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Biomedical subjects

M Levine

Publications and source records attributed to M Levine.

At least 199 records · Page 11Linked to original sources
PubMed1996

The Ontario Cancer Treatment Practice Guidelines Initiative.

The Ontario Cancer Treatment Practice Guidelines Initiative was established in 1993 to develop clinical practice guidelines for cancer treatment in Ontario, Canada. First, an organizational structure, consisting of a coordinating committee, a methods resource group, and disease site groups, was put in place. Central to the development of guidelines are the 10 provincial site groups, which use a methodologic framework, the practice guidelines development cycle, to formulate the guidelines. When a preliminary evidence-based recommendation is developed by a site group, it is sent out to a sample of community practitioners for input and is modified based on their feedback. The final product is the practice guideline. Further research is required to determine optimal dissemination strategies and evaluate the impact of these guidelines.

Evidence-Based Medicine↗
PubMed1995

Transcriptional repression in the Drosophila embryo.

Transcriptional repression is essential for the conversion of crude maternal gradients into sharp territories of tissue differentiation in the Drosophila embryo. Evidence will be presented suggesting that some of the embryonic repressors function through a short-range 'quenching' mechanism, whereby a repressor works over short distances (ca. 50 b.p.) to block neighbouring activators within a target enhancer. This type of repression can explain how different enhancers work autonomously within complex modular promoters. However, at least one of the repressors operating in the early embryo works through a long-range, or silencing, mechanism. The binding of a silencer to a given enhancer leads to the inactivation of all enhancers within a complex promoter. The analysis of chromatin boundary elements suggest that silencers and enhancers might work through distinct mechanisms. We speculate that silencers constrain the evolution of complex promoters.

Animals↗
PubMed1995

Modulation of enhancer-promoter interactions by insulators in the Drosophila embryo.

Insulator DNAs, or boundary elements, functionally isolate neighbouring genes by blocking interactions between distal enhancers and inappropriate target promoters. The best-characterized insulators in Drosophila correspond to a 340-base-pair (bp) fragment from the gypsy retrotransposon, and the scs and scs' sequences flanking the 87A1 hsp70 locus. Here we demonstrate that both insulators block the interaction of defined even-skipped (eve) stripe enhancers when positioned between the enhancer and the target promoter. The simultaneous use of two stripe enhancers (eve stripes 2 and 3) provides evidence that enhancers lying distal to the insulator are selectively blocked. The insertion of stripe-insulator-stripe sequences between two divergently transcribed promoters indicates that enhancers barred from acting on one basal promoter are fully accessible to appropriate regulatory factors for activating the other promoter. These results suggest that insulators do not propagate changes in chromatin structure. Finally, we present evidence that the gypsy insulator does not block interactions between a silencer element and a basal promoter. Taken together, these results suggest that insulators might not be restricted to the functional isolation of neighbouring genetic loci. Rather, they might function as flexible regulatory elements that modulate enhancer-promoter interactions within complex promoters and complex genetic loci.

Animals↗
PubMed1995

Accumulation of vitamin C (ascorbate) and its oxidized metabolite dehydroascorbic acid occurs by separate mechanisms.

It is unknown whether ascorbate alone (vitamin C), its oxidized metabolite dehydroascorbic acid alone, or both species are transported into human cells. This problem was addressed using specific assays for each compound, freshly synthesized pure dehydroascorbic acid, the specially synthesized analog 6-chloroascorbate, and a new assay for 6-chloroascorbate. Ascorbate and dehydroascorbic acid were transported and accumulated distinctly; neither competed with the other. Ascorbate was accumulated as ascorbate by sodium-dependent carrier-mediated active transport. Dehydroascorbic acid transport and accumulation as ascorbate was at least 10-fold faster than ascorbate transport and was sodium-independent. Once transported, dehydroascorbic acid was immediately reduced intracellularly to ascorbate. The analog 6-chloroascorbate had no effect on dehydroascorbic acid transport but was a competitive inhibitor of ascorbate transport. The Ki for 6-chloroascorbate (2.9-4.4 microM) was similar to the Km for ascorbate transport (9.8-12.6 microM). 6-Chloroascorbate was itself transported and accumulated in fibroblasts by a sodium-dependent transporter. These data provide new information that ascorbate and dehydroascorbic acid are transported into human neutrophils and fibroblasts by two distinct mechanisms and that the compound available for intracellular utilization is ascorbate.

Ascorbic Acid↗
PubMed1995

Multiple modes of dorsal-bHLH transcriptional synergy in the Drosophila embryo.

Synergistic interactions between the maternal regulatory factor dorsal (dl) and basic helix-loop-helix (bHLH) activators are essential for initiating differentiation of the mesoderm and neuroectoderm in the early Drosophila embryo. Here we present evidence that dl-bHLH interactions mediating gene expression in the neuroectoderm and mesoderm are fundamentally distinct. Close proximity of dl and bHLH binding sites is essential for the synergistic activation of gene expression in the lateral neuroectoderm, where there are diminishing levels of the dl regulatory gradient. In contrast, sharp on/off patterns of gene expression in the presumptive mesoderm do not require linkage of these sites. Analysis of minimal and synthetic promoter elements suggests that dl and bHLH activators, such as twist, might interact with different rate-limiting components of the transcription complex. These results are consistent with two distinct modes of dl-bHLH synergy: cooperative binding to DNA (requiring linkage of sites) and synergistic contact of basal transcription factors (not requiring linkage). Finally, the characterization of a 57 bp synthetic minimal stripe unit (MSU) provides evidence for a third tier of dl-bHLH synergy. Tandem copies of the MSU function as a bona fide enhancer and can mediate neuroectoderm expression in transgenic embryos even when placed 4.5 kb downstream of a test promoter. Multiple copies of the MSU function synergistically only when linked, but not when separated. We propose that this linkage requirement provides the basis for the evolution of modular promoters composed of discrete, non-overlapping enhancers.

Animals↗
PubMed1995

Can periodic breathing have advantages for oxygenation?

A model of the chemoreceptor mediated control of breathing is analysed. Hypoxia is simulated as low equilibrium arterial oxygen both at altitude and at sea level. Conditions for stable and unstable equilibria are examined. Transition to instability leads to periodic breathing and the model predicts that this can cause arterial oxygen to oscillate asymmetrically about the equilibrium in some cases, causing the average to rise. Periodic forcing functions have been applied to cerebral blood flow with the same effect on arterial oxygen. Such asymmetric oscillations leading to enhanced oxygenation have been observed in pulse oxymeter recordings from elderly postoperative patients. This may be important in interpreting studies of unstable breathing patterns and their possible relation to morbidity or mortality in infants (e.g. SIDS) and in the elderly (e.g. sleep apnoea, postoperative hypoxia). Periodic breathing could act as a protective adaptation to counteract pre-existing hypoxia.

Chemoreceptor Cells↗
PubMed1995

Ascorbic acid transport and distribution in human B lymphocytes.

Ascorbic acid (vitamin C) transport was investigated in human B lymphocytes. The vitamin was transported by two components. The first was a high-affinity activity with an apparent Km of 7-10 microM and Vmax of 0.14 mM/h (3.11 x 10(-4) mumol x h-1 x mg protein-1). The activity was concentration and temperature dependent, saturable, and inhibited by carbonylcyanide-p-trifluoromethoxyphenylhydrazone and ouabain and generated ascorbic acid accumulation against a concentration gradient. Kinetics for the second component were indeterminate because ascorbate was not accumulated against a concentration gradient. Subcellular fractionation revealed that intracellular ascorbic acid in human B lymphocytes was > 90% localized to the cytosol and not protein bound. Kinetic parameters of high-affinity ascorbic acid transport could operate effectively with plasma concentrations normally found in humans.

Ascorbic Acid↗
PubMed1995

Design and validation of a bedside decision instrument to elicit a patient's preference concerning allogenic bone marrow transplantation in chronic myeloid leukemia.

The objective of this study was to design and validate a bedside decision instrument to be used by patients with chronic myeloid leukemia and their physicians in deciding between the therapeutic alternatives of bone marrow transplantation and conservative management during the early phase of disease. A decision board was constructed containing detailed scenarios associated with the treatment alternatives, together with estimates of survival probabilities at various periods of followup. The instrument was tested on 42 healthy hospital personnel and validated by measuring the extent to which systematic alterations in the scenarios with respect to toxicities and survival probabilities produced predicted shifts in treatment preferences. A subgroup of respondents was randomized to receive information through the decision board alone or a shorter and less informative version of the instrument, followed by the decision board. The direction and strength of stated preferences were compared, together with satisfaction for these preferences. The direction and strength of preferences between bone marrow transplantation or conservative chemotherapy were influenced in a predictable way by changes in the toxicity and survival descriptions in the scenarios. Using the test-retest method in 16 subjects, the stated preferences were found to be highly reliable (intraclass correlation coefficient, 0.87). The mean level of satisfaction with the stated preference, on a scale from not at all satisfied = 1 to very satisfied = 5, was higher for those exposed to the decision board (3.7, SD 1.06) compared with those presented with the short version (2.95, SD 0.67) (P < 0.01). The results demonstrate the feasibility and acceptability of the instrument in healthy individuals. The preferences elicited by the instrument appear to be reliable and valid according to prespecified constructs of the relation between the information provided and the preferences predicted. These results support further testing of this approach in actual patients.

Bone Marrow Transplantation↗
PubMed1995

Second messenger systems in Tourette's syndrome.

Abnormalities within second messenger systems have been hypothesized as the underlying pathophysiologic mechanism in a variety of neuropsychiatric disorders. In the Gilles de la Tourette syndrome (TS) prior studies have shown that the concentration of adenosine 3',5'-monophosphate (cAMP) is reduced in cortical and putamen brain regions. In this study, postmortem cortical tissues from 4 adults (mean age 59.5 years) with the lifetime diagnosis of TS and 5 controls (mean age 63.8 years) were analyzed for functional activities within the cAMP and phosphoinositide systems. In addition, plasma cAMP was quantified in children with TS (n = 33) and controls (n = 17). In frontal (A4, A6) and occipital (A17) cortical tissues there were no significant differences for adenylyl cyclase activity whether assayed under basal conditions or after stimulation with GTP gamma S (a non-hydrolyzable GTP analog), forskolin (a selective enzyme stimulator), or (-)-isoproterenol (a beta-adrenergic agonist). D2 receptor activation (quinpirole) and assessment of the inhibitory guanine nucleotide protein also showed no significant alterations in TS samples. Activity of cAMP phosphodiesterase was increased insignificantly in A4 and A17 TS brain regions. Plasma concentrations of cAMP in plasma were similar in children with TS (135.4 +/- 8.3 pmol/ml) and controls (132.6 +/- 7.9 pmol/ml). Postmortem membrane receptor binding for markers within the phosphoinositide (PI) system showed that TS samples had increased [3H]phorbol ester binding to protein kinase C sites in area A17, but normal binding in A4. In contrast, [3H] inositol 1,4,5-triphosphate binding to IP3 receptors showed no significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1995

Acclimation of a non-indigenous sub-Arctic population: seasonal variation in thyroid function in interior Alaska.

Total, as well as free, T4 and T3 levels were obtained over four seasons for young male infantry soldiers assigned to interior Alaska. Significant seasonal variations were found in both T3 and T4. Total T4 and T3 levels were highest in winter, while free T4 and T3 levels were highest in early spring. Correlations with melatonin levels from a concurrent study showed an association between late day (17.00) mean spot melatonin levels during the preceding summer and T3 levels in winter and spring. Differences in seasonal T4 and T3 levels between indigenous and newly arrived people in the sub-Arctic may be related not only to cold acclimation but also to light.

Acclimatization↗
PubMed1995

Race: a Drosophila homologue of the angiotensin converting enzyme.

We report the isolation and characterization of a putative angiotensin converting enzyme (ACE) in Drosophila, called Race. General interest in mammalian ACE stems from its association with high blood pressure; ACE has also been implicated in a variety of other physiological processes including the processing of neuropeptides and gut peristalsis. Mammalian ACE is a membrane associated zinc binding protease that converts angiotensin I (A I) into angiotensin II (A II). A II functions as a potent vasoconstrictor by triggering a G-coupled receptor system in the smooth muscles that line blood vessels. Drosophila Race is composed of 615 amino acid residues, and shares extensive sequence identity with mammalian ACE over its entire length (over 42% overall identity and greater than 60% similarity). Evidence is presented that Race might correspond to a target of the homeobox regulatory gene, zerknullt (zen). Soon after zen expression is restricted to the dorsal-most regions of the embryonic ectoderm, Race is activated in a coincident pattern and becomes associated with the amnioserosa during germ band elongation, shortening and heart morphogenesis. After germ band elongation, Race is also expressed in both the anterior and posterior midgut, where it persists throughout embryogenesis. Race expression is lost from the dorsal ectoderm in either zen- or dpp- mutants, although gut expression is unaffected. P-transformation assays and genetic complementation tests suggest that Race corresponds to a previously characterized lethal complementation group, 1(2)34Eb. Mutants die during larval/pupal development, and transheterozygotes for two different lethal alleles exhibit male sterility. We propose that Race might play a role in the contractions of the heart, gut, or testes and also suggest that Hox genes might be important for coordinating both developmental and physiological processes.

Amino Acid Sequence↗
PubMed1995

Determination of optimal vitamin C requirements in humans.

Although the recommended dietary allowance provides an estimate for vitamin C ingestion in humans, optimal vitamin C requirements are unknown. We define optimal vitamin C requirements operationally based on the following: dose-function relations, availability in the food supply, steady state concentrations in plasma and tissues achieved at each dose of vitamin C, urinary excretion, bioavailability, toxicity, and epidemiologic observations. Optimal vitamin C requirements can be estimated when information is available for at least some of these criteria.

Ascorbic Acid↗
PubMed1995

Clinical characteristics of sevoflurane in children. A comparison with halothane.

BACKGROUND: For pediatric patients, sevoflurane may be an alternative to halothane, the anesthetic agent used most commonly for inhalational induction. The induction, maintenance, and emergence characteristics were studied in 120 unpremedicated children 1-12 yr of age randomly assigned to receive one of three anesthesia regimens: sevoflurane with oxygen (group S), sevoflurane with nitrous oxide and oxygen (group SN), or halothane with nitrous oxide and oxygen (group HN). METHODS: Anesthetic was administered (via a Mapleson D, F or Bain circuit) beginning with face mask application in incremental doses to deliver maximum inspired concentrations of 4.5% halothane or 7% sevoflurane. End-tidal concentrations of anesthetic agents and vocal cord position were noted at the time of intubation. Elapsed time intervals from face mask application to loss of the eyelash reflex, intubation, surgical incision, and discontinuation of the anesthetic were measured. Heart rate, systolic, diastolic, and mean blood pressures, and end-tidal anesthetic concentrations were measured at fixed intervals. Anesthetic MAC-hour durations were calculated. The end-tidal concentration of anesthetic was adjusted to 1 MAC (0.9% halothane, 2.5% sevoflurane) for at least the last 10 min of surgery. Intervals from discontinuation of anesthetic to hip flexion or bucking, extubation, administration of first postoperative analgesic, and attaining discharge criteria from recovery room were measured. Venous blood was sampled at anesthetic induction, at the end of anesthesia, and 1, 4, 6, 12, and 18-24 h after discontinuation of the anesthetic for determination of plasma inorganic fluoride content. RESULTS: Induction of anesthesia was satisfactory in groups SN and HN. Induction in group S was associated with a significantly greater incidence of excitement (35%) than in the other groups (5%), resulting in a longer time to intubation. The end-tidal minimum alveolar concentration multiple of potent inhalational anesthetic at the time of intubation was significantly greater in patients receiving halothane than in patients receiving sevoflurane. Induction time, vocal cord position at intubation, time to incision, duration of anesthesia, and MAC-hour duration were similar in the three groups. During emergence, the time to hip flexion was similar among the three groups, whereas the time to extubation, time to first analgesic, and time to attaining discharge criteria were significantly greater in group HN than in groups S and SN. Mean heart rate and systolic blood pressure decreased during induction in group HN but not in groups S and SN. The maximum serum fluoride concentration among all patients was 28 microM. CONCLUSIONS: Sevoflurane with nitrous oxide provides satisfactory anesthetic induction and intubating conditions; however, induction using sevoflurane without nitrous oxide is associated with a high incidence of patient excitement and prolonged time to intubation. There were greater decreases in heart rate and systolic blood pressure during induction with halothane than with sevoflurane; however, these differences may be dose-related. The more rapid emergence with sevoflurane when compared with halothane is consistent with the low solubility of sevoflurane in blood and tissues. Children receiving sevoflurane for up to 9.6 MAC-hours did not develop high serum fluoride concentrations.

Anesthesia, Inhalation↗
PubMed1995

Vancomycin pharmacokinetics and dosing in premature neonates.

We prospectively studied the pharmacokinetic parameters of vancomycin in premature neonates given vancomycin according to a dosage protocol developed in our neonatal unit. Study infants were administered vancomycin according to four postconceptional age (PCA) groups: (0) 18 mg/kg every 36 h for PCA < 27 weeks; (I) 16 mg/kg every 24 h for PCA 27-30 weeks; (II) 18 mg/kg every 18 h for PCA 31-36 weeks; and (III) 15 mg/kg every 12 h for PCA > or = 37 weeks. Pharmacokinetic parameters were calculated from peak and trough serum vancomycin concentrations at steady state. Results in 44 infants (PCA, 27-44 weeks) showed that our dosage regimen achieved target peak serum vancomycin concentrations in 64% of neonates in Groups I-III, although it tended to undershoot the target trough concentrations. Volume of distribution (Vd), normalized for body weight, remained constant throughout the PCA range, with a mean value of 0.56 L/kg, whereas absolute clearance (r = 0.81) and normalized clearance (r = 0.48) increased with PCA (p < 0.005). The increase in clearance with PCA is associated with a greater elimination rate constant and shorter half-life. Vancomycin therapy can be initiated in a standard fashion according to our protocol or by individualizing the dosage regimen based on a Vd of 0.56 L/kg and clearance estimated from the infant's body weight and PCA groups.

Anti-Bacterial Agents↗
PubMed1995

Autotaxin is an N-linked glycoprotein but the sugar moieties are not needed for its stimulation of cellular motility.

Autotaxin is a 125kD autocrine motility factor that stimulates both random and directed motility in producing the human A2058 melanoma cell line. The recently cloned autotaxin has been demonstrated to bind strongly and specifically to concanavalin A (con A). In this study, we show that the oligosaccharide side chains on autotaxin are exclusively asparagine linked, since N-glycosidase F, but not neuraminidase or O-glycosidase, decreases the protein molecular mass to 100-105kD, which is the calculated molecular mass of the deduced autotaxin polypeptide. Furthermore, removal of oligosaccharide side chains by N-glycosidase F can be performed under mild conditions that retain motility-stimulating activity, suggesting that the oligosaccharide side chains are not necessary for autotaxin to activate its receptor. Finally, when melanoma cells are treated with inhibitors of carbohydrate processing, such as N-methyl-1-deoxynojirimycin, 1-deoxymannojirimycin and swainsonine, they still secrete a motility-stimulating autotaxin. Therefore, the carbohydrate side chains on autotaxin are not necessary to stimulate motility; however, they may still play a role in folding, secretion or maintenance of the active conformation of the protein.

Amidohydrolases↗
PubMed1995

Specificity of Rel-inhibitor interactions in Drosophila embryos.

The Rel family of transcription factors participate in a diverse array of processes, including acute responses to injury and infection, lymphocyte differentiation, and embryonic patterning. These proteins show homology in an extended region spanning about 300 amino acids (the Rel homology domain [RHD]). The RHD mediates both DNA binding and interactions with a family of inhibitor proteins, including I kappa B alpha and cactus. Previous studies have shown that an N-terminal region of the RHD (containing the sequence motif RXXRXRXXC) is important for DNA binding, while the C-terminal nuclear localization sequence is important for inhibitor interactions. Here we present a structure-function analysis of the Drosophila dorsal RHD. These studies identify another sequence within the RHD (region I) that is essential for inhibitor interactions. There is a tight correlation between the conservation of region I sequences and the specificity of Rel-inhibitor interactions in both flies and mammals. Point mutations in the region I sequence can uncouple DNA binding and inhibitor interactions in vitro. The phenotypes associated with the expression of a modified dorsal protein in transgenic Drosophila embryos suggest a similar uncoupling in vivo. Recent crystallographic studies suggest that the region I sequence and the nuclear localization sequence might form a composite surface which interacts with inhibitor proteins.

Amino Acid Sequence↗
PubMed1995

Very low-dose warfarin prophylaxis to prevent thromboembolism in women with metastatic breast cancer receiving chemotherapy: an economic evaluation.

PURPOSE: A recent double-blind, randomized trial demonstrated that very low-dose warfarin (VLDW) reduced the incidence of venous thromboembolism (VTE) without increasing the rate of bleeding in women with metastatic breast cancer receiving chemotherapy. We have evaluated the economic impact on the health care system of using VLDW in such patients. METHODS: The records of patients entered onto the trial and a simultaneous, fully allocated, costing model for a tertiary care hospital in Hamilton, Canada were used to determine the difference in costs associated with the care of patients with and without VLDW. RESULTS: The cost of providing VLDW was $ 21,854 (Canadian dollars) per 100 patients. This therapy led to a reduction in costs of $ 24,297 per 100 patients, thus saving the health care system $ 2,443 per 100 patients. In the sensitivity analysis, VLDW prophylaxis still did not increase health care costs unless the cost of VLDW was greatly increased, the cost of treating thromboembolic episodes was markedly reduced, or the incidence of either VTE or bleeding with VLDW was increased above the rates observed in the trial. CONCLUSION: We conclude that for women receiving chemotherapy for metastatic breast cancer, the benefits of VLDW can be realized without increased health care costs.

Breast Neoplasms↗