrane receptors comprising epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3, and c-erbB-4. Both EGFR and c-erbB-2 are associated with poor prognosis in certain tumours. AIMS: There is very little information concerning expression patterns of the full range of type 1 growth factor receptors, especially with respect to c-erbB-3 and c-erbB-4. Therefore, this study was designed to compare the expression of each, and to assess whether expression of any of the factors was related to patient survival in a clinical series. METHODS: Type 1 growth factor receptor expression was investigated by means of immunohistochemistry in a series of node positive patients with breast cancer (n = 66), and statistical analysis was carried out to determine associations between variables and survival analysis for each variable. RESULTS: There were several correlations between variables, and overexpression of EGFR, c-erbB-2, and c-erbB-4 was found to be associated with adverse clinical outcome, although the results were significant only for c-erbB-4 (p = 0.002). CONCLUSION: Although patient numbers are small, this is the first report describing c-erbB-4 as an adverse prognostic marker. These findings are in contrast to previous investigations and may relate to the fact that the patients studied all had advanced stage disease and had undergone similar chemotherapy regimens in the context of a clinical trial.

Biomarkers, Tumor↗
PubMed2003

The role of the tumour suppressor p33 ING1b in human neoplasia.

The inhibitor of growth (ING) genes (ING1-4) probably descend from tumour suppressor genes. ING1 was the first to be identified and later isolated using an approach to detect genes whose expression is suppressed in cancer. The others were isolated through homology and similarity searches in human and mouse databases. All members contain a plant homeodomain involved in macromolecule recognition. Apart from the extensively studied ING1, little is known about the number of transcripts encoded by the other members or their gene structure. ING1 encodes several differentially spliced mRNAs, which may produce a family of proteins. The most widely expressed protein isoform is p33(INGb1), which is involved in restriction of cell growth and proliferation, apoptosis, tumour anchorage independent growth, cellular senescence, maintenance of genomic stability, and modulation of cell cycle checkpoints. ING1 gene mutation is uncommon in cancer, although the subcellular localisation of p33(INGb1) may have an effect on its function. The p33(INGb1) cellular compartmental shift from the nucleus to the cytoplasm may cause loss of normal cellular function, and may play a central role in the pathogenesis of several cancers.

Apoptosis↗
PubMed2003

Downregulation of nuclear expression of the p33(ING1b) inhibitor of growth protein in invasive carcinoma of the breast.

BACKGROUND/AIMS: The inhibitor of growth gene 1 (ING1) is a modulator of cell cycle checkpoints, apoptosis, and cellular senescence. The most widely expressed ING1 isoform is p33(ING1b), which can modulate p53, a molecule that is frequently altered in breast cancer. Reduced ING1 mRNA expression has been observed in primary breast cancer expressing wild-type p53. METHODS: p33(ING1b), p53, oestrogen receptor (ER), and progesterone receptor (PgR) expression was studied in 86 primary invasive breast cancers using immunohistochemistry. RESULTS: Reduced nuclear expression of p33(ING1b) was found in cancer cells, both in intensity and the proportion of cells staining. This was associated with enhanced cytoplasmic p33(ING1b) expression in a proportion of cases. Analysis of several known biological factors indicated that high grade tumours were of larger size and more often negative for ER and PgR expression. However, larger tumours were more frequently p53 negative. These results provide evidence that p33(ING1b) alterations are associated with more poorly differentiated tumours. Positive correlations were found between nuclear p33(ING1b) expression and both ER and PgR expression. CONCLUSIONS: Optimum function of p53 is dependent on p33(ING1b) so that a reduction of nuclear p33(ING1b) expression, as seen in this series, would be predicted to compromise p53 function. This study showed that p33(ING1b) alterations were associated with more poorly differentiated tumours. Therefore, p33(ING1b) expression could be used as a marker of differentiation in invasive breast cancer. These results support the view that loss of p33(ING1b) may be an important molecular event in the differentiation and pathogenesis of invasive breast cancer.

Adult↗
PubMed2002

Nuclear to cytoplasmic compartment shift of the p33ING1b tumour suppressor protein is associated with malignancy in melanocytic lesions.

AIMS: Cutaneous malignant melanoma is an unpredictable neoplasm. Studies of cell cycle and proliferation-associated proteins may help in the understanding of the genesis of melanomas. The tumour suppressor gene TP53 has been shown to be involved in melanomas. However, the incidence of TP53 malfunction in cutaneous melanoma is unclear, and other regulators of cell cycle control are likely to be involved in both the development and progression of melanocytic neoplasia. A candidate is the ING1 gene, which co-operates with TP53 in growth suppression and apoptosis. Thus loss of ING1 function may have similar consequences to loss of TP53 function and may contribute to tumorigenesis. Therefore we have studied the expression of p33ING1b protein in cutaneous melanocytic neoplasia. METHODS AND RESULTS: Sixty-seven melanocytic lesions were studied by immunohistochemistry for the expression of p33ING1b. In our series there was loss of nuclear p33ING1b expression in invasive malignant melanoma compared with normal cutaneous melanocytes or the melanocytes of benign melanocytic naevi. This was associated with an enhancement of cytoplasmic p33ING1b expression which was particularly prominent in invasive malignant melanoma. CONCLUSIONS: Cytoplasmic immunostaining for p33ING1b using MAb GN2 is strongly associated with 'activated' melanocytic lesions; therefore it is possible that this MAb could be of value in diagnostic practice. Furthermore, the reduction in p33ING1b expression and perhaps translocation from the nucleus to the cytoplasm may play a central role in the development and progression of melanomas.

Adolescent↗
PubMed2002

Loss of nuclear expression of the p33(ING1b) inhibitor of growth protein in childhood acute lymphoblastic leukaemia.

BACKGROUND/AIMS: p33(ING1b) is a tumour suppressor protein involved in growth control and apoptosis. Suppression of p33(ING1b) expression is associated with the loss of cellular growth control and immortalisation, whereas its overexpression causes cell cycle arrest. Moreover, normal p33(ING1b) expression is essential for optimal function of p53. Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood, accounting for one third of all childhood malignancies. A variety of cytogenetic abnormalities have been described but there is no single abnormality common to all cases. Deregulation of the TP53 pathway is a common genetic abnormality in human malignancies. However, TP53 mutations are uncommon in ALL. It is possible that alternative mechanisms of regulation of the TP53 apoptosis pathway, such as modulation of p33(ING1b) expression, may be important in ALL. The aim of this study was to assess the expression of p33(ING1b) in childhood ALL. METHODS: One hundred and forty five patients with childhood ALL were investigated in this immunohistochemical study of the expression of p33(ING1b). RESULTS: Loss of nuclear expression of p33(ING1b) was seen in 78% of cases. This was associated with increased cytoplasmic expression of the protein. Kaplan Meier survival analysis demonstrated a trend towards a better prognosis for patients with tumours that had lost nuclear p33(ING1b). CONCLUSION: These results suggest that the loss of nuclear p33(ING1b) expression may be an important molecular event in the pathogenesis of childhood ALL.

Adolescent↗
PubMed2001

Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis.

OBJECTIVE: To develop criteria for symptomatic improvement in patients with ankylosing spondylitis (AS), using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs). METHODS: Patient data from 5 short-term, randomized, controlled trials were used to assess equivalence, reliability, and responsiveness of multiple items in the 5 outcome domains for AS treatment: physical function, pain, spinal mobility, patient global assessment, and inflammation. At least one measure per domain was responsive (standardized response mean of > 0.5), except for the spinal mobility domain, which was omitted from the criteria. We developed and tested candidate improvement criteria in a random two-thirds subset from the 3 largest trials and used the remaining one-third for validation. These 3 largest trials included 923 patients (631 receiving NSAIDs, 292 in placebo groups). We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of < or = 25%. RESULTS: Candidate definitions were changes in single domains and in multiple measure indices, as well as combinations of improvements in multiple domains. Worsening in a domain was defined as a change for the worse of > or = 20% and a net change for the worse of > or = 10 units on a scale of 0-100. Partial remission (for comparison purposes) was defined as an end-of-trial value of < 20/100 in each of the 4 domains. Among 20 candidate criteria, change of > or = 20% and > or = 10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset (51% of patients improved with NSAIDs, 25% with placebo; chi2 = 36.4, P < 0.001). Results were confirmed in the validation subset. Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion. Among all 923 patients, improvement rates using this criterion were 49% for NSAID-treated patients and 24% for placebo-treated patients. CONCLUSION: Although further validation using data from new trials is still needed, we conclude that we have developed a clinically valid, easy-to-use measure of short-term improvement in AS.

Adult↗
PubMed2001

Deriving a risk-adjustment model for pressure ulcer development using the Minimum Data Set.

OBJECTIVE: To use the Minimum Data Set (MDS) to derive a risk-adjustment model for pressure ulcer development that may be used in assessing the quality of nursing home care. DESIGN: Perspective observational study using MDS data from 1997. SETTING: A large, for-profit, nursing home chain. PARTICIPANTS: Our unit of analysis was 39,649 observations made on 14,607 nursing home residents who were without a stage 2 or larger pressure ulcer on an index assessment. MEASUREMENTS: Pressure ulcer status was determined at an outcome assessment approximately 90 days after an index assessment. Potential predictors of pressure ulcer development were examined for bivariate associations, contributing to the development of a multivariate logistic regression model. RESULTS: A stage 2 or larger pressure ulcer developed in 2.3% of the observations. Seventeen resident characteristics were found to be associated with pressure ulcer development. These included dependence in mobility and transferring, diabetes mellitus, peripheral vascular disease, urinary incontinence, lower body mass index, and end-stage disease. A risk-adjustment model based on these characteristics was well calibrated and able to discriminate among residents with different levels of risk for ulcer development (model c-statistic = 0.73). CONCLUSION: A clinically credible risk-adjustment model with good performance properties can be developed using the MDS. This model may be useful in profiling nursing homes on their rate of pressure ulcer development.

Aged↗
PubMed2001

Evaluation of a risk-adjustment model for pressure ulcer development using the Minimum Data Set.

OBJECTIVE: To validate a previously derived risk-adjustment model for pressure ulcer development in a separate sample of nursing home residents and to determine the extent to which use of this model affects judgments of nursing home performance. DESIGN: Retrospective observational study using Minimum Data Set (MDS) data from 1998. SETTING: A large, for-profit, nursing home chain. PARTICIPANTS: Twenty-nine thousand and forty observations were made on 13,457 nursing home residents who were without a pressure ulcer on an index assessment. MEASUREMENTS: We used logistic regression in our validation sample to calculate new coefficients for the 17 previously identified predictors of pressure ulcer development. Coefficients from this new sample were compared with those previously derived. Expected rates of pressure ulcer development were determined for 108 nursing homes. Unadjusted and risk-adjusted rates of pressure ulcer development from these homes were also calculated and outlier identification using these two approaches was compared. RESULTS: Predictors of pressure ulcer development in the derivation sample generally showed similar effects in the validation sample. The model c-statistic was also unchanged at 0.73, but it was not calibrated as well in the validation sample. On applying the model to the nursing homes, expected rates of ulcer development ranged from 1.1% to 3.2% (P <.001). The observed rates ranged from 0% to 12.1% (P <.001). There were 12 outliers using unadjusted rates and 15 using adjusted performance. Ten nursing homes were identified as outliers using both approaches. CONCLUSIONS: Our MDS risk-adjustment model for pressure ulcer development performed well in this new sample. Nursing homes differ significantly in their expected rates of pressure ulcer development. Outlier identification also differs depending on whether unadjusted or risk-adjusted performance is evaluated.

Aged↗
PubMed2001

Isoflavones inhibit proliferation of ovarian cancer cells in vitro via an estrogen receptor-dependent pathway.

Incidence rates of ovarian cancer remain lowest in Asian nations, which consume diets rich in soy products, whereas they remain among the highest in the United States and other Western nations, which consume low amounts of soy foods. The hypothesis of this study is that soy-derived isoflavones inhibit the proliferation of ovarian cancer cells in vitro by regulating cytokine synthesis. Cell proliferation was evaluated by bromodeoxyuridine and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. DNA synthesis of Caov-3 and NIH:OVCAR-3, two ovarian cancer cell lines, was significantly inhibited by genistein or daidzein at dietarily relevant concentrations (10(-8)-10(-10) M). Also, the number of viable cells was significantly lower (45-75%) in all isoflavone-treated groups than in the control group (P < 0.01). The addition of ICI-182780, an estrogen antagonist, blocked these inhibitory effects. In addition, interleukin-6 synthesis by these two cell lines was inhibited by genistein or daidzein; production was decreased by approximately 20% compared with the control group (P < 0.05). In contrast, transforming growth factor-beta 1 production in ovarian cancer cells incubated with genistein or daidzein was significantly greater, i.e., by approximately 30%, than in the control group (P < 0.05). Addition of ICI-182780 also neutralized the effects of isoflavones on the production of these two cytokines by ovarian cancer cells. In summary, genistein and daidzein independently modify cytokine production and reduce ovarian cancer cell proliferation via, at least in part, an estrogen receptor-dependent pathway.

Cell Division↗
PubMed2001

Calcium requirements during adolescence to maximize bone health.

The calcium requirements of boys and girls during adolescence have largely been based on balance studies, including more recently the use of stable nuclides. Bone measurements by dual energy X-ray absorptiometry (DXA) and similar instruments have provided an end-point by which to assess skeletal development, either of the entire skeleton or of specific bones, in relation to the consumption of calcium and other nutrients and to physical activity. Several cross-sectional studies, using measurements of bone mineral density (BMD) and bone mineral content (BMC), suggest that optimal calcium intakes for female adolescents may be somewhat lower than published as the Adequate Intakes (AIs) by the Institute of Medicine in 1997, but they may be somewhat higher for adolescent males. These results suggest that gender should be considered in establishing recommendations for calcium. In addition, other studies have provided evidence that prepubertal and postpubertal skeletal growth of males and females is enhanced by regular physical activities and that the optimal attainment of BMC and BMD by females by late adolescence may not be dependent on such a high calcium intake as previously thought, although males may need at least the recommended amount. Therefore, physical activity should also be considered in establishing recommendations for calcium. In summary, two lines of evidence suggest that more extensive information on diet and lifestyle should be considered in the future for making more specific recommendations on calcium intakes for optimal skeletal development for prepubertal and postpubertal boys and girls.

Adolescent↗
PubMed2001

Health care reorganization and quality of care: unintended effects on pressure ulcer prevention.

BACKGROUND: Health care reorganizations, with a change in focus from inpatient to outpatient care, are becoming increasingly frequent. Little is known regarding how reorganizations may affect risk-adjusted outcomes for those programs, usually inpatient, that lose resources as a result of the change in organizational focus. OBJECTIVES: To determine changes in risk-adjusted rates of pressure ulcer development over an 8-year period, the final 3 of which were characterized by a significant reorganization of the health care system. DESIGN: This was an observational study that used an existing database. SUBJECTS: Subjects were residents of Department of Veterans Affairs long-term care units between 1990 and 1997 who were without a pressure ulcer at an index assessment. MEASURES: The study examined risk-adjusted rates of pressure ulcer development, and proportions of new ulcers that were severe (stages 3 or 4) were calculated for successive 6-month periods. RESULTS: Between 1990 and 1994, risk-adjusted rates of pressure ulcer development declined significantly, by 27%. However, beginning in 1995, rates began to increase, and in 1997 they were similar to those in 1990. The proportion of new ulcers that were severe increased significantly over time (P = 0.01). CONCLUSIONS: The reorganization of the VA that began in 1995, with its emphasis on outpatient care, was associated with an increase in rates of pressure ulcer development. This highlights the need to carefully monitor the quality of care in programs that may be losing resources as a result of the reorganization.

Aged↗
PubMed2001

Evaluating diagnosis-based case-mix measures: how well do they apply to the VA population?

BACKGROUND: Diagnosis-based case-mix measures are increasingly used for provider profiling, resource allocation, and capitation rate setting. Measures developed in one setting may not adequately capture the disease burden in other settings. OBJECTIVES: To examine the feasibility of adapting two such measures, Adjusted Clinical Groups (ACGs) and Diagnostic Cost Groups (DCGs), to the Department of Veterans Affairs (VA) population. RESEARCH DESIGN: A 60% random sample of veterans who used health care services during FY 1997 was obtained from VA inpatient and outpatient administrative databases. A split-sample technique was used to obtain a 40% sample (n = 1,046,803) for development and a 20% sample (n = 524,461) for validation. METHODS: Concurrent ACG and DCG risk adjustment models, using 1997 diagnoses and demographics to predict FY 1997 utilization (ambulatory provider encounters, and service days-the sum of a patient's inpatient and outpatient visit days), were fitted and cross-validated. RESULTS: Patients were classified into groupings that indicated a population with multiple psychiatric and medical diseases. Model R-squares explained between 6% and 32% of the variation in service utilization. Although reparameterized models did better in predicting utilization than models with external weights, none of the models was adequate in characterizing the entire population. For predicting service days, DCGs were superior to ACGs in most categories, whereas ACGs did better at discriminating among veterans who had the lowest utilization. CONCLUSIONS: Although "off-the-shelf" case-mix measures perform moderately well when applied to another setting, modifications may be required to accurately characterize a population's disease burden with respect to the resource needs of all patients.

Aged↗
PubMed2001

Topoisomerase II alpha and II beta expression in childhood acute lymphoblastic leukaemia: relation to prognostic factors and clinical outcome.

BACKGROUND/AIMS: Many regimens used in the treatment of childhood acute lymphoblastic leukaemia (ALL) include Daunorubicin or Etoposide, which act as topoisomerase poisons. It has been suggested that there may be a relation between topoisomerase expression and response to topoisomerase poisons, based mainly on results from in vitro studies. Therefore, the aim of this study was to investigate this relation in a clinical setting and determine whether topoisomerase II alpha and II beta might be of predictive value in ALL. METHODS: Cellular expression of topoisomerases II alpha and II beta was assessed in 177 cases of ALL by immunohistochemistry using monoclonal antibodies to the two enzymes. The percentages of cell nuclei showing positive staining for topoisomerase II alpha and II beta expression were assessed. RESULTS: Taking the series as a whole, a clear separation of survival curves was seen with the established prognostic markers white blood cell (WBC) count, CD10 status, and sex. However, topoisomerase II alpha and II beta expression showed no relation to survival. No association was found between the topoisomerases and the prognostic markers CD10 and WBC count; however, topoisomerase II alpha expression was found to be related to sex, with expression being lower in girls (p = 0.002). CONCLUSIONS: These results suggest that the response to topoisomerase poisons cannot be predicted by the assessment of topoisomerase II alpha and II beta expression as defined by immunohistochemistry.

Adolescent↗