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Biomedical subjects

R Paul

Publications and source records attributed to R Paul.

At least 19 recordsLinked to original sources
PubMed1999

Novel multidrug resistance reversal agents.

A series of 59 alpha-aryl-alpha-thioether-alkyl, -alkanenitrile, and -alkanecarboxylic acid methyl ester tetrahydroisoquinoline and isoindoline derivatives (15a-48) were synthesized and evaluated as multidrug resistance (MDR) reversal agents. The compounds were tested on S1-B1-20 human colon carcinoma cells selected for resistance to bisantrene. Both the cytotoxicity of the reversal agents and their ability to resensitize the cells to bisantrene were determined. All but two of these compounds (15q, 40) were more effective MDR reversal agents in vitro than verapamil (VRP), a calcium channel antagonist which also has been shown to possess MDR modulating activity. Several showed good activity in this assay (IC50's < 0.5 microM), the most potent being isoindolines 44 (IC50 0.26 microM) and 46 (IC50 0.26 microM) and tetrahydroisoquinolines 47 (IC50 0.29 microM) and 15m (IC50 0.30 microM). A number of compounds were evaluated in vivo against vincristine (VCR)-resistant murine P388 leukemia, as well as against human epidermoid carcinoma KB/8.5 implanted sc in athymic mice. The reversal agents which consistently showed the highest activity, together with low toxicity, were alpha-aryl-alpha-thiotolylalkanenitrile tetrahydroisoquinoline derivatives with electron-rich alkoxy substituents on the aromatic rings. Of the tested compounds, the most effective reversal agents for both tumor lines were 15h (33% increased life span at 12.5 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 59% relative tumor growth at 50 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model) and 39a (48% increased life span at 50 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 46% relative tumor growth at 25 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model). The mechanism of action of these compounds is believed to involve blocking the drug efflux pump, P-glycoprotein.

Animals↗
PubMed1999

Differential expression of matrix metalloproteinases in bacterial meningitis.

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined. We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats. In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals. Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity. The mRNA expression pattern of six other MMPs was investigated. Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated. In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged. As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption. Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings. Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system.

Animals↗
PubMed1999

Assessing speech, language and communication.

This article discusses the assessment of communication skills in children from birth to 5 years of age. The different methods appropriate for different developmental levels and the relationship of collateral areas, such as hearing, cognition, and speech motor control to the communication process, are addressed. The need for standardized and informal measures is emphasized. Case studies are presented to illustrate the principles outlined.

Child, Preschool↗
PubMed1999

Leakage flow at mechanical heart valve prostheses: improved washout or increased blood damage?

BACKGROUND AND AIMS OF THE STUDY: An essential problem of mechanical heart valve (MHV) prostheses is the risk of thromboembolic events and consequent need of lifetime anticoagulation due to unnatural hemodynamics that results in traumatization of red blood cells and platelets. The precise spatial and tidal localization of blood-damaging events within the flow is poorly understood. The present study addresses the question whether leakage flow at MHV, which is claimed to improve washout in the hinge areas of microthrombi and platelet-activating agents, is responsible for significant blood damage. METHODS: This study investigated leakage flow in vitro, primarily within turbulent leakage jets of currently used mechanical valves. St. Jude Medical, Sorin Bicarbon, Duromedics-Edwards and CarboMedics valves were analyzed in the mitral position of a circulatory mock loop. Jet configuration was determined by echocardiography; velocity and shear stress distributions within jets were measured using laser-Doppler anemometry (LDA). A blood damage index (BDI) was developed in terms of lactate dehydrogenase release by platelets and hemoglobin release by red blood cells (RBC), as a function of exposure time and shear stresses within the flow field. BDIs were validated by direct measurement of hemolysis caused by leakage flow, using porcine blood. RESULTS: All valves showed characteristic and reproducible jet patterns, mainly emerging from the hinge areas. Maximum velocities up to 1.7 m/s were measured. Maximum turbulent shear stresses > 80 Pa were found. The investigated MHV revealed significant differences in calculated BDIs. The Sorin Bicarbon had a significantly lower BDI for RBC damage, as well as for platelet damage; this was validated by direct hemolysis measurements. CONCLUSIONS: The relevance of the leakage-induced blood damage was demonstrated from a literature investigation of hemolysis as a function of valve type and implant position.

Echocardiography, Doppler↗
PubMed1999

Communication and its disorders.

This article defines communication and describes its various disorders. Some of these disorders are associated with other DSM-IV conditions, such as mental retardation or pervasive developmental disorder. Others are specific to the language-learning process. The interactions between communication and psychiatric disorders are discussed. Suggestions for integrating treating approaches among communication disorders and mental health professionals are presented.

Child↗
PubMed1999

Multiplex developmental disorders. The role of communication in the construction of a self.

This article discusses the integration of various aspects of the child's development, particularly the development of language and communication and the way in which these developments interact to enable the child to construct a coherent sense of self. Multiplex developmental disorder is presented as an example of a disorder that affects several of these crucial strands of development. Recent research and controversies regarding the diagnostic descriptions of multiplex and other pervasive developmental disorders are presented. This discussion is used to illustrate the ways in which such disorders affect not only the individual aspects of development, but the child's ability to form a cohesive sense of self. The implications of these difficulties in self-definition for treating children with disorders that affect a variety of aspects of development are also discussed.

Child↗
PubMed1998

Direct and indirect estimates of HIV-1 incidence in a high-prevalence population.

While the worldwide AIDS epidemic continues to expand, directly measured incidence data are difficult to obtain. Methods to reliably estimate human immunodeficiency virus type 1 (HIV-1) incidence from more easily available data are particularly relevant in those parts of the world where prevalence is rising in heterosexually exposed populations. The authors set out to estimate HIV-1 incidence in a population of heterosexual sexually transmitted disease clinic attendees in Trinidad who had a known high prevalence of HIV-1 subtype B. Over the period 1987-1995, HIV-1 incidence estimates from serial cross-sectional studies of HIV-1 prevalence, passive follow-up of clinic recidivists, modeling of early markers of HIV-1 infection (p24 antigen screening), and a cohort study of seronegative genital ulcer disease cases were compared. Measuring incidence density in the genital ulcer disease cases directly gave the highest estimate, 6.9% per annum. Screening for the detection of early HIV-1 markers yielded an incidence of 5.0% per annum, while estimating incidence from serial cross-sectional prevalence data and clinic recidivists gave estimates of 3.5% and 4.5% per annum, respectively. These results were found to be internally consistent. Indirect estimates of incidence based on prevalence data can give accurate surrogates of true incidence. Within limitations, even crude measures of incidence are robust enough for health planning and evaluation purposes. For planning vaccine efficacy trials, consistent conservative estimates may be used to evaluate populations before targeting them for cohort studies.

Blotting, Western↗
PubMed1998

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in viral meningitis: upregulation of MMP-9 and TIMP-1 in cerebrospinal fluid.

A hallmark of viral meningitis is the invasion of monocytes, lymphocytes and, in the initial phase of the disease, neutrophils into the subarachnoidal space. By their degradation of different macromolecular components in the extracellular connective tissue, matrix metalloproteinases (MMPs) may be essential for the breakdown of the vessel wall in the meninges and the choroid plexus. In this study, the occurrence of MMP-1, MMP-2, MMP-3 and MMP-9 and the two tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2, was monitored in the cerebrospinal fluid (CSF) from patients with viral meningitis. Of the proteinases, MMP-9 was found in 13 of 39 (33%) patients, but not in controls; the levels being correlated with the neutrophil cell number in CSF. The CSF concentration of TIMP-1 was increased three-fold compared to the control group (median 233 ng/ml; range 9.4-1252.5 ng/ml) and was correlated to the levels of total protein in CSF. Of the other MMPs and TIMPs assayed, MMP-2 and TIMP-2 were constitutively expressed and not upregulated in viral meningitis. High levels of MMP-9 and MMP-2, as measured by ELISA, was associated with high proteolytic activity detected in CSF by zymography. In conclusion, invasion of the leukocytes into the CSF compartment in viral meningitis may involve MMP-9, its proteolytic effect likely being controlled by expression of TIMP-1.

Adolescent↗
PubMed1998

Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

BACKGROUND: Whether low-dose aspirin prevents preeclampsia is unclear. It is not recommended as prophylaxis in women at low risk for preeclampsia but may reduce the incidence of the disease in women at high risk. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in four groups of pregnant women at high risk for preeclampsia, including 471 women with pregestational insulin-treated diabetes mellitus, 774 women with chronic hypertension, 688 women with multifetal gestations, and 606 women who had had preeclampsia during a previous pregnancy. The women were enrolled between gestational weeks 13 and 26 and received either 60 mg of aspirin or placebo daily. RESULTS: Outcome data were obtained on all but 36 of the 2539 women who entered the study. The incidence of preeclampsia was similar in the 1254 women in the aspirin group and the 1249 women in the placebo group (aspirin, 18 percent; placebo, 20 percent; P=0.23). The incidences in the aspirin and placebo groups for each of the four high-risk categories were also similar: for women with pregestational diabetes mellitus, the incidence was 18 percent in the aspirin group and 22 percent in the placebo group (P=0.38); for women with chronic hypertension, 26 percent and 25 percent (P= 0.66); for those with multifetal gestations, 12 percent and 16 percent (P=0.10); and for those with preeclampsia during a previous pregnancy, 17 percent and 19 percent (P=0.47). In addition, the incidences of perinatal death, preterm birth, and infants small for gestational age were similar in the aspirin and placebo groups. CONCLUSIONS: In our study, low-dose aspirin did not reduce the incidence of preeclampsia significantly or improve perinatal outcomes in pregnant women at high risk for preeclampsia.

Adult↗
PubMed1998

Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis.

In this study, we investigated the involvement of matrix metalloproteinases (MMPs) in the pathophysiology of bacterial meningitis. By using an enzyme immunoassay, high concentrations of MMP-9 were detected in the cerebrospinal fluid (CSF) of adult patients with bacterial meningitis but not in controls, and in patients with Guillain-Barré syndrome. Moreover, we observed significantly elevated concentrations of the tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CSF of patients with bacterial meningitis, compared with controls. In a rat model of meningococcal meningitis, intracisternal injection of heat-killed meningococci caused a disruption of the blood-brain barrier (BBB), an increase in intracranial pressure, and CSF pleocytosis paralleled by the occurrence of MMP-9 activity in the CSF 6 hours after meningococcal challenge. The MMP inhibitor batimastat (BB-94) significantly reduced the BBB disruption and the increase in intracranial pressure irrespective of the time of batimastat administration (15 minutes before and 3 hours after meningococcal challenge) but failed to significantly reduce CSF white blood cell counts. In conclusion, our results suggest that MMPs are involved in the alterations of BBB permeability during experimental meningococcal meningitis.

Adult↗
PubMed1998

[Anti-androgen withdrawal syndrome].

Since the mid-forties androgen deprivation is regarded the standard treatment of incurable prostate cancer. Antiandrogens can be given either as monotherapy or in combination with bilateral orchidectomy or gonadotropin-releasing-hormone analoga. Recently reports have been published that withdrawal of antiandrogens in patients with hormone-resistant prostate cancer caused reduction of PSA and clinical improvement. Thus, in patients who progress under maximal androgen blockade or antiandrogen-monotherapy the antiandrogen should first be withdrawn and-in case of monotherapy-be replaced by GnRH-analoga. In approximately 30-50% of the cases a reduction of serum-PSA can be expected lasting for approx. 6 months. In some patients an improvement of symptoms and objective remission is observed.

Androgen Antagonists↗
PubMed1998

Maternal serum thromboxane B2 concentrations do not predict improved outcomes in high-risk pregnancies in a low-dose aspirin trial. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medical Units.

OBJECTIVE: The aim of the study was too determine whether, in a low-dose aspirin trial in high-risk pregnancies, a decrease in maternal serum thromboxane B2 level predicted improved pregnancy outcomes. STUDY DESIGN: This multicenter, randomized, double-blind trial included 2539 women, 1010 of whom had sufficient serum samples at enrollment and at 24 to 28 weeks' gestation, 34 to 38 weeks' gestation, or both to assess longitudinal changes in thromboxane B2 level and their effects on pregnancy outcomes. Women were randomly assigned between 13 and 26 weeks' gestation to receive daily aspirin (60 mg) or placebo. RESULTS: Overall and in all subgroups women assigned to receive aspirin had markedly lower maternal thromboxane B2 concentration values than did those assigned to receive a placebo (P =.0001). Changes in thromboxane levels were not, however, correlated with adverse pregnancy outcomes. Women with >/=50% reduction in maternal serum thromboxane B2 concentrations from baseline had occurrences of preeclampsia (P =.922), preterm birth (P =.375), small for gestational age neonates (P =.938), and grade III or IV intraventricular hemorrhage (P = 1.000) similar to those of women who had <50% reduction. Similar results were found for women with thromboxane B2 level decreases of <15 versus >15 ng/mL and women with thromboxane B2 level decreases to <10 versus >/=10, <5 versus >/=5, and <1 versus >/=1 ng/mL. Maternal thromboxane B2 concentrations at enrollment were also not predictive of adverse outcomes. CONCLUSION: Neither maternal serum thromboxane B2 concentrations at enrollment nor their subsequent reduction were predictive of adverse pregnancy outcomes in a low-dose aspirin trial.

Aspirin↗
PubMed1998

Predictors of pre-eclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

OBJECTIVE: We assessed several variables as predictors for pre-eclampsia risk in a group of women at high risk. STUDY DESIGN: We studied 2503 women with either diabetes mellitus, chronic hypertension, multifetal gestation, or pre-eclampsia in a previous pregnancy who participated in a multicenter study comparing aspirin and placebo in preventing pre-eclampsia. We evaluated multiple variables for predicting pre-eclampsia risk with use of univariate and multivariable analysis. RESULTS: Parity and mean arterial pressure at randomization were most predictive of pre-eclampsia risk. The risk was 8% with a mean arterial pressure at enrollment of <75 mm Hg versus 27% with a mean arterial pressure >85 mm Hg (relative risk and 95% confidence interval 3.3 [2.4 to 4.4]). The risk of pre-eclampsia was 26% in nulliparous patients versus 17% in parous subjects (relative risk and 95% confidence interval 1.5 [1.3-1.8]). CONCLUSIONS: The finding that second-trimester mean arterial pressure affects pre-eclampsia risk suggests that the pathophysiologic process of preeclampsia is initiated before that time.

Adult↗
PubMed1998

Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients.

To determine whether matrix metalloproteinase (MMP)-9 is a potential mediator involved in the frequently detected blood-brain barrier leakage in human immunodeficiency virus (HIV)-infected patients, zymography was used to detect MMP-9 activity in cerebrospinal fluid (CSF) samples of 80 HIV-infected patients and of 10 control patients. CSF MMP-9 activity was detected in 40% of HIV-infected patients (but not in controls) and was significantly more frequent in HIV-infected patients than in those without neurologic deficits (50% vs. 13.6%). The frequency of CSF MMP-9 activity did not significantly differ between neurologically symptomatic HIV-infected patients with or without opportunistic central nervous system disease (51.6% vs. 48.1%). Additionally, the presence of CSF MMP-9 activity in HIV-infected patients was associated with an increased CSF white blood cell count and an elevated CSF-to-serum albumin ratio, suggesting that it may play a role in blood-brain/CSF barrier leakage in HIV-infected patients.

CD4 Lymphocyte Count↗
PubMed1998

Cognitive efficiency in alcoholics and polysubstance abusers.

Previous studies have found alcoholics to be impaired on tests of cognitive efficiency. However, it is unclear to what extent individuals who abuse drugs in addition to alcohol exhibit similar deficits. To answer this question, 63 healthy control subjects were compared with 40 individuals who abused alcohol only, 24 individuals who abused alcohol and stimulants, 16 individuals who abused alcohol and marijuana, and 41 individuals who abused alcohol and depressants/narcotics, or alcohol and two or more other drugs. All subjects were administered tests of short-term memory, spatial orientation, visual-spatial perception, and problem-solving. Results from the study indicated that control subjects and individuals who abused both alcohol and marijuana performed significantly better than the other groups on most tests. These results were not attributable to differences on measures of affect or chronicity of alcohol consumption.

Adult↗