Biomedical subjects

D Zhou

Publications and source records attributed to D Zhou.

At least 181 records · Page 10Linked to original sources

PubMed1998

In vitro and in vivo effect of levopraziquantel, dextropraziquantel versus racemic praziquantel on different developmental stages of Schistosoma japonicum.

AIM: To compare the antischistosomal effect of racemic praziquantel (Pra) and its enantiomers, levopraziquantel (L-Pra) and dextropraziquantel (D-Pra), on different developmental stages of Schistosoma japonicum. METHODS: The in vitro effects of the drugs were determined in different stages of schistosomes maintained in RPMI 1640 supplemented with 20% calf serum. In vivo study mice infected with schistosome cercariae were treated intragastrically (ig) with Pra, L-Pra or D-Pra at different intervals after infection. The efficacy of the drugs was evaluated by residual mean worm number. RESULTS: Based on the degree of tegument damage induced by L-Pra, d28 and d35 schistosomes were most susceptible to L-Pra, while d14 schistosomules being least susceptible. At comparable concentrations of 0.1-1 g/ml, L-Pra was more active than Pra even when the concentration of L-Pra was reduced to one-half of the minimum effective concentration of Pra. At above-mentioned concentrations D-Pra exhibited no apparent in vitro effect on different stages of schistosomes. When infected mice were treated ig with L-Pra, Pra or D-Pra at a single dose of 300 mg/kg or 500 mg/kg, only the former two drugs showed apparent effect on d0, d21, d28 and d35 schistosomes and less or much less effect on d3, d7 and d14 schistosomules. D-Pra only exhibited a negligible effect on d35 adult schistosomes as compared with L-Pra and Pra. When mice infected with d35 adult schistosmes were treated ig with L-Pra 150 mg/kg, the efficacy was similar to that of mice treated with Pra 300 mg/kg. CONCLUSION: L-Pra is the principal active component against schistosomes in racemic Pra.

Animals↗

PubMed1998

[A new genus of oral bacteria in human].

A strain, No. 90-1, is isolated from the oral cavity of a patient with periodontophthy. This strain is a Gram-positive, non-endospore-forming, facultative anaerobe with spherical cells, 0.9-1.5 microns in diameter, occuring in pairs and seldom in short chains of four cells, and motile by one flagellum per cell. The optimum growing temperature is 35-37 degrees C; appreciable growth is not found below 10 degrees C, but growth at 53 degrees and tolerance to 60 degrees C for 30 min. This strain is microhalophilous and grows best, well and poorly in the medium containing 2%, 10%-15% and 25% NaCl respectively. Catalase and urease are positive and nitrate is reduced. Acid is produced from many carbohydrates, but no gas. Gelatin can be hydrolyzed, but starch, cellulose and dextrin do not. G + C content in DNA is 41.34 mol%(Tm). The strain(90-1) is considered to be a new species belonging to a new genus because its some characteristics are different from those of the known coccus genuera and designated as Stomatostreptococcus microhalophilus Ping, Zhou, Sun et Fan gen. nov. sp. nov. according to its source and microhalophilic trait.

Humans↗

PubMed1997

Targeted deletion of the lipopolysaccharide (LPS)-binding protein gene leads to profound suppression of LPS responses ex vivo, whereas in vivo responses remain intact.

Gram-negative bacterial lipopolysaccharide (LPS) stimulates phagocytic leukocytes by interacting with the cell surface protein CD14. Cellular responses to LPS are markedly potentiated by the LPS-binding protein (LBP), a lipid-transfer protein that binds LPS aggregates and transfers LPS monomers to CD14. LBP also transfers LPS to lipoproteins, thereby promoting the neutralization of LPS. LBP present in normal plasma has been shown to enhance the LPS responsiveness of cells in vitro. The role of LBP in promoting LPS responsiveness in vivo was tested in LBP-deficient mice produced by gene targeting in embryonic stem cells. Whole blood from LBP-deficient animals was 1,000-fold less responsive to LPS as assessed by the release of tumor necrosis factor (TNF)-alpha. Blood from gene-targeted mice was devoid of immunoreactive LBP, essentially incapable of transferring LPS to CD14 in vitro, and failed to support cellular responses to LPS. These activities were restored by the addition of exogenous recombinant murine LBP to the plasma. Despite these striking in vitro findings, no significant differences in TNF-alpha levels were observed in plasma from wild-type and LBP-deficient mice injected with LPS. These data suggest the presence of an LBP-independent mechanism for responding to LPS. These LBP knockout mice may provide a tool for discovering the nature of the presumed second mechanism for transferring LPS to responsive cells.

Acute-Phase Proteins↗

PubMed1997

Cryopreservation of microencapsulated porcine pancreatic islets: in vitro and in vivo studies.

BACKGROUND: If the transplantation of immunoisolated porcine islets into human diabetics is to become reality, the development of a long-term storage method represents an important prerequisite. However, information on cryogenic storage of porcine islets is scanty and fragmentary. METHODS: Porcine pancreatic islets microencapsulated in alginate-polylysine-alginate membranes were cryopreserved and assessed both in vitro by static glucose challenge and in vivo in a transplantation study. Two separate methods of islet cryopreservation were compared: method A, using the Bio Cool III freezing machine, and method B, which uses the Nalgene isopropyl alcohol insulated cooler. RESULTS: Method A was found to have better preserved the ability of the microencapsulated cryopreserved islets to respond to high-glucose static challenge (7 out of 10 lots) compared with method B (1 out of 10 lots). Upon exposure to high glucose, the islet batches that did retain the ability to respond to glucose were shown to have secreted an average of 1220+/-73 pM/24 hr/islet of insulin as compared with 1528+/-118 pM/24 hr/islet for fresh islets. The presence of isobutyl methylxanthine further potentiated insulin secretion to 1805+/-81 pM/24 hr/islet and to 2410+/-104 pM/24 hr/islet for cryopreserved and free islets, respectively. Intraperitoneal transplantation of 2000 cryopreserved microencapsulated porcine islets into streptozotocin-diabetic mice resulted in the reversal of hyperglycemia in 6 out of 10 recipients for the duration of the 90-day study. CONCLUSIONS: The effective protection of the delicate porcine endocrine tissue during the cryopreservation process and the subsequent long-term storage were demonstrated with considerable success in this study.

Animals↗

PubMed1997

An examination of current control strategies for Asian schistosomiasis in the Dongting lake region of China. II. A five year follow-up survey on Qingshan island.

In 1995-1996 we conducted an epidemiological survey in two communities (1656 individuals) on Qingshan island, Hunan province P.R. China, in order to determine the efficacy of current control strategies since their upgrading in 1991. In 1996, the overall prevalence for Schistosoma japonicum, Ascaris lumbricoides, Ancylostoma duodenale, and Trichuris trichiura had decreased moderately since 1991. The age-specific prevalence for S. japonicum for each of the representative age groups decreased slightly, but there was a significant reduction in these prevalences for the 5-9 (P < 0.01), 55-59 (P < 0.05) and the over 60 (P < 0.01) age groups. The 1996 intensities of infection for schistosomiasis were higher for all the age categories except for those aged 0-4 and 25-29 years of age. When the study population was further classified according to the percent uninfected, lightly infected (8-100 eggs/g (epg)), moderately infected (101-400 epg) and heavily infected (> 400 epg) for S. japonicum, there were fewer (5.6%) people infected in 1996 but the proportions of moderately (21.3 vs. 15.5%) and heavily (7.6 vs. 2.3%) infected individuals were higher than those observed in 1991. The reported cases of weakness and hepatomegaly (MSL > or = 3) were significantly lower (P < 0.01) in 1996 for both uninfected and infected (all intensities) individuals. General episodes of diarrhoea were also significantly lower in 1996 for those lightly (P < 0.05) and heavily (P < 0.01) infected. Likewise, the occurrence of splenomegaly (Hackett's > or = 2) was significantly lower among uninfected (P < 0.01) and heavily infected (P < 0.05) patients. In summary, although significant progress has been made in controlling schistosomiasis and other helminth infections in this highly endemic focus for schistosomiasis, there is still room for improvement. Chemotherapy for bovines and humans, mollusciding for Oncomelania control and health education should be initiated and upgraded if the health and well being of these island communities is to further improve.

Adolescent↗

PubMed1997

Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines.

Dendritic cells (DC) are migratory cells that exhibit complex trafficking properties in vivo. The present study was designed to characterize receptor expression and responsiveness to chemoattractants of human DC obtained from PBMC by culture with granulocyte/macrophage-CSF and IL-13. DC expressed appreciable levels of the CCR1, CCR2, and CCR5 receptors for the CC chemokines and the chemokine receptors CXCR1, CXCR2, and CXCR4. DC increased intracellular free calcium and migrated in response to the CC chemokines MCP-3, MCP-4, RANTES, MIP-1alpha, MIP-1beta, and MIP-5/HCC2 and the CXC chemokine SDF-1. In contrast, the CC chemokines MCP-1 and eotaxin had little or no activity in the concentration range tested (up to 1 microg/ml). IL-8 and Gro-beta (CXC) and lymphotactin (C chemokines) were also inactive. DC did not respond to 5-HETE, whereas platelet-activating factor was an active agonist. Selected chemokines active on DC in terms of migration and calcium fluxes were examined for their capacity to modulate endocytosis and Ag presentation. Under conditions in which TNF-alpha was active, MCP-1, MCP-3, MIP-1alpha, and RANTES did not affect these two responses. Thus, among hemopoietic elements, DC respond to a unique set of CC and CXC chemokines, and their responsiveness is restricted to migration with no effect on Ag capture and presentation. Chemokines may play a role in the trafficking of DC under resting or stimulated conditions. Chemokine receptors expressed in DC are likely to underlie HIV infection of this cell type.

Base Sequence↗

PubMed1997

Long-term food restriction down-regulates the density of serotonin transporters in the rat frontal cortex.

The influence of feeding rats only half the amount of their normal daily intake of a complete rat chow on the affinity and the density of serotonin (5-HT) transporters was measured in membrane preparations of the frontal cortex and the midbrain by a [3H]paroxetine binding assay. In young rats (10 weeks), a significant reduction of about 30% of the Bmax values of [3H]paroxetine binding occurred in the frontal cortex after 1 and 2 weeks of restricted food intake. No starvation-induced decline of the density of 5-HT transporters was seen in the midbrain. When older rats (50 weeks) were subjected to the same 50% reduction of daily food intake for 2 weeks, no such down-regulation of the density of cortical 5-HT transporters was observed. The affinity of the 5-HT transporters, as indicated by the unchanged Kd values of [3H]paroxetine binding, was not affected by semistarvation in both regions and at both ages. The observed decline of [3H]paroxetine binding sites in the frontal cortex of young adult rats is the first demonstration of long-term regulatory phenomena of brain 5-HT transporters triggered by a physiologic stimulus.

Aging↗

PubMed1997

Effects of epidermal growth factor and insulin on the activity of N-acetylglucosaminyltransferase V.

When quiescent rat hepatocellular carcinoma 7919 cells were treated with epidermal growth factor (EGF) or insulin (stimulators of receptor tyrosine kinase activity), the activity of N-acetylglucosaminyltransferase V was increased. The effect of EGF reached a maximum after 10 min and remained high for 30 min, while the effect of insulin reached a maximum after 5 min and decreased after 15 min. Preincubation of the cells with 1-O-octadecyl-2-O-methylglycerophosphocholine (Et18-OH3), which blocked the activation of mitogen-activated protein kinase by EGF, also blocked the activation of N-acetylglucosamyltransferase V by this hormone, whereas the activation of N-acetylglucosamyltransferase V by insulin could not be blocked by Et18-OH3. Our results suggest that N-acetylglucosamyltransferase V may be regulated by different receptor protein tyrosine kinase pathways.

Animals↗

PubMed1997

The carboxyl terminus of mouse delta-opioid receptor is not required for agonist-dependent activation.

The pharmacological effects caused by use of opiate are exerted through the opioid receptors (ORs). ORs couple to the inhibitory G protein (Gi) and result in decreased cAMP levels upon activation by specific agonists. To initiate study of the structure-function relationship during this process, we first ectopically expressed the wild-type delta OR and a C-terminally truncated mutant in CHO cells to investigate the necessity of its C-terminus. The binding potency of both the wild-type and truncated delta ORs to ligands including DPDPE, DSLET, DAGO, and U-50488 was compared. Their membrane localization and ability to mediate signal transduction were also studied. We conclude that the C-terminus of delta OR is not essential for plasma membrane targeting, ligand specificity, and agonist-dependent activation.

Amino Acid Sequence↗

PubMed1997

Hydrocarbon Drainage along Corners of Noncircular Capillaries

An approximate solution for liquid flow along corners of noncircular capillaries is proposed that relates the flow resistance to the geometry of a capillary and to the contact angle of the interfaces. The theory predicts liquid flow rates for both two-phase (hydrocarbon/air) and three-phase (hydrocarbon/air/water) drainage. This solution is found to be superior to other expressions in the literature. Drainage rates of two different hydrocarbons along corners of square capillaries are measured with both air and water as stationary phases. The new solution was used to predict the measured hydrocarbon drainage rates successfully. Comparison of the measured and predicted drainage rates indicates that a free boundary is appropriate for the air/hydrocarbon interface and a no-flow boundary condition is valid for the water/hydrocarbon interface. The effect of spreading coefficient on drainage rates is also demonstrated by the measurements and is compared with the proposed solution. A brief discussion of three-phase relative permeabilities is offered based on the measured drainage rates and proposed solution.

Journal Article↗

PubMed1997

Small, membrane-bound, alternatively spliced forms of ankyrin 1 associated with the sarcoplasmic reticulum of mammalian skeletal muscle.

We have recently found that the erythroid ankyrin gene, Ank1, expresses isoforms in mouse skeletal muscle, several of which share COOH-terminal sequence with previously known Ank1 isoforms but have a novel, highly hydrophobic 72-amino acid segment at their NH2 termini. Here, through the use of domain-specific peptide antibodies, we report the presence of the small ankyrins in rat and rabbit skeletal muscle and demonstrate their selective association with the sarcoplasmic reticulum. In frozen sections of rat skeletal muscle, antibodies to the spectrin-binding domain (anti-p65) react only with a 210-kD Ank1 and label the sarcolemma and nuclei, while antibodies to the COOH terminus of the small ankyrin (anti-p6) react with peptides of 20 to 26 kD on immunoblots and decorate the myoplasm in a reticular pattern. Mice homozygous for the normoblastosis mutation (gene symbol nb) are deficient in the 210-kD ankyrin but contain normal levels of the small ankyrins in the myoplasm. In nb/nb skeletal muscle, anti-p65 label is absent from the sarcolemma, whereas anti-p6 label shows the same distribution as in control skeletal muscle. In normal skeletal muscle of the rat, anti-p6 decorates Z lines, as defined by antidesmin distribution, and is also present at M lines where it surrounds the thick myosin filaments. Immunoblots of the proteins isolated with rabbit sarcoplasmic reticulum indicate that the small ankyrins are highly enriched in this fraction. When expressed in transfected HEK 293 cells, the small ankyrins are distributed in a reticular pattern resembling the ER if the NH2-terminal hydrophobic domain is present, but they are uniformly distributed in the cytosol if this domain is absent. These results suggest that the small ankyrins are integral membrane proteins of the sarcoplasmic reticulum. We propose that, unlike the 210-kD form of Ank1, previously localized to the sarcolemma and believed to be a part of the supporting cytoskeleton, the small Ank1 isoforms may stabilize the sarcoplasmic reticulum by linking it to the contractile apparatus.

Alternative Splicing↗

PubMed1997

Molecular basis of the catalytic differences among DT-diaphorase of human, rat, and mouse.

DT-diaphorase (EC 1.6.99.2), also referred to as NAD(P)H:(quinone-acceptor) oxidoreductase, is involved in the reductive activation process of several cytotoxic antitumor quinones and nitrobenzenes. It has been observed in our and other laboratories that the rat enzyme is significantly more effective in activating these drugs than the human and mouse enzymes. These results indicate that the available cytotoxic drugs are better substrates for the rat enzyme and are not the most ideal prodrugs for activation by DT-diaphorase in human tumors. In this study, using site-directed mutagenesis to replace residues in the rat enzyme with the human sequences and residues in the human enzyme with the rat sequences, we have found that residue 104 (Tyr in the rat enzyme and Gln in the human and mouse enzymes) is an important residue responsible for the catalytic differences between the rat and the human (and mouse) enzymes. With an exchange of a single amino acid, the rat mutant Y104Q behaved like the wild-type human enzyme, and the human mutant Q104Y behaved like the wild-type rat enzyme in their ability to reductively activate the cytotoxic drug CB 1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide). The study also confirms the conclusion of the x-ray structural analysis of rat enzyme that residue 130 (Thr in the rat enzyme and Ala in the human and mouse enzymes) is positioned near the binding region of the nicotinamide portion of NAD(P)H. This structural information is very important for designing suitable drugs and approaches for human cancer chemotherapy mediated by DT-diaphorase.

Amino Acid Sequence↗

PubMed1997

Long-term modulation of presynaptic 5-HT-output: experimentally induced changes in cortical 5-HT-transporter density, tryptophan hydroxylase content and 5-HT innervation density.

Whereas experimentally induced long-term changes of postsynaptic mechanisms of 5-HT neurotransmission have been studied in great detail, much less is currently known about the effects of certain treatments on the presynaptic components governing the output of 5-HT in individual brain regions. This contribution summarizes the results of a series of experiments on the influence of different physiologic and pharmacologic manipulations on three different parameters of 5-HT presynapses, 5-HT transporter density, tryptophan hydroxylase content, and serotonin level in the rat frontal cortex. The combined measurement of several parameters of 5-HT presynapses allows to differentiate between treatments which exclusively affect the density of 5-HT transporters (long-term food restriction), which exclusively affect the level of tryptophan hydroxylase apoenzyme (imipramine treatment of olfactory bulbectomized rats) or which cause a parallel increase (bulbectomy, chronic administration of tranylcypramine to rats with chemical lesions of their cortical 5-HT innervation) or a parallel decrease (administration of p-chloroamphetamine) of both parameters, indicating treatment-induced changes in the density of 5-HT presynapses in the frontal cortex. Each of these changes may lead to an altered output of serotonergic afferences, and may therefore act to either potentiate or to attenuate the impact of serotonin-mediated effects on the activity of local networks located in a certain brain region.

Animals↗

PubMed1997

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") and its congeners.

The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromise the ability of 5-HT terminals to maintain their functional and structural integrity. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromised all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca(++)-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto "buffered" personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.

Amphetamine-Related Disorders↗

PubMed1997

Butyrate inhibits deoxycholate-induced increase in colonic mucosal DNA and protein synthesis in vivo.

PURPOSE: Crypt surface hyperproliferation is an intermediate biomarker of colon cancer risk. In vitro studies indicate that the short-chain fatty acid and antineoplastic agent butyrate may reverse the crypt surface hyperproliferation induced by the secondary bile acid and tumor promoter, deoxycholate. We hypothesized that butyrate may reverse deoxycholate-induced crypt surface proliferation in vivo. METHODS: Thirty-one Sprague-Dawley rats (250-300 g) underwent surgical isolation of the colon and 24-hour luminal instillation of either sodium chloride, butyrate, deoxycholate, or butyrate plus deoxycholate (all solutions, 2 ml; pH 7; total sodium = 20 mM). Study variables included colon weight, mucosal DNA, mucosal protein, and proliferating cell nuclear antigen immunohistochemistry, labeling of which was determined in five crypt compartments from base to surface (12 crypts per rat). Labeling indexes were calculated as proliferating cell nuclear antigen immunohistochemistry-labeled cells divided by total counted cells in the whole colonic crypt and each of five crypt compartments. The phi(h) value (an index of premalignant risk) was calculated as the ratio of labeled cells in the two surface compartments divided by the total labeled cells. RESULTS: Deoxycholate significantly increased colon wet weight, mucosal protein, total crypt labeling indexes, crypt surface labeling indexes, and the phi(h) value and raised the mucosal DNA content. Butyrate alone slightly reduced total mucosal DNA and protein content. The combination of butyrate plus deoxycholate significantly decreased mucosal DNA and tended to reduce mucosal protein compared with deoxycholate alone. In contrast to prior in vitro findings, butyrate plus deoxycholate did not reverse the deoxycholate-induced surface hyperproliferative changes as measured by proliferating cell nuclear antigen labeling. CONCLUSIONS: Because co-treatment with butyrate plus deoxycholate inhibits deoxycholate-induced increases in total mucosal DNA and protein content, we conclude that butyrate may play a role in maintaining the proliferative balance of the colonic mucosa, in vivo. However, co-treatment with butyrate plus deoxycholate does not reverse the deoxycholate-induced increases in colon weight and proliferating cell nuclear antigen labeling indexes under the studied experimental conditions.

Animals↗

PubMed1997

No evidence for a physiological coupling between melatonin and glucocorticoids.

Much has been speculated about the existence of a physiological coupling between melatonin and glucocorticoid secretion and about a possible anti-stress action of melatonin. We examined the relationship between melatonin and glucocorticoid secretion under close-to-physiological conditions, when the plasma concentration of either melatonin or glucocorticoids was elevated acutely or chronically in both rats and humans. Tryptophan administration caused a massive rise of plasma melatonin, but had no effect on corticosterone levels in rats or on cortisol levels in humans. The acute and long-lasting exposure of rats to uncontrollable stress resulted in a significant rise of adrenal corticosterone secretion, but had no effect on circulating melatonin levels. Orchectomy caused an initial increase in circulating corticosterone (when melatonin was unaffected) and a delayed rise in circulating melatonin (when corticosterone levels were normalized). In humans, no correlation was found between the nocturnal urinary excretion of melatonin and cortisol, either among healthy subjects, or among patients suffering from panic disorder (with an increased urinary excretion of cortisol) or among insomnia patients (with a high incidence of low melatonin secretion). Furthermore, no evidence was found for a suppressive action of melatonin on dexamethasone-mediated thymus regression in rats and on dexamethasone-mediated suppression of lymphocyte proliferation in vitro. Taken together, the results of this study provide no evidence for the existence of mutual influences between melatonin and glucocorticoid secretion, nor do they support the proposed attenuation of glucocorticoid-mediated effects on target cells or tissues by melatonin under physiological conditions.

Adult↗

PubMed1997

Multidrug resistance gene expression in acute myeloid leukemia: major prognosis significance for in vivo drug resistance to induction treatment.

The clinical significance of the multidrug resistance (MDR 1) gene phenotype was investigated in newly diagnosed AML and was compared with other clinical and biological prognostic factors in patients who received at least one course of induction therapy with intercalating agents and conventional doses of Ara-C. MDR 1 gene was overexpressed in 40% of the 110 cases of AML at presentation, MRP in 15% of the 48 patients tested for both markers. Both gene expressions were closely linked (p = 0.008). Except for a lower frequency in the "good risk" cytogenetic group, MDR 1 overexpression was not associated with other prognostic factors. In univariate analysis, MDR 1 overexpression, age over 50 years, and cytogenetic were associated with a higher rate of resistance to induction treatment. The overall survival was shorter in the case of intermediate or poor cytogenetics, high leukocytosis, MDR 1 overexpression, age over 50 years, secondary AML, and poor cytologic differentiation. Using multivariate analysis on 64 patients receiving intensive treatment, MDR 1 overexpression was the first significant prognostic factor for resistance to the first course of induction treatment. Cytogenetic analysis maintained its prognostic value only in MDR 1-negative patients. These data underline the value of MDR 1 gene expression as a powerful prognostic factor in AML for response to the first induction treatment and overall survival, sustaining the use of MDR 1 modulators for first-line therapy in this disease.

ATP-Binding Cassette Transporters↗

PubMed1997

Lesions of regions for in vitro ventilatory genesis eliminate gasping but not eupnea.

Medullary regions, termed 'pre-inspiratory' and 'pre-Bötzinger', are considered critical for the neurogenesis of rhythmic ventilatory activity of in vitro preparations of the neonatal rat. We examined the influence of destruction of neurons in these regions, by microinjections of kainic acid, upon eupnea and gasping in vivo. Decerebrate, vagotomized, paralyzed and ventilated rats of age 8-15 days were used; the phrenic nerve activity was recorded. Eupnea was not consistently altered following destruction of neurons in any region. However, in the majority of animals, anoxia-induced gasping was not observed following injections of kainic acid into the 'pre-inspiratory' region, 'pre-Bötzinger' complex or lateral tegmental field; the latter region is important for the neurogenesis of gasping in adults. Injections into other regions did not prevent the elicitation of gasping. These results do not support the possibility that neuronal activities which are responsible for respiratory rhythm generation in vitro underlie the neurogenesis of eupnea in vivo.

Animals↗