PubMed Health⌕ Search

Biomedical subjects

K Owens

Publications and source records attributed to K Owens.

At least 19 recordsLinked to original sources
PubMed2001

Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.

CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown. OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations. DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999). MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo. RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive. CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

Adult↗
PubMed2001

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

Animals↗
PubMed2001

Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors.

Ampakines are small benzamide compounds that allosterically produce the positive modulation of AMPA receptors and improve performance on a variety of behavioral tasks. To test if the native synaptic membrane is necessary for the effects of such positive modulators, the mechanism of action of the Ampakine 1-(1,3-benzodioxol-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine (CX509) was investigated in isolated rat brain AMPA receptors reconstituted in lipid bilayers. The drug increased the open time of AMPA-induced single channel current fluctuations with an EC(50) of 4 microM. The action of CX509 was highly selective since it had no effect on the amplitude or close time of channel events. The open time effect had a maximum enhancement of 70-fold and the modulated currents were blocked by CNQX. It is concluded that the synaptic membrane environment is not necessary for Ampakine effects. In fact, CX509 was about 100 times more potent on the reconstituted AMPA receptors than on receptors in their native membrane. These findings indicate that centrally active Ampakines modulate specific kinetic properties of AMPA currents. They also raise the possibility that AMPA receptors are regulated by factors present in situ, thus explaining the more efficient modulatory effects of CX509 when acting on receptors removed from their synaptic location.

Animals↗
PubMed2000

The relationship between insight and clinical factors for persons with schizophrenia.

This correlational study examined the relationship of insight with positive and negative symptoms and level of functioning among persons with schizophrenia or schizoaffective disorder. Poor insight as a symptom of schizophrenia is the conceptual framework. Thirty-seven people receiving assertive community treatment, inpatient hospitalization, or outpatient treatment were assessed using 2 self-rating insight scales, the Scale for Assessment of Positive Symptoms (SAPS), the Scale for Assessment of Negative Symptoms (SANS), and the Global Assessment of Functioning (GAF). A significant negative correlation was found between insight and positive formal thought disorder. No significant relationships were found between insight and negative symptoms or level of functioning. Reactions to the self-rating insight tools suggest necessary revisions of the insight tool.

Adult↗
PubMed2000

Vestibular dysfunction in Gulf War syndrome.

METHODS: Vestibular complaints of Gulf War veterans were characterized by a nested case-control study of 23 veterans with 3 different Gulf War syndromes and 20 matched control subjects. All subjects completed a standardized symptom questionnaire and underwent standard audiovestibular tests administered by audiologists blinded to group identities. RESULTS: The prevalence of reported dizzy spells was higher in veterans with Gulf War syndromes 1 (100%), 2 (85%), and 3 (100%) than in controls (25%, P < 0.0001). Dizzy spells were more frequent, lasted longer, and involved a wider variety of accompanying symptoms in veterans with syndrome 2 than in those with syndromes 1 and 3. Audiovestibular testing showed greater interocular asymmetry of nystagmic velocity on sinusoidal harmonic acceleration in syndromes 1 (P = 0.015) and 2 (P = 0.002), greater asymmetry of saccadic velocity in syndrome 2 (P = 0.4), diminished nystagmic velocity after caloric stimulation bilaterally in syndrome 3 (P = 0.02 to 0.04), more subjects with pathologic nystagmus (P = 0. 09), and greater interside asymmetry of wave I to III interpeak latency on auditory brain stem response in syndromes 1 (P = 0.005) and 2 (P = 0.07). Asymmetry of gain on sinusoidal harmonic acceleration and pathologic nystagmus were most strongly associated with symptoms of paroxysmal vertigo (P = 0.002 and 0.07, respectively); asymmetry of saccadic velocity, with the severity of vertigo (P = 0.004); and abnormal caloric response, with chronic dysequilibrium (P = 0.006). CONCLUSIONS: The findings are compatible with a subtle neurologic injury from organophosphate-induced delayed neurotoxicity.

Adult↗
PubMed1999

Genomic views of human history.

New tools of genomic analysis shed light on historical puzzles. Migrations of ancient peoples, differences in migration patterns of males and females, historical demography of cultures with ancient roots, and patterns of human genetic diversity are increasingly the focus of integrated analysis by historians, anthropologists, and geneticists.

Anthropology↗
PubMed1999

Gynecologic care of medically complicated adolescents.

Gynecologic care of adolescents presents a challenge under the best of circumstances, but when the patient has significant medical processes that interact with the process of puberty, the care of these patients may become extremely difficult. A review of the more common medical illnesses of adolescents and the interaction on the events of puberty and normal menstrual function is presented with emphasis on contraception and future fertility. Although many of the contraceptive options present a possible increased risk to these patients, it must be kept in mind that these adolescent patients will develop emotionally and become sexually active at some point in their lives, and the potential risk of the resultant pregnancy must be weighed carefully. The various options of management for gynecologic problems are discussed.

Adolescent↗
PubMed1994

Squamous cell carcinoma antigen: clinical utility in squamous cell carcinoma of the uterine cervix.

This study further defines the clinical utility of squamous cell carcinoma antigen (SCC-Ag) in initial squamous carcinoma of the cervix, response to treatment, and in the detection of recurrence. Serum specimens were drawn and analyzed from patients with squamous cell carcinoma. Charts were reviewed on 272 patients with 1053 samples evaluated. Treatment of patients prior to the availability of the assay and patients lost to follow-up resulted in lower total numbers of initial and recurrent values. Data were analyzed to detect trends during and after treatment. All values at or above the lowest detectable level of antigen were included; that is, 1.5 ng/ml and above. A SCC-Ag value > or = 2.0 ng/ml drawn at any time during the disease process has a 96.3% positive predictive value, while a value < 2.0 ng/ml is 97.2% specific for absence of disease. Fifty-three percent of 103 patients had elevated SCC-Ag levels prior to treatment, with the proportion increasing accordingly with advancing stage at diagnosis. In 70 patients with recurrence, 81% had elevated values. Squamous cell carcinoma antigen predicted recurrence an average of 6.9 months prior to detection of clinically evident disease. Patients with initially negative SCC-Ag levels may demonstrate elevated values with tumor recurrence. This marker accurately reflects the response to treatment in patients who have elevated levels prior to treatment. Squamous cell carcinoma antigen is a useful tumor marker in the management of patients with squamous cell carcinoma of the uterine cervix.

Antigens, Neoplasm↗
PubMed1989

Localization to the inner surface of the cytoplasmic membrane by immunoelectron microscopy of enzyme I of the phosphoenolpyruvate:sugar phosphotransferase system of Escherichia coli.

The phosphoenolpyruvate:sugar phosphotransferase system of Escherichia coli constitutes a major pathway for sugar translocation. It is composed of integral membrane proteins (enzyme II components) that recognize specific extracellular sugars as well as phosphocarrier proteins, one of which is called enzyme I. While enzyme I plays a role in energizing the enzyme II for sugar transfer, its precise cellular distribution had not previously been defined. This study was designed to elucidate the cellular location of this protein by immunoelectron microscopy. Enzyme I antibody bound to E. coli cryosections was visualized with protein A-gold. The gold particles in sections of wild-type E. coli were found primarily associated with the surface of the inner membrane. A strain of E. coli harboring a plasmid encoding the gene for enzyme I was also tested for its distribution of enzyme I. Consistent with the biochemically established overproduction of enzyme I, this strain showed an approximately 80-fold higher density of gold particles per unit cell volume than the wild-type cells. The substantial overproduction of immunoreactive enzyme I was associated with a significant (approximately 20-fold) increase in the amount of that protein bound to the inner membrane. In addition, a substantial fraction of the total enzyme I accumulated within a 60-nm-wide zone in the vicinity of the inner membrane. A model to explain the zonal distribution of enzyme I under conditions of overexpression of the protein is presented.

Cell Membrane↗
PubMed1989

Cloning of the crystalline cell wall protein gene of Bacillus licheniformis NM 105.

A protein with a tetragonal pattern, defined as RS protein, was found on the wall surface of an alkaline phosphatase secretion-deficient mutant (NM 105) of Bacillus licheniformis 749/C. The protein was present on the wall surface of the exponential-growth-phase cells, but at the stationary growth phase it was overproduced and hypersecreted. This protein was precipitated to homogeneity from the culture fluid by 80% ammonium sulfate saturation and chilled acetone. The molecular mass of the protein was 98 kilodaltons, and it had a single subunit in a sodium dodecyl sulfate gel. Specific anti-RS antibody was generated in rabbits and used to immunolabel the RS protein on the cells at different growth phases. In early-exponential-growth-phase cells, the outside surface of the wall, the cytoplasm, and the inside surface of the cytoplasmic membrane were labeled. In stationary-growth-phase cells, the cytoplasm was poorly labeled, but the labeling on the outside surface of the wall was high. AB. licheniformis NM 105 gene library was made by using the lambda phage EMBL3. The RS protein expression from this gene library was detected by a modified autoradiographic procedure. One of the amplified RS protein-positive plaques (4213-1) containing recombinant DNA was chosen, and the restriction map of this DNA was prepared. The RS protein expressed in Escherichia coli NM 539 infected with 4213-1 recombinant phage had a lower molecular mass than the purified authentic RS protein. The 4.5-kilobase-pair (kbp) SalI-EcoRI fragment of the recombinant DNA was cloned in the shuttle plasmid pMK4 to construct pMK462, which was expressed in B. subtilis MI112 and produced the RS protein identical in molecular mass to the purified authentic RS protein. The RS protein expression was also demonstrated in cryosections of transformed E. coli and B. subtilis cells by immunoelectron microscopy. The 1.2-kbp SalI-HindIII and 1.8-kbp HindIII-HindIII recombinant DNA restriction enzyme fragments, respectively, from the right of the restriction map produced anti-RS antibody cross-reacting proteins. The expression of the 1.2-kbp SalI-HindIII DNA fragment cloned in pUC8 could be induced with isopropyl-beta-D-thiogalactopyranoside. The 1.8-kbp DNA restriction fragment hybridized with both the chromosomal DNA of strain NM 105 and the recombinant phage 4213-1 DNA. The RS gene expression was finally demonstrated in transformed E. coli 539 cells by in situ hybridization of frozen thin sections with the 1.8-kbp HindIII biotin-dATP probe and immunolabeling these with anti-biotin immunoglobulin G and protein A-gold.

Bacillus↗
PubMed1987

Effect of a zinc-deficient diet on mitochondrial and microsomal lipid composition in TEPC-183 plasmacytoma.

A zinc-deficient diet caused an increase in microsomal membrane phospholipid levels compared to ad libitum controls. Cholesterol levels were found to be decreased 50% compared to either pair-fed or ad libitum controls, resulting in a sharp decline in the cholesterol/phospholipid ratio. No differences were observed in the distribution of phospholipid classes among all three groups, either in mitochondrial or microsomal membrane fractions. Fatty acid analysis of PC and PE revealed a rise in the 18:2 fraction from zinc-deficient mitochondrial and microsomal membrane fractions. Mitochondrial PE and PC from zinc-deficient animals revealed a rise in the 22:6 fatty acid fraction while microsomal PC also revealed a corresponding decrease in 20:4. None of the zinc-deficient preparations differed significantly from either ad libitum or pair-fed controls in the content of long-chain alk-l-enyl ethers. The results of this study point to an effect of a zinc-deficient diet on lipid metabolism in tumor subcellular membranes which may account for the decreased rate of tumor growth observed in zinc-deficient animals.

Animals↗
PubMed1985

Perturbations of sarcolemmal and microsomal enzymes by amphiphilic lipids and drugs.

Sarcolemmal (SL) and microsomal (MC) membranes were prepared from adult canine cardiocytes. SL Na+, K+-ATPase (2.35 mumole/min per mg) was enriched 117-fold over the homogenate and MC rotenone-insensitive NADH cytochrome c reductase (RINCR) was enriched 41-fold. Preincubation of SL with 50 microM arachidonyl-CoA (20:4 CoA) stimulated Na+, K+-ATPase almost 2-fold; 250 microM 20:4 CoA inhibited the enzyme by 85%. However, RINCR was inhibited 80% by only 0.2 microM 20:4 CoA. Thus, each of these myocardial lipid-dependent enzymes showed a different sensitivity to perturbation by lipid amphiphiles. In further experiments, SL preincubated with 50 microM 20:4 CoA + 2.5 mM propranolol (which had no effect alone) exhibited a synergistic inhibition of the Na+, K+-ATPase: The enzymatic activity declined 8.5-fold when compared to sarcolemma treated with 50 microM 20:4 CoA alone. Thus, the presence of lipid amphiphiles may result in greater inhibition of the Na+, K+-ATPase when propranolol is present in the membrane.

Acyl Coenzyme A↗
PubMed1985

Characterization of sarcolemma from calcium-tolerant canine cardiocytes.

Large numbers of calcium-tolerant canine cardiocytes can be isolated from the collagenase-perfused canine myocardium. An average yield of 500 million cells provides abundant tissue for the preparation of subcellular fractions. Using nitrogen cavitation, along with extraction by 0.6 M potassium chloride/sucrose buffer, we have been able to prepare, after differential and sucrose gradient centrifugation, membrane fractions that are more than 100-fold enriched in sarcolemmal marker enzymes. This preparation of sarcolemma has the advantage of being essentially free of plasma membranes from endothelial, smooth muscle, and other cell types residing in the myocardium.

Animals↗
PubMed1984

Inhibition of myocardial rotenone-insensitive NADH cytochrome c reductase by amphiphilic compounds.

Because myocardial ischemia is correlated with both an elevation of intracellular levels of amphiphilic lipid metabolites and a decrease in the rotenone-insensitive NADH cytochrome c reductase (RINCR), we investigated the effects in vitro of some amphiphilic lipid metabolites and synthetic detergents on the activity of RINCR-enriched subfractions of microsomes from isolated cardiac myocytes. RINCR activity was unaffected in vitro by the addition of lysophosphatidylethanolamine (up to 0.5 mM) but was inhibited (maximum 63%) by lysophosphatidylcholine (8 microM). Palmitoyl carnitine (up to 2 mM) was ineffective, but the coenzyme A thioesters of palmitate, stearate, oleate, and arachidonate were inhibitory at concentrations (less than 3 microM) below their critical micellar concentrations. Arachidonyl CoA was approximately one order of magnitude more inhibitory than the other long-chain acyl CoA thioesters. Kinetic analyses revealed the effect of arachidonyl CoA on RINCR activity to be exclusively an alteration of the Vmax with no change in the Km for cytochrome c. The inhibition of myocytic RINCR activity by long-chain acyl CoA may be unrelated to the bulk-phase detergency of this lipid amphiphile since the effects were observed at concentrations below the critical micellar concentration, and other lipid amphiphiles had no effect on RINCR activity. Inhibition of microsomal RINCR activity may result from localized disruption of the membrane microenvironment of the enzyme complex by penetration or dissolution of long-chain acyl CoA into the membrane. The pronounced sensitivity of myocytic RINCR activity to long-chain acyl CoA suggests a relationship between the decreased RINCR activity and the increased levels of this class of lipid metabolites observed in the ischemic myocardium.

Acyl Coenzyme A↗
PubMed1983

Cardiac sarcolemmal Na+-K+-ATPase: combined effects of propranolol and arachidonyl CoA.

Sarcolemma from adult canine cardiac myocytes (Na+-K+-ATPase activity 71.8 +/- 3.4 mumol . mg protein-1 . h-1) was preincubated (10 min at 37 degrees C, pH 7.2) with 1) 5-250 microM arachidonyl CoA, 2) 2.5 nM- 2.5 mM propranolol, 3) 5-250 microM arachidonyl CoA plus 2.5 mM propranolol or 4) 2.5 nM-2.5 mM propranolol plus 50 microM arachidonyl CoA; after preincubation the Na+-stimulatable activity was assayed. Arachidonyl CoA alone (50 microM, expt 1) elicited maximum stimulation (89% above control), whereas concentrations greater than 125 microM were inhibitory. Preincubation with propranolol alone (expt 2) had no significant effect on activity. However, when membranes were pretreated with both arachidonyl CoA and 2.5 mM propranolol (expt 3) activity was significantly inhibited. Preincubation with concentrations of propranolol greater than 25 microM were required to reverse the stimulatory effect of 50 microM arachidonyl CoA (expt 4). Propranolol and arachidonyl CoA do not have to be present simultaneously to produce an inhibitory effect. Activity was greatly inhibited (87%) when membranes were preincubated with 100 microM arachidonyl CoA followed by addition of 2.5 mM propranolol; no inhibition was observed if preincubation conditions were reversed. These data suggest that propranolol-induced inhibition of the Na+-K+-ATPase is reversible but becomes irreversible when sarcolemma is pretreated with the fatty acyl CoA, either prior to or during propranolol preincubation.

Acyl Coenzyme A↗
PubMed1982

Effects of fatty acid intermediates on Na+-K+-ATPase activity of cardiac sarcolemma.

The effect of amphiphilic lipid intermediates on the Na+-stimulatable activity of the Na+-K+-ATPase of sarcolemma from adult canine cardiac myocytes was studied. Sarcolemma (mean Na+-stimulatable ATPase activity of 73 mumol.mg sarcolemmal protein-1.h-1) was preincubated (37 degrees C for 10 min at pH 7.2) or rapidly mixed at 0 degrees C with amphiphilic lipid intermediates prior to dilution and assay of enzyme activity. Their effects were dependent on temperature, initial concentration, and the ratio of bound amphiphile to sarcolemmal protein. In particular, pretreatment of freshly prepared sarcolemma at 0 degrees C with arachidonyl CoA (up to 0.25 mM) caused 110% stimulation above control activity; palmitoyl CoA or palmitoyl carnitine under the same conditions caused no significant effect. Despite strong binding to the sarcolemmal vesicles, palmitoyl carnitine (up to 0.4 mM or 5 mumol/mg protein) and palmitoyl CoA (0.1 mM or 1.0 mumol of membrane-bound palmitoyl CoA/mg protein) were ineffective even with preincubation. Palmitoyl CoA was inhibitory above this level. Preincubation (22 degrees C for 10 min) with lysophosphatidylcholine only produced inhibition (40% at 0.75 mM). Thus fatty acyl thioesters of CoA and lysophosphatidyl choline but not palmitoyl carnitine perturb sarcolemmal Na+-K+-ATPase activity.

Acetylcarnitine↗