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Biomedical subjects

L M Shaw

Publications and source records attributed to L M Shaw.

At least 37 records · Page 2Linked to original sources
PubMed2000

Substance use measures among women in early pregnancy.

OBJECTIVE: Our purpose was to compare self-reported and biochemical measures for tobacco, marijuana, and cocaine exposures among women early in pregnancy. STUDY DESIGN: Women who were in the early stages of pregnancy and were examined in an inner-city emergency department were enrolled. Tobacco, marijuana, and cocaine use was measured by self-report and urinalysis. Cocaine use was also assessed by hair analysis. RESULTS: Data were available for 789 women. Among those reporting past use of tobacco, marijuana, and cocaine, 25.2%, 23.9%, and 22.7%, respectively, had positive results of urinary assays; among those reporting current use, 77.2%, 86.6%, and 75.9% had positive findings, whereas among those reporting never use 5.6%, 5. 7%, and 3.6% of results were positive. Hair analysis, in comparison with urine testing, for cocaine identified 4 times as many exposures among women who reported never using cocaine. CONCLUSIONS: Urinary assays were equally likely to be positive among women reporting never use and those reporting past use of tobacco, marijuana, or cocaine. Thus women with a positive biologic assay result were as likely to deny use of tobacco as they were to deny marijuana, or cocaine.

Cannabinoids↗
PubMed2000

Pharmacokinetics and concentration-control investigations of mycophenolic acid in adults after transplantation.

Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

Area Under Curve↗
PubMed2000

Pharmacokinetics of mycophenolic acid in renal insufficiency.

Mycophenolate mofetil (MMF) is now widely used in solid organ transplantation. MMF is rapidly converted to its active form, mycophenolic acid (MPA), upon reaching the systemic circulation. MPA is metabolized to its glucuronide metabolite, mycophenolic acid glucuronide (MPAG), by glucoronyl transferases in the liver and possibly elsewhere. MPAG is then excreted by the kidney. MPA is extensively and avidly bound to serum albumin. Previous studies have demonstrated that it is only the free (non-protein-bound) fraction of MPA that is available to exert its action. In vivo and in vitro studies demonstrate that renal insufficiency decreases the protein binding of MPA and increases free MPA concentrations. This decrease in protein binding seems to be caused both by the uremic state itself and by competition with the retained metabolite MPAG. The disposition of MPA in patients with severe renal impairment may be significantly affected by this change in protein binding.

Biotransformation↗
PubMed2000

Violent injuries among women in an urban area.

The national statistics are familiar by now: each year, more than 2 million women are raped and/or physically assaulted; more than one-third of them are injured during their most recent assault. Annually, more than 500,000 women seek medical services as a result of violence-related injuries, often from hospital emergency departments. But national statistics cannot fully capture the extent of violence experienced by women in inner-city areas, nor do they point to modifiable risk factors at a community level. This Issue Brief highlights a new study that investigates the circumstances and correlates of violent injuries among women in one urban, low-income community.

Emergency Medical Services↗
PubMed1999

Violent injuries among women in an urban area.

BACKGROUND: Although the rate of death from injuries due to violent acts is much higher among black women than among white women in the United States, little is known about the nature and correlates of violent injuries among black women living in urban areas. METHODS: In this case-control study conducted at three emergency departments in one inner-city community (in west Philadelphia), we studied 405 adolescent girls and women who had been intentionally injured and 520 adolescent girls and women (control subjects) who had health problems not related to violent injury. Data were collected by conducting standardized interviews with use of questionnaires and by screening urine for illicit drugs. Individual logistic-regression models were constructed to identify factors associated with violent injuries inflicted by partners and those inflicted by persons other than the partners of the victims. RESULTS: The male partners of the injured women were much more likely than the male partners of control subjects to use cocaine (odds ratio, 4.4; 95 percent confidence interval, 2.3 to 8.4) and to have been arrested in the past (odds ratio, 3.1; 95 percent confidence interval, 1.8 to 5.2). Fifty-three percent of violent injuries to the women had been perpetrated by persons other than their partners. Women's use of illicit drugs and alcohol abuse were factors associated with both violence on the part of partners and violence on the part of other persons. Neighborhood characteristics, including low median income, a high rate of change of residence, and poor education, were independently associated with the risk of violent injuries among women. CONCLUSIONS: Women in this urban, low-income community face violence from both partners and other persons. Substance abuse, particularly cocaine use, is a significant correlate of violent injuries. Standard Census data may help identify neighborhoods where women are at high risk for such violence and that would benefit from community-level interventions.

Adolescent↗
PubMed1999

Evidence that distinct states of the integrin alpha6beta1 interact with laminin and an ADAM.

Integrins can exist in different functional states with low or high binding capacity for particular ligands. We previously provided evidence that the integrin alpha6beta1, on mouse eggs and on alpha6-transfected cells, interacted with the disintegrin domain of the sperm surface protein ADAM 2 (fertilin beta). In the present study we tested the hypothesis that different states of alpha6beta1 interact with fertilin and laminin, an extracellular matrix ligand for alpha6beta1. Using alpha6-transfected cells we found that treatments (e.g., with phorbol myristate acetate or MnCl2) that increased adhesion to laminin inhibited sperm binding. Conversely, treatments that inhibited laminin adhesion increased sperm binding. Next, we compared the ability of fluorescent beads coated with either fertilin beta or with the laminin E8 fragment to bind to eggs. In Ca2+-containing media, fertilin beta beads bound to eggs via an interaction mediated by the disintegrin loop of fertilin beta and by the alpha6 integrin subunit. In Ca2+-containing media, laminin E8 beads did not bind to eggs. Treatment of eggs with phorbol myristate acetate or with the actin disrupting agent, latrunculin A, inhibited fertilin bead binding, but did not induce laminin E8 bead binding. Treatment of eggs with Mn2+ dramatically increased laminin E8 bead binding, and inhibited fertilin bead binding. Our results provide the first evidence that different states of an integrin (alpha6beta1) can interact with an extracellular matrix ligand (laminin) or a membrane-anchored cell surface ligand (ADAM 2).

ADAM Proteins↗
PubMed1999

Cocaine and tobacco use and the risk of spontaneous abortion.

BACKGROUND: Cigarette smoking and cocaine use may be risk factors for spontaneous abortion, but data supporting such a link are limited. METHODS: We studied the associations between cocaine and tobacco use and spontaneous abortion among pregnant adolescents and women (age range, 14 to 40 years) who sought care at an inner-city emergency department. A total of 400 adolescents and women had spontaneous abortions either at study entry or during follow-up (which lasted until 22 weeks' gestation), and 570 adolescents and women remained pregnant past 22 weeks' gestation. Cocaine use was measured at base line by self-reports and analysis of urine and hair samples. Cigarette smoking was measured by self-reports and urine analysis. RESULTS: The adolescents and women in both groups were predominantly black and of lower socioeconomic status. Among those who had spontaneous abortions, 28.9 percent used cocaine on the basis of hair analysis and 34.6 percent smoked on the basis of a urine cotinine assay, as compared with 20.5 percent and 21.8 percent, respectively, of the adolescents and women who did not have spontaneous abortions. The presence of cocaine in hair samples was independently associated with an increase in the occurrence of spontaneous abortion (odds ratio, 1.4; 95 percent confidence interval, 1.0 to 2.1) after adjustment for demographic and drug-use variables. However, the use of cocaine as measured by self-reports and by urine analysis was not. The presence of cotinine in urine was also independently associated with an increased risk of spontaneous abortion (odds ratio, 1.8; 95 percent confidence interval, 1.3 to 2.6). Twenty-four percent of the risk of spontaneous abortion could be related to cocaine or tobacco use. CONCLUSIONS: Cocaine and tobacco use were common in our study population and were associated with a significant risk of spontaneous abortion.

Abortion, Spontaneous↗
PubMed1999

Differences in phosphorylation of the IL-2R associated JAK/STAT proteins between HTLV-I(+), IL-2-independent and IL-2-dependent cell lines and uncultured leukemic cells from patients with adult T-cell lymphoma/leukemia.

To determine activation status of the IL-2R-associated (Jak/STAT) pathway in the HTLV-I infected cells, we examined tyrosine phosphorylation of Jak3, STAT3, and STAT5 in several HTLV-I(+) T-cell lines and in uncultured leukemic T cells isolated from patients with adult T-cell lymphoma/leukemia (ATLL). Constitutive basal phosphorylation of Jak3 and, usually, STAT3 and STAT5 was detected in all four IL-2-independent cell lines tested, but in none of the three IL-2-dependent cell lines. Similarly, there was no detectable basal phosphorylation of Jak3 and STAT5 in the leukemic cells from ATLL patients (0/8 and 0/3, respectively). However, stimulation with IL-2 resulted in Jak3 and STAT5 phosphorylation in both leukemic ATLL cells and IL-2-dependent lines. Furthermore, expression of SHP-1 phosphatase which is a negative regulator of cytokine receptor signaling, was lost in most IL-2 independent cell lines (3/4) but not in the leukemic ATLL cells (0/3). Finally, the HTLV-I(+) T-cell lines (313) but not the control, HTLV-I(-) T-cell lines were resistant to rapamycin and its novel analog RAD. We conclude that (1) HTLV-I infection per se does not result in a constitutive phosphorylation of the Jak3, STAT3, and STAT5 proteins; (2) malignant transformation in at least some cases of ATLL does not require the constitutive, but may require IL-2-induced, activation of the IL-2R Jak/STAT pathway; and (3) there are major differences in T-cell immortalization mechanism(s) which appear to involve SHP-1 and target molecules for rapamycin and RAD.

DNA-Binding Proteins↗
PubMed1999

Current opinions on therapeutic drug monitoring of immunosuppressive drugs.

The pharmacokinetics of the immunosuppressive drugs cyclosporine, tacrolimus, mycophenolate mofetil (MMF), and sirolimus are complex and unpredictable. A narrow therapeutic index unique to each patient, as well as variable absorption, distribution, and elimination, are characteristics of these drugs. Therapeutic drug monitoring plays a key role in helping clinicians maintain blood and plasma levels of immunosuppressive drugs within their respective therapeutic ranges. Variation in concentrations outside the narrow therapeutic ranges can result in adverse clinical outcomes. Therapeutic drug monitoring ensures that concentrations are not too high or too low, thereby reducing the risks of toxicity or rejection, respectively. Therapeutic monitoring of immunosuppressive drugs has been based on several choices of assay and biologic fluid (i.e., whole blood, plasma) appropriate for a particular drug. High-performance liquid chromatography (HPLC) remains the gold standard among assay methods used to monitor immunosuppressive drugs. Although HPLC is the assay of choice for cyclosporine, newer monoclonal assays are suitable as well for routine monitoring. HPLC is also widely used for therapeutic drug monitoring of mycophenolic acid, the active metabolite of MMF, and an immunoassay (used in European centers) has been developed. Therapeutic drug monitoring of tacrolimus has been improved with the recent development of assays with greater sensitivity and specificity for tacrolimus than those previously available. No commercial assays are currently available for the therapeutic monitoring of sirolimus. It is also important to identify a specific pharmacokinetic parameter for each individual drug, whether it is trough or area under the concentration-time curve, that may be most useful as a tool for optimal therapeutic drug monitoring in clinical practice. With an increased understanding of the pharmacokinetics of immunosuppressive drugs, therapeutic drug monitoring guidelines will be more clearly defined to ensure the safe and effective management of transplant recipients.

Cyclosporine↗
PubMed1999

Integrin function in breast carcinoma progression.

The differentiation and function of mammary epithelial cells is dependent upon the combined action of growth factor/hormone receptors and integrin receptors, which act in concert to control the signals required for normal cell function. It is now becoming clear that integrin receptors also contribute to carcinoma cell behavior and that alterations in expression and function during transformation have a large impact on breast carcinoma progression. The focus of this review is to discuss integrin-dependent functions that can be manipulated as targets for the therapeutic intervention of breast cancer. A combination of correlative and mechanistic studies have contributed to the identification of specific integrin receptors, namely alpha2beta1, alpha6beta1, and alpha6beta4, implicated in breast carcinoma progression. Although this field is still emerging and much remains to be learned, potential integrin-dependent signaling targets have been identified.

Animals↗
PubMed1999

Analysis of whole blood tacrolimus concentrations in liver transplant patients exhibiting impaired liver function.

In transplant patients with impaired liver function, HPLC methodologies have been suggested for monitoring whole blood tacrolimus concentrations because of the reported inaccuracy of immunoassay for whole blood tacrolimus concentrations. One hundred fifty whole blood samples from 50 subjects enrolled in a multicenter liver transplant trial were chosen for HPLC/MS/MS analysis without consideration of the clinical status of the patient at the time of sampling. These samples were chosen to represent the sampling intervals during the 12-week posttransplantation period. Retrospectively, the authors identified a subset of 39 samples from 27 subjects exhibiting impaired liver function as demonstrated by bilirubin concentrations > 3.0 mg/dL (mean +/-SD = 7.5 +/- 5.6 mg/dL). The authors compared the agreement of concentrations obtained from the PRO-Trac II ELISA and HPLC/MS/MS by least squares linear regression analysis and Bland/Altman analysis, in this subset against the agreement of concentrations for 76 samples with normal bilirubin. In the samples obtained from patients with impaired liver function the resulting regression equation was: ELISA = 1.19(HPLC) + 0.7; r = 0.9. The mean difference (HPLC/MS/MS - ELISA) was -2.5 ng/mL +/- 2.9 ng/mL (mean +/- SD). While 71% of samples agreed within 3 ng/mL, 3% (n = 1) exhibited a difference >10 ng/ml. The corresponding evaluation of the samples with normal bilirubin concentrations resulted in the regression equation ELISA = 0.96(HPLC) + 0.9; r = 0.9, and a mean difference of -0.6 ng/mL +/- 2.3 ng/mL. The authors conclude that while a small subset of patients with cholestasis may require closer evaluation with a more specific methodology, the majority of the patients may be satisfactorily monitored with the PRO-Trac II ELISA.

Adult↗
PubMed1999

The effect of renal insufficiency on mycophenolic acid protein binding.

Mycophenolate mofetil (MMF) is commonly used in solid organ transplant recipients. MMF is converted to mycophenolic acid (MPA) upon reaching the systemic circulation. Many acidic drugs have altered protein binding in renal failure, and it is possible that MPA protein binding may be decreased. The authors studied 23 renal transplant recipients: 8 transplant patients (7 kidney, 1 kidney/pancreas) with chronic renal insufficiency (CRI) and 15 renal transplant patients with preserved renal function. Plasma was obtained for kinetic profiles of total MPA, free MPA, and its glucuronide metabolite (MPAG). Plasma was obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess in vitro differences in MPA protein binding. Average free fraction of MPA in patients with chronic renal insufficiency was more than double that of patients with normal renal function (5.8 +/- 2.7 vs. 2.5 +/- 0.4, p < 0.01). Free MPAAUC was almost doubled in the patients with chronic renal insufficiency versus controls (2.04 +/- .08 vs. 1.03 +/- 0.6, p < 0.01). MPA protein binding is decreased, and free MPA concentrations are increased in patients with chronic renal failure.

Abdominal Pain↗
PubMed1999

Anticholinergic toxicity associated with lupine seeds as a home remedy for diabetes mellitus.

We describe a case of sparteine intoxication associated with using a preparation from lupine seeds. A female patient of Portuguese origin presented to the emergency department with classic anticholinergic signs after ingestion of a lupine seed extract. She took the preparation with the belief it represented a cure for her recently diagnosed diabetes. Analysis of the patient's lupine bean extract identified the preponderant compound as oxo-sparteine by gas chromatography/mass spectrometry. Intoxication by lupine seeds rarely occurs in human beings. To our knowledge, no medical or toxicologic evidence supports a belief that lupine extract could lower serum glucose levels. This case highlights the need for emergency care providers to be aware of the health hazards that can be associated with the use of such home remedies.

Aged↗
PubMed1999

Pharmacokinetics of amifostine: effects of dose and method of administration.

Findings of pharmacokinetic studies of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) in animal models and in human cancer patients support the hypothesis that amifostine pharmacokinetics are nonlinear. The nonlinear pharmacokinetic behavior of amifostine suggests that administration of doses higher than 740 mg/m2 does not increase the amount of drug available due to urinary excretion of the excess parent drug and its metabolites. Although the intravenous formulation of amifostine is the only one currently used in the treatment of cancer patients, there is growing interest in the investigation of subcutaneous administration as a practical alternative. A pilot pharmacokinetic evaluation of subcutaneous administration of amifostine in 12 healthy male volunteers compared the relative bioavailability of 500 mg of amifostine administered subcutaneously with that of 200 mg/m2 given intravenously.

Administration, Oral↗
PubMed1999

The apparent inhibition of inosine monophosphate dehydrogenase by mycophenolic acid glucuronide is attributable to the presence of trace quantities of mycophenolic acid.

BACKGROUND: Mycophenolic acid glucuronide, the primary metabolite of the immunosuppressive agent mycophenolic acid, affords weak inhibition of proliferating and resting lymphocytes and recombinant human inosine monophosphate dehydrogenase in comparison to the active drug. We evaluated the hypothesis that mycophenolic acid is a trace contaminant of the glucuronide metabolite preparation and that this accounts for the observed effects of mycophenolic acid glucuronide on human inosine monophosphate dehydrogenase catalytic activity both in lymphocytes and the pure enzyme. METHODS: We used negative ion electrospray HPLC-mass spectrometry (HPLC-MS) and HPLC-tandem MS (HPLC-MS-MS) to identify mycophenolic acid as a contaminant of mycophenolic acid glucuronide. Quantification of the mycophenolic acid contaminant was achieved using a negative ion electrospray HPLC-MS method in the selected-ion monitoring mode. RESULTS: Trace amounts of mycophenolic acid were detected and definitively identified in the mycophenolic acid glucuronide preparation by the HPLC-MS-MS analysis. In addition to having identical HPLC retention times, pure mycophenolic acid and the contaminant produced the following major fragments upon HPLC-MS-MS analysis: deprotonated molecular ion, m/z 319; and fragment ions, m/z 275, 243, 205, and 191 (the most abundant fragment ion). Using the negative ion electrospray HPLC-MS procedure in the selected-ion monitoring mode, the quantity of the contaminant mycophenolic acid was determined to be 0.312% +/- 0.0184% on a molar basis. CONCLUSION: These data provide strong support for the proposal that the apparent inhibition of the target enzyme inosine monophosphate dehydrogenase by mycophenolic acid glucuronide is attributable to the presence of trace amounts of contaminant mycophenolic acid.

Chromatography, High Pressure Liquid↗
PubMed1999

Analytical validation of the PRO-Trac II ELISA for the determination of tacrolimus (FK506) in whole blood.

BACKGROUND: The analytical validation of multiple lots of the PRO-Trac II ELISA (DiaSorin) for the determination of tacrolimus in whole blood is described. METHODS: The analytical parameters assessed included analytical sensitivity, dilution linearity, functional sensitivity, values in samples containing no tacrolimus, intra- and interassay precision, supplementation and recovery, metabolite cross-reactivity, interference studies, and method comparisons HPLC-tandem mass spectrometry (HPLC/MS/MS) and the IMx Tacrolimus II multiparticle enzyme immunoassay. Where appropriate, assessments were performed according to NCCLS guidelines. RESULTS: The mean analytical detection limit was <0.25 microg/L for all lots, whereas the functional sensitivity was 1.0 microg/L. Excellent linear correlation (r = 0.985) was observed for dilution linearity. The intraassay imprecision was <7%, and the total imprecision by ANOVA was <10%. Recovery was 109% +/- 11%. Metabolite cross-reactivity was consistent with previous reports for this antibody. No interference was observed for 35 tested drugs. Method comparison with HPLC/MS/MS showed no statistically significant differences. Samples exhibited stability through four freeze/thaw cycles and for 1 week at room temperature. CONCLUSION: These data demonstrate that the PRO-Trac II ELISA is a robust, accurate, and precise tool for the assessment and management of tacrolimus blood concentrations in transplant patients.

Chromatography, High Pressure Liquid↗
PubMed1998

Release of cAMP gating by the alpha6beta4 integrin stimulates lamellae formation and the chemotactic migration of invasive carcinoma cells.

The alpha6beta4 integrin promotes carcinoma in-vasion by its activation of a phosphoinositide 3-OH (PI3-K) signaling pathway (Shaw, L.M., I. Rabinovitz, H.H.-F. Wang, A. Toker, and A.M. Mercurio. Cell. 91: 949-960). We demonstrate here using MDA-MB-435 breast carcinoma cells that alpha6beta4 stimulates chemotactic migration, a key component of invasion, but that it has no influence on haptotaxis. Stimulation of chemotaxis by alpha6beta4 expression was observed in response to either lysophosphatidic acid (LPA) or fibroblast conditioned medium. Moreover, the LPA-dependent formation of lamellae in these cells is dependent upon alpha6beta4 expression. Both lamellae formation and chemotactic migration are inhibited or "gated" by cAMP and our results reveal that a critical function of alpha6beta4 is to suppress the intracellular cAMP concentration by increasing the activity of a rolipram-sensitive, cAMP-specific phosphodiesterase (PDE). This PDE activity is essential for lamellae formation, chemotactic migration and invasion based on data obtained with PDE inhibitors. Although PI3-K and cAMP-specific PDE activities are both required to promote lamellae formation and chemotactic migration, our data indicate that they are components of distinct signaling pathways. The essence of our findings is that alpha6beta4 stimulates the chemotactic migration of carcinoma cells through its ability to influence key signaling events that underlie this critical component of carcinoma invasion.

1-Methyl-3-isobutylxanthine↗