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Biomedical subjects

M Levine

Publications and source records attributed to M Levine.

At least 91 records · Page 5Linked to original sources
PubMed2000

Vancomycin pharmacokinetics and Bayesian estimation in pediatric patients.

The vancomycin pharmacokinetic profile was characterized in six pediatric patients and the potential of nonlinear mixed effects modeling and Bayesian forecasting for vancomycin monitoring was explored using NONMEM V (1.1). Based on steady state serial vancomycin concentrations, the estimates of mean t1/2, Vd, and Cl derived by the Sawchuk and Zaske method (1) were 3.52 hours, 0.57 L/kg, and 0.12 L/h per kg, respectively. NONMEM analysis demonstrated that a weight-adjusted two-compartment model described individual patients' data better than a comparable one-compartment model. The two-compartment estimates of mean t1/2alpha, t1/2beta, Vss, and Cl were 0.80 hour, 5.63 hours, 0.63 L/kg, and 0.11 L/h per kg, respectively. The relatively long mean t1/2alpha suggests that peak vancomycin concentrations measured earlier than 4 hours postdose do not reflect postdistributional serum concentrations. NONMEM population modeling revealed that a weight-adjusted two-compartment model provided a better fit than a comparable one-compartment model. The resulting population parameters and variances were fixed in NONMEM to obtain Bayesian predictions of individual vancomycin serum concentrations. Bayesian estimation with either a single midinterval or trough sample has the potential to provide accurate and precise predictions of vancomycin concentrations. This should be evaluated using a vancomycin population pharmacokinetic model based on a larger sample of pediatric patients.

Anti-Bacterial Agents↗
PubMed2000

Optimization of inspiratory work in periodic breathing in infants.

In periodic breathing, there are repeated cycles of bursts of breaths separated by pauses several seconds long. We consider the mechanics of periodic breathing in human infants using calibrated traces of tidal volume and esophageal pressure recorded during the first few days after delivery. Each cycle of periodic breathing was analyzed in terms of the inspiratory time and beginning and end inspiratory volumes for each breath, the number of breaths in the cycle, and the total observed inspiratory work. A simple model was used to characterize the mechanics of the lung during inspiration, and the recordings were used to calculate the parameters of this model. These varied from breath to breath. A theoretical formula is derived for the sum of external work performed during inspiration for each burst. It is shown mathematically that there exists a local minimum in the calculated work as the values of the individual tidal volumes in this formula are allowed to vary, with the constraint that the sum of the ventilation during the cycle is as measured. The measured values of inspiratory timing, the starting volume and pressure, and the mechanical parameters for each inspiration are also used. We show that during each cycle of periodic breathing, the total of the observed external work is highly correlated with this theoretical minimum work. In addition, during the cycle, there is a pattern of overshoot and subsequent undershoot in the work with respect to the theoretical optimum, which suggests a control process operating during the cycle to minimize the work.

Blood Gas Analysis↗
PubMed2000

Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo.

The dorsal ectoderm of the Drosophila embryo is subdivided into different cell types by an activity gradient of two TGF(&bgr;) signaling molecules, Decapentaplegic (Dpp) and Screw (Scw). Patterning responses to this gradient depend on a secreted inhibitor, Short gastrulation (Sog) and a newly identified transcriptional repressor, Brinker (Brk), which are expressed in neurogenic regions that abut the dorsal ectoderm. Here we examine the expression of a number of Dpp target genes in transgenic embryos that contain ectopic stripes of Dpp, Sog and Brk expression. These studies suggest that the Dpp/Scw activity gradient directly specifies at least three distinct thresholds of gene expression in the dorsal ectoderm of gastrulating embryos. Brk was found to repress two target genes, tailup and pannier, that exhibit different limits of expression within the dorsal ectoderm. These results suggest that the Sog inhibitor and Brk repressor work in concert to establish sharp dorsolateral limits of gene expression. We also present evidence that the activation of Dpp/Scw target genes depends on the Drosophila homolog of the CBP histone acetyltransferase.

Animals↗
PubMed2000

Epirubicin in breast cancer: present and future.

Epirubicin, a member of the anthracycline family of chemotherapeutic agents, has been widely used throughout the world both as adjuvant therapy in early breast cancer and in metastatic breast cancer. Clinical trials with epirubicin have examined the importance of a dose-response relationship, therapeutic dose, and optimum duration of chemotherapy. In addition, pharmacokinetic studies have provided data on ideal combinations with other agents. Epirubicin-containing regimens are considered to be superior to those containing cyclophosphamide, methotrexate, and fluorouracil (CMF) and are also used in patients with locally advanced stage IIIA/IIIB breast cancer. Combinations with other chemotherapeutic agents (eg, epirubicin plus a taxane, sequential or combined use of these agents) are being evaluated in ongoing clinical trials. Moreover, recent studies have suggested that biologic markers, such as tumor HER2/neu overexpression, predict responses to dose-intensive anthracycline chemotherapy, and combinations with nonchemotherapeutic regimens (eg, trastuzumab) may provide additional benefits, but such strategies require further evaluation.

Antibiotics, Antineoplastic↗
PubMed2000

An algorithm to aid in the investigation of thalassemia trait in multicultural populations.

CONTEXT: The differentiation between iron deficiency and a thalassemia syndrome is an important consideration in the investigation of microcytic anemia. OBJECTIVE: An established statistical method was used to demonstrate the importance of considering ethnic background in combination with mean cell volume (MCV) in the investigation of beta-thalassemia trait in a multicultural urban population. DESIGN: Posttest probabilities for beta-thalassemia trait were calculated using likelihood ratios for various microcytic MCV ranges in conjunction with published pretest probabilities for beta-thalassemia trait based on ethnic background. SETTING: Regional hemoglobinopathy laboratory, St Joseph's Hospital, Hamilton, Ontario, Canada. PATIENTS: Patient data were derived from a previously published study. The original study cohort consisted of 789 patients aged 18 years or older who had an MCV less than 80 fL and were referred for routine complete blood count during a 6-month period. MAIN OUTCOME MEASURES: Posttest probabilities. RESULTS: Simplified tables for the determination of posttest probabilities for beta-thalassemia trait in individual patients based on ethnic background and MCV are provided. An algorithm to assist in determining when thalassemia investigations are indicated is presented. CONCLUSIONS: A high index of suspicion based on ethnic background and low MCV can provide increased sensitivity and specificity for the detection of thalassemia trait in centers with multicultural populations similar to the study population.

Algorithms↗
PubMed2000

A novel process for updating recommendations for managing hypertension: rationale and methods.

BACKGROUND: There are numerous hypertension consensus recommendations intended for practising physicians. However, recommendations in their current format have limited impact on improving hypertension control. MATERIALS AND METHODS: A group of national societies, headed by the Canadian Hypertension Society, the Heart and Stroke Foundation of Canada, the Canadian Coalition for High Blood Pressure Prevention and Control, and Health Canada has developed strategies to maintain annually updated recommendations for hypertension management and to provide greater opportunities for their implementation into clinical practice. The process is overseen by a steering committee. Subcommittees have been formed for each of a list of topics seen as important to the control of hypertension. The subcommittees, with the aid of a central librarian, conduct annual literature reviews in accordance with Cochrane Collaboration strategies. Modified existing and new recommendations are forwarded to a group with expertise in clinical epidemiology. Grades of evidence are assigned to each recommendation. Revised recommendations based on the above process will be presented annually at the conjoint Canadian Hypertension Society/Canadian Cardiovascular Congress meeting. Under the leadership of the Cardiovascular Disease Division of the Laboratory Centre for Disease Control, Health Canada, a committee has been charged with the implementation process. CONCLUSIONS: The improvements of the current process over previous national hypertension recommendations are four-fold. First, the recommendations will be updated annually. Second, the methodology has been improved. Third, the grading system can be used in the evaluation of complex study designs. Finally, the implementation process is extended. The authors are optimistic that these changes will contribute to the improvement of hypertension control in the Canadian population.

Canada↗
PubMed1999

A novel cis-regulatory element, the PTS, mediates an anti-insulator activity in the Drosophila embryo.

The Abd-B Hox gene contains an extended 3' cis-regulatory region that is subdivided into a series of separate lab domains. The lab-7 domain activates Abd-B in parasegment 12 (ps12), whereas lab-8 controls expression in ps13. iab-7 is flanked by two insulators, Fab-7 and Fab-8, which are thought to prevent regulatory factors, such as Polycomb silencers, from influencing neighboring iab domains. This organization poses a potential paradox, since insulator DNAs can work in a dominant fashion to block enhancer-promoter interactions over long distances. Here, we present evidence for a novel cis-regulatory sequence located within lab-7, the promoter targeting sequence (PTS), which permits distal enhancers to overcome the blocking effects of Fab-8 and the heterologous su(Hw) insulator. We propose that the PTS converts dominant, long-range insulators into local regulatory elements that separate neighboring lab domains.

Animals↗
PubMed1999

Cloning and functional characterization of the human sodium-dependent vitamin C transporters hSVCT1 and hSVCT2.

Two sodium-dependent vitamin C transporters, hSVCT1 and hSVCT2, were cloned from a human kidney cDNA library. hSVCT1 had a 1797 bp open reading frame encoding a 598 amino acid polypeptide. The 1953 bp open reading frame of hSVCT2 encoded a 650 amino acid polypeptide. Using a Xenopus laevis oocyte expression system, both transporters were functionally expressed. By Eadie-Hofstee transformation the apparent K(m) of hSVCT1 for ascorbate was 252.0 microM and of hSVCT2 for ascorbate was 21.3 microM. Both transporters were sodium-dependent and did not transport dehydroascorbic acid. Incubation of oocytes expressing either transporter with phorbol 12-myristate 13-acetate (PMA) inhibited ascorbate transport activity. Availability of the human transporter clones may facilitate new strategies for determining vitamin C intake.

Amino Acid Sequence↗
PubMed1999

Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis.

BACKGROUND: The safety and efficacy of taking low-molecular-weight heparin at home was previously demonstrated in a clinical trial in which patients with acute proximal deep vein thrombosis were randomized to receive either intravenous standard heparin in the hospital or subcutaneous low-molecular-weight heparin administered primarily at home. Treatment in the home has the potential to substantially reduce the cost to the health care system. METHODS: To conduct an economic evaluation we prospectively collected data on resource use and health-related quality of life (Medical Outcomes Study Short-Form 36) on the 300 patients who formed the trial stratum presenting with proximal vein thrombosis as outpatients, of whom 151 received standard heparin and 149 received low-molecular-weight heparin. The primary viewpoint of the analysis was societal, and costs included health care costs, patient travel costs, and productivity costs as a result of time off work. Costs were assessed over a period of 3 months from randomization. Quality of life was assessed as the change in Short-Form 36 domain scores from baseline to day 7 for each treatment group. All costs are reported in 1997 Canadian dollars. RESULTS: There were 11 recurrent thromboembolic events and 1 bleed in the 151 patients who received standard heparin; the corresponding data for the 149 patients receiving low-molecular-weight heparin were 10 and 4, respectively. The mean cost per patient who received standard heparin was Can $5323 compared with Can $2278 for low-molecular-weight heparin, a total societal cost savings per patient using low-molecular-weight heparin of Can $3045 (95% confidence interval, Can $2012-$4050). There was no difference in quality of life between the 2 groups except for the domain of social functioning, where a greater improvement from baseline to day 7 was observed for the low-molecular-weight heparin group vs the standard heparin group (P =.005). CONCLUSIONS: For patients with acute proximal deep vein thrombosis, treatment at home with low-molecular-weight heparin is less costly than hospital-based treatment with standard heparin. The economic evidence in favor of outpatient treatment with low-molecular-weight heparin exhibits dominance; a situation of reduced cost is created with no compromise in clinical outcomes or patients' quality of life.

Adult↗
PubMed1999

Recurrent venous thrombosis and heparin therapy: an evaluation of the importance of early activated partial thromboplastin times.

BACKGROUND: The presence of an association between early subtherapeutic activated partial thromboplastin times (aPTTs) and recurrent venous thromboembolism (VTE) remains controversial. OBJECTIVE: To determine the relation between early subtherapeutic aPTTs and recurrent VTE in patients who were treated with intravenous (i.v.) unfractionated heparin (UFH). PATIENTS AND METHODS: We studied 961 patients with acute VTE who received i.v. UFH in 3 randomized trials that compared the use of i.v. UFH (loading dose: 5000 U i.v.; initial infusion, 1250-1280 U/h) with that of subcutaneous low-molecular-weight heparin. According to aPTT criteria, patients were classified as being in a subtherapeutic or a therapeutic state during the first 24 and 48 hours of treatment. All episodes of possible recurrent VTE were adjudicated by an independent committee that was unaware of the aPTTs. RESULTS: At 24 hours, in 886 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 6.7% (11/163) compared with 5.3% (38/723) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 24 hours was 1.30 (95% confidence interval: 0.64-2.63; P = .46). At 48 hours, in 917 patients who were eligible for the analysis, the rate of recurrent VTE in the subtherapeutic group was 7.8% (5/64) compared with 5.7% (49/853) in the therapeutic group. The odds ratio for recurrence in patients in the subtherapeutic vs the therapeutic group at 48 hours was 1.32 (95% confidence interval: 0.51-3.44; P = .56). CONCLUSION: In patients with acute VTE who receive an i.v. bolus of 5000 U, followed by a starting dose of at least 1250 U/h of UFH, a subtherapeutic aPTT response during the first 48 hours of treatment is not associated with a large increase in the risk of recurrent VTE.

Aged↗
PubMed1999

Specificity of ascorbate analogs for ascorbate transport. Synthesis and detection of [(125)I]6-deoxy-6-iodo-L-ascorbic acid and characterization of its ascorbate-specific transport properties.

Cellular ascorbic acid accumulation occurs in vitro by two distinct mechanisms: transport of ascorbate itself or transport and subsequent intracellular reduction of its oxidized product, dehydroascorbic acid. It is unclear which mechanism predominates in vivo. An easily detectable compound resembling ascorbate but not dehydroascorbic acid could be a powerful tool to distinguish the two transport activities. To identify compounds, 21 ascorbate analogs were tested for inhibition of ascorbate or dehydroascorbic acid transport in human fibroblasts. The most effective analogs, competitive inhibitors of ascorbate transport with K(i) values of 3 microM, were 6-deoxy-6-bromo-, 6-deoxy-6-chloro-, and 6-deoxy-6-iodo-L-ascorbate. No analog inhibited dehydroascorbic acid transport. Using substitution chemistry, [(125)I]6-deoxy-6-iodo-L-ascorbate (1.4 x 10(4) mCi/mmol) was synthesized. HPLC detection methods were developed for radiolabeled and nonradiolabeled compounds, and transport kinetics of both compounds were characterized. Transport was sodium-dependent, inhibited by excess ascorbate, and similar to that of ascorbate. Transport of oxidized ascorbate and oxidized 6-deoxy-6-iodo-L-ascorbate was investigated using Xenopus laevis oocytes expressing glucose transporter isoform GLUT1 or GLUT3. Oxidation of ascorbate or its analog in media increased uptake of ascorbate in oocytes by 6-13-fold compared with control but not that of 6-deoxy-6-iodo-L-ascorbate. Therefore, 6-deoxy-6-iodo-L-ascorbate, although an effective inhibitor of ascorbate transport, either in its reduced or oxidized form was not a substrate for dehydroascorbic acid transport. Thus, radiolabeled and nonradiolabeled 6-deoxy-6-iodo-L-ascorbate provide a new means for discriminating dehydroascorbic acid and ascorbate transport in ascorbate recycling.

Animals↗
PubMed1999

Brachyury downstream notochord differentiation in the ascidian embryo.

The ascidian tadpole represents the most simplified chordate body plan. It contains a notochord composed of just 40 cells, but as in vertebrates Brachyury is essential for notochord differentiation. Here, we show that the misexpression of the Brachyury gene (Ci-Bra) of Ciona intestinalis is sufficient to transform endoderm into notochord. Subtractive hybridization screens were conducted to identify potential Brachyury target genes that are induced upon Ci-Bra misexpression. Of 501 independent cDNA clones that were surveyed, 38 were specifically expressed in notochord cells. These potential Ci-Bra downstream genes appear to encode a broad spectrum of divergent proteins associated with notochord formation.

Animals↗
PubMed1999

The Rpd3 histone deacetylase is required for segmentation of the Drosophila embryo.

Previous studies have implicated histone deacetylation and chromatin condensation as critical mechanisms of transcription repression in yeast and mammals. A specific histone deacetylase, Rpd3, interacts with a variety of sequence-specific transcriptional repressors, including Mad-Max heterodimers and members of the nuclear receptor superfamily. Here, we present evidence that a strong hypomorphic mutation in the Drosophila Rpd3 gene causes embryonic lethality and a specific pair-rule segmentation phenotype. The analysis of a number of segmentation genes suggests that the repressor function of Even-skipped (Eve) may be diminished, causing an indirect loss of Ftz-mediated activation of engrailed. The relatively mild defects observed in Rpd3 mutants suggest that the recently identified Groucho and dCtBP corepressor proteins do not function solely through the recruitment of histone deacetylases. We discuss the possibility that Eve mediates multiple mechanisms of repression, so that Rpd3 mutants disrupt the regulation of just a subset of Eve target genes.

Animals↗
PubMed1999

Does clinical case management improve outpatient addiction treatment.

This project evaluated whether clinical case managers (CCMs) could increase access and utilization of social services in the community; and thereby improve outcomes of addiction treatment. No case management (NoCM)--patients received standard, group-based, abstinence-oriented, outpatient drug abuse counseling, approximately twice weekly. Clinical case management (CCM)--patients were treated in the same programs but also were assigned a CCM who provided access to pre-contracted, support services such as drug free housing, medical care, legal referral, and parenting classes from community agencies. CCM patients received more alcohol, medical, employment, and legal services than NoCM patients during treatment. At 6 month follow-up CCM patients showed significantly more improvement in alcohol use, medical status, employment, family relations, and legal status than NoCM patients. We conclude that CCM was an effective method of improving outcomes for substance abuse patients in community treatment programs. Essential elements for successful implementation included extensive training to foster collaboration; and pre-contracting of services to assure availability.

Adult↗
PubMed1999

Transcriptional coregulators in development.

Small differences in the levels of an extracellular signaling molecule can specify cell fate during development. Threshold responses are often determined at the level of transcription. Cell-specific and spatially localized patterns of gene expression depend on combinations of sequence-specific activators and repressors that bind to extensive cis-regulatory regions. Different mechanisms for integrating this complex regulatory information are discussed, particularly the role of coregulatory proteins, which are recruited to the DNA template by sequence-specific transcription factors. Recent studies suggest that a growing set of coactivators and corepressors mediate communication between diverse upstream regulatory proteins and the core RNA polymerase II transcription complex.

Animals↗