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Biomedical subjects

D Morris

Publications and source records attributed to D Morris.

At least 55 records · Page 3Linked to original sources
PubMed1999

Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support.

C-erbB-2/HER-2 (designated HER-2) is overexpressed in both primary and metastatic breast cancer and predicts poor prognosis. We investigated the expression of HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy (HDCT) with autologous blood stem cell (ABSC) support and correlated the presence (positive) or absence (negative) of HER-2 overexpression in these patients with response to treatment, progression-free survival (PFS) and overall survival (OS). The level of HER-2 expression was analyzed in 57 patients with metastatic breast cancer undergoing HDCT with ABSC support. Plasma from peripheral blood was taken at three different time points during the course of treatment and was analyzed using an enzyme immunoassay (EIA) to detect circulating levels of the extracellular portion of HER-2. HER-2 levels were elevated (>0.2 U/mg protein) in 27/57 (47.4%) patients at one or more time points during treatment. The level of HER-2 varied during the course of treatment. Following induction chemotherapy (ICT), five patients who were negative initially, showed overexpression of HER-2. Three patients overexpressed HER-2 only after HDCT/ABSC. Response to treatment was similar in patients independent of plasma HER-2 levels. Overexpression of HER-2 was associated with a significantly shorter PFS (P = 0.004, log rank) and OS (P = 0.003, log rank) after HDCT/ABSC. HER-2 overexpression, patient age, estrogen receptor status, progesterone receptor status, and previous hormone treatment were assessed by univariate and multivariate analysis. Univariate analysis determined that only HER-2 overexpression correlated significantly with decreases in progression free survival (P = 0.005, Cox regression). Decreased overall survival correlated significantly with HER-2 overexpression (P = 0.004) and decreased expression of both estrogen receptor (P = 0.032) and progesterone receptor (P = 0.039). In multivariate analysis of these variables, only HER-2 expression levels proved to be of independent statistical significance in predicting outcome for both PFS (P = 0.007) and OS (P = 0.002). These results suggest that overexpression of HER-2, measured by EIA in plasma may predict a shorter PFS and OS in patients with metastatic breast cancer treated with HDCT and ABSC support.

Adult↗
PubMed1999

mdm-2 gene amplification in 3T3-L1 preadipocytes.

In this study the regulation of the murine double minute-2 (mdm-2) gene was examined in NIH 3T3-L1 preadipocytes. The 3T3-L1 cell line, under proper conditions, has the capacity to differentiate from fibroblasts into adipocytes [15]. A recent report demonstrated that mdm-2 overexpression could block myogenesis [12]. While examining the regulation of the mdm-2 gene during adipogenesis, it was discovered that 3T3-L1 cells possess a 36-fold elevation of mdm-2 mRNA relative to A31 cells, another immortalized Balb/c 3T3 fibroblast cell line that lacks the capacity to differentiate. Based on Southern blot analysis, the increase in mdm-2 mRNA was the result of a mdm-2 gene amplification. The level of Mdm-2 protein in undifferentiated 3T3-L1 cells was elevated relative to A31 fibroblasts and resulted from translation of mRNA transcripts initiating from the p53-independent P1 promoter. We also examined how mdm-2 and p53 levels changed as undifferentiated fibroblasts converted to adipocytes. While mdm-2 mRNA levels remained elevated, p53 mRNA, protein, and DNA-binding activity decreased. These results suggest that adipogenesis is unaffected by elevated Mdm-2 levels and that the overexpression of mdm-2 mRNA is predominantly p53 independent.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Serum cytosolic beta-glucosidase elevation and early ischemic injury to guinea pig small intestine.

BACKGROUND: The lack of an early, sensitive marker for intestinal ischemia has led to delay in diagnosis and worsended outcome for patients with acute onset of this condition. Our preliminary studies revealed that guinea pig cytosolic beta-glucosidase (CBG) is expressed predominantly in the small intestine, with lower levels in the liver and pancreas and undetectable levels in other organs. Cytosolic beta-glucosidase was investigated as a serum marker of small intestinal ischemia in a guinea pig model. METHODS: Guinea pigs underwent anesthesia, sham laparotomy, 30 minutes of mesenteric ischemia followed by 6 hours of reperfusion 6 hours of sustained mesenteric ischemia, or closed-loop small bowel obstruction. Serum samples were assayed for CBG activity. At the conclusion of the ischemia/reperfusion experiments, small bowel samples were assayed for residual enzyme activity, and paraffin sections were graded for the severity of histologic injury. RESULTS: Serum CBG activity rose rapidly after intestinal ischemia with and without reperfusion. Peak enzyme activities were elevated 23-fold for reperfused animals (P < .001) by 4 hours. For nonreperfused animals, peak serum CBG activities reached 29-fold above baseline and were significantly higher than the CBG activities of reperfused animals at 4 hours (P < .01) and at 6 hours (P < .05). Mucosal injury ranged from undetectable to moderate and corresponded in severity with both peak serum enzyme activity and decreased residual activity in the small bowel. In animals subjected to closed-loop obstruction, there was a mean increase of serum CBG of 9.2-fold from 4 to 6 hours after establishment of obstruction (P < .05). CONCLUSIONS: In the guinea pig model, CBG is a sensitive marker of ischemic injury caused by arterial occlusion or closed-loop obstruction of the small bowel.

Animals↗
PubMed1999

Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340.

Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas.

Animals↗
PubMed1999

Association between prenatal exposure to methylmercury and developmental outcomes in Seychellois children: effect modification by social and environmental factors.

UNLABELLED: The Seychelles Child Development Study (SCDS) is testing the hypothesis that prenatal exposure to low doses of MeHg from maternal consumption of fish is associated with the child's developmental outcomes. No deleterious relationships between exposure to MeHg and cognitive functions have been identified in the primary analysis of the main cohort through 66 months of age. We performed secondary analyses to determine if effect modification (EM) from social and environmental factors was affecting associations between MeHg and outcomes. METHODS: MeHg exposure was determined by analysis of maternal hair growing during pregnancy. Children in our Main Study cohort were evaluated at 6.5 months (N = 740) for visual recognition memory and visual attention using the Fagan Infantest, at 19 months (N = 738) and 29 months (N = 736) with the Bayley Scales of Infant Development (BSID). Interactions between MeHg and Caregiver Intelligence, Family Income and Home Environment were examined by multiple regression analysis. RESULTS: The median prenatal MeHg exposure was 5.9 ppm (Range 0.5-26.7 ppm). No EM occurred for preferential looking or visual attention at 6.5 months, for the BSID Psychomotor Scale at either 19 or 29 months, or for activity level at 29 months as measured by the BSID Infant Behavior Record. Interactions between MeHg level and both caregiver intelligence and family income were statistically significant for the BSID Mental Scale at 19 months but not at 29 months. These showed enhancement of MDI scores with increasing maternal MeHg in higher caregiver IQ groups at several levels of family income. CONCLUSIONS: In Seychellois children, consistent major EM by social or environmental factors were not identified. The small EM by caregiver intelligence and social factors at 19 months is consistent with the enhanced performance we reported when this cohort was examined at 66 months.

Attention↗
PubMed1998

Role of TGF-beta in RA-induced cleft palate in CD-1 mice.

Retinoic acid (RA) plays an important role in embryogenesis, by regulating morphogenesis, cell proliferation, differentiation, and extracellular matrix production. RA exposure on gestational day (GD) 12 in CD-1 mice results in delayed palatal shelf elevation and subsequent clefts in the secondary palate. Given the dynamic and complex nature of palate development, it is not surprising that this system is susceptible to changes in retinoid levels. There is evidence that experimental manipulation of retinoid status during development alters normal transforming growth factor-beta (TGF-beta) status. To study the role of perturbation in TGF-beta levels in RA-induced cleft palate, gravid CD-1 mice were treated with 70 mg/kg RA on GD 12. We examined changes in TGF-beta proteins and the steady-state level of TGF-beta mRNA within the first 24 hr after exposure. The interactions between RA and TGF-beta s were very complex. RA differentially regulated the mRNA and protein levels of TGF-beta 1. Changes in mRNA steady-state levels were rapid and transient in nature, indicating a direct mediation by RA. Differential regulation was evident, because RA treatment resulted in an increase in TGF-beta 1 mRNA steady levels followed by a decrease in the intracellular and extracellular forms of TGF-beta 1 protein. Moreover, the patterns of localization and levels of TGF-beta 2 and TGF-beta 3 proteins were not dramatically affected, although there was an increase in TGF-beta 3 mRNA steady-state levels. The increases in mRNA steady-state levels for TGF-beta 2 and TGF-beta 3, as for TGF-beta 1, were rapid and transient in nature, again arguing for direct mediation by RA. These data provide evidence for interactions between RA and TGF-beta s, and indicate that RA is capable of differentially regulating TGF-beta isoforms through processes involving different stages of TGF-beta synthesis and secretion. Further, changes in TGF-beta isoforms were observed prior to changes in mesenchyme morphology and must be considered as mediators of RA's effects on mesenchyme development.

Animals↗
PubMed1998

Phylogenetics of social behavior in Australian gall-forming thrips: evidence from mitochondrial DNA sequence, adult morphology and behavior, and gall morphology.

Six species of Australian gall-forming thrips (Insecta: Thysanoptera) on Acacia exhibit soldier castes, individuals with reduced wings and enlarged forelegs that defend their gall against interspecific invaders. We used data from two mitochondrial genes (cytochrome oxidase I and 16S rDNA), adult morphology and behavior, and gall morphology to infer a phylogeny for Acacia gall-forming thrips with and without soldiers, and we used this phylogeny to evaluate hypotheses concerning soldier evolution. Phylogenies inferred from each data set analyzed separately yielded large numbers of most-parsimonious trees and weak support for most nodes. However, when analyzed together the data sets complemented and reinforced one another in such a way as to yield a well-resolved phylogeny. Our phylogeny implies that soldiers originated once or twice early in the history of this clade, that soldiers were lost once or twice, and that soldiers evolved from winged dispersers rather than from nonsoldier within-gall reproductive offspring of foundresses. The phylogeny also provides evidence for long-term morphological stasis, an ancient split between eastern and western gall thrips species, and a high degree of conservatism in host-plant affiliations.

Acacia↗
PubMed1998

The local neutron flux at low Earth-orbiting altitudes.

The COMPTEL instrument onboard the Compton Gamma Ray Observatory (CGRO) has been used to measure the variation of the atmospheric neutron flux below 5 MeV as a function of vertical cutoff rigidity and spacecraft orientation at an altitude of 450 km. The instrumental 2.2 MeV background line, resulting from thermal neutron capture on hydrogen, was used for the measurement. The dependence of the 2.2 MeV rate on rigidity and geocentre zenith can be described by an analytic function: the line rate decreases linearly with geocentre zenith, and decreases exponentially with the vertical cutoff rigidity. The flux varies on average by about a factor of 3.7 between the extremes in rigidity, and by a factor of 1.7 between the extremes of spacecraft orientation with respect to the Earth. We believe that mass shielding is more important in attenuating the atmospheric albedo than as a source of secondary neutrons. The COMPTEL instrument is well suited for a long-duration study of the dependence of the neutron flux on the vertical cutoff rigidity and the solar cycle.

Altitude↗
PubMed1998

Extended spectrum beta-lactamase production and fluorquinolone resistance in pathogens associated with community acquired urinary tract infection.

We have evaluated the susceptibility of 199 pathogens isolated in pure culture from consecutive urine samples submitted from the community. Rates of susceptibility for all organisms were ampicillin, 48%; amoxycillin/clavulanic acid, 88%; cephalothin, 57%; cefuroxime axetil, 74%; nalidixic acid, 85%; ciprofloxacin, 99%; nitrofurantoin, 78%; and trimethoprim, 67%. Ciprofloxacin resistance and production of extended spectrum beta-lactamase enzymes were detected in Escherichia coli strains isolated from patients in the community.

Anti-Infective Agents↗
PubMed1998

Health problems and health actions among community-dwelling older adults: results of a health diary study.

This study examined the health problems and health actions reported by a sample of older adults (N = 60) who maintained health diaries over a 4-week period. The diary sample was 78% (n = 47) White; 52% (n = 31) were women, with a mean age of 75 years (SD = 5.3). Content analysis was used to examine the types of health problems reported in the diaries, which health problems were likely to be considered an illness, and what health actions were reported. Respondents reported an average of four different types of health problems over the 4-week diary period. There were differences in symptom reports related to gender, age, or race. The most frequently reported health problems were musculoskeletal problems (n = 38), runny nose and respiratory problems (n = 24), gastrointestinal problems (n = 22), and headaches (n = 22). Only 36% of all health problems were considered to be illnesses. Subjects recorded a number of health actions in response to their health complaints, including over-the-counter (OTC) medication use (83%), prescription medication use (53%), self-care activities (72%), and professional consultation (43%). Specific strategies that subjects used to deal with various health problems, implications of the findings, and the usefulness of health diaries as a clinical tool are discussed.

Aged↗
PubMed1997

The active site region of the vitamin K-dependent carboxylase includes both the amino-terminal hydrophobic and carboxy-terminal hydrophilic domains of the protein.

In order to localize the active site of the vitamin K-dependent carboxylase, we developed an affinity probe containing the propeptide and the first two carboxylatable glutamate residues conserved in many native substrates. This probe crosslinked to both the hydrophobic amino-terminal and hydrophilic carboxy-terminal domains of the carboxylase, in contrast with previous work which localized both the catalytic and the propeptide binding site within the amino-terminal hydrophobic domain. Amino acid analysis revealed that the mass of an amino-terminal fragment is seriously underestimated by SDS-PAGE. Reanalysis of the published data in light of this information suggests that a portion of the propeptide binding site resides within the carboxy-terminal hydrophilic domain.

Amino Acid Sequence↗
PubMed1997

Fish consumption and the 30-year risk of fatal myocardial infarction.

BACKGROUND: Epidemiologic data on the possible benefit of eating fish to reduce the risk of coronary heart disease have been inconsistent. We used data from the Chicago Western Electric Study to examine the relation between base-line fish consumption and the 30-year risk of death from coronary heart disease. METHODS: The study participants were 1822 men who were 40 to 55 years old and free of cardiovascular disease at base line. Fish consumption, as determined from a detailed dietary history, was stratified (0, 1 to 17, 18 to 34, and > or = 35 g per day). Mortality from coronary heart disease, ascertained from death certificates, was classified as death from myocardial infarction (sudden or nonsudden) or death from other coronary causes. RESULTS: During 47,153 person-years of follow-up, there were 430 deaths from coronary heart disease; 293 were due to myocardial infarctions (196 were sudden, 94 were nonsudden, and 3 were not classifiable). Cox proportional-hazards regression showed that for men who consumed 35 g or more of fish daily as compared with those who consumed none, the relative risks of death from coronary heart disease and from sudden or nonsudden myocardial infarction were 0.62 (95 percent confidence interval, 0.40 to 0.94) and 0.56 (95 percent confidence interval, 0.33 to 0.93), respectively, with a graded relation between the relative risks and the strata of fish consumption (P for trend = 0.04 and 0.02, respectively). These findings were accounted for by the relation of fish consumption to nonsudden death from myocardial infarction (relative risk, 0.33; 95 percent confidence interval, 0.12 to 0.91; P for trend= 0.007). CONCLUSIONS: These data show an inverse association between fish consumption and death from coronary heart disease, especially nonsudden death from myocardial infarction.

Adult↗
PubMed1997

Depression during mania. Treatment response to lithium or divalproex.

BACKGROUND: Little information exists from controlled studies about clinical characteristics that predict treatment response in mania. The presence of depressive symptoms during manic episodes may be associated with poor response to psychopharmacological treatments. This is an investigation of the relation between depressive symptoms and treatment response in acute manic episodes. METHODS AND DESIGN: In a parallel-group, double-blind study, 179 patients hospitalized for acute manic episodes were randomized to receive divalproex sodium, lithium carbonate, or placebo (ratio, 2:1:2). The study was carried out at 9 academic medical centers. Patients had comprehensive evaluations of behavior and symptoms before and during 3 weeks of treatment. The primary outcome measure, change in mania factor scores derived from the Schedule for Affective Disorders and Schizophrenia: Change Version, was compared in patients with and without depressive symptoms at baseline according to nurse- or physician-rated scales. RESULTS: Depressive symptoms were associated with poor antimanic response to lithium and with better response to divalproex. This was not due to differences in overall severity of illness, substance abuse, gender, age, or history. CONCLUSIONS: These data suggest that even a modest level of pretreatment depression-related symptoms is a robust predictor of lithium nonresponse, and is associated with better response to divalproex. Although their overall efficacy in acute mania is similar, lithium and divalproex may be most effective in clinically and biologically distinct groups of patients.

Adult↗
PubMed1997

Effect size of efficacy measures comparing divalproex, lithium and placebo in acute mania.

Effect size (ES) is a statistical concept that can be used to improve the interpretation of results from psychopharmacological studies. ES may aid interpretation of results when sample size is unbalanced or small or when units or levels of baseline measures differ across items. Usually, an investigator can define a threshold value for a clinically meaningful ES based on published data and clinical judgment or by resorting to conventions, e.g., a medium ES = 0.5 S.D., which can usually be discerned by the trained clinician. In the present study, we apply ES analysis to results from a study comparing the effectiveness of divalproex (DIVAL), lithium (LI), and placebo (PLA) in hospitalized, acutely manic patients. One hundred seventy-six patients were randomly assigned to DIVAL, LI, or PLA in a 2:1:2 ratio, with drug administered in a double-blind, parallel group design for 21 days. The primary efficacy measure was the Mania Rating Scale from the Schedule for Affective Disorders and Schizophrenia, composed of the Manic Syndrome Score (MSS) from items that are relatively specific to the manic state, and the Behavior and Ideation Score (BIS), which reflects severe but nonspecific psychopathology. Improvement of the MSS after 5 days of treatment was difficult to interpret based on percentage change (DIVAL = 19%, LI = 13.5%, PLA = 8.5%). However, the corresponding effect sizes of 0.79, 0.55, and 0.35 indicated a medium to marked ES for DIVAL, a medium ES for LI, and a small ES for PLA at this early point in treatment. Similarly, the ES for change on the MSS at the end of treatment indicated a large, readily observable improvement with both DIVAL (ES = 1.01) and LI (ES = 0.79) vs. an ES of 0.37 for PLA. ES analysis also indicated that the BIS is a less robust indicator of change to either drug. The ES at the end of treatment for the BIS was 0.67 for DIVAL-, 0.62 for LI-, and 0.25 for PLA-treated patients.

Adolescent↗