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Biomedical subjects

D Morgan

Publications and source records attributed to D Morgan.

At least 109 records · Page 6Linked to original sources
PubMed1999

Arthrotec: the evidence speaks for itself.

This article examines the most recently published scientific literature on arthritis therapy options and available mucosal-protective agents. Emphasis is placed on the risks of current nonsteroidal anti-inflammatory drug (NSAID) therapy, the options for reducing such risks, and the published information that either supports or refutes current thinking in these areas. A comprehensive evaluation is made of clinical data related to the use of Arthrotec (diclofenac/misoprostol) in the treatment of arthritis. A recent meta-analysis of the prophylaxis of NSAID-associated upper gastrointestinal complications is reviewed. The results of this meta-analysis should help to consolidate much of the current scientific literature on the safe and effective treatment of arthritis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Identification of mouse CPX-1, a novel member of the metallocarboxypeptidase gene family with highest similarity to CPX-2.

The recent finding that Cpe(fat)/Cpe(fat) mice, which lack carboxypeptidase E (CPE) activity because of a point mutation, are still capable of a reduced amount of neuroendocrine peptide processing suggested that additional carboxypeptidases (CPs) participate in this processing reaction. Searches for novel members of the CPE gene family led to the discovery of CPD, CPZ, AEBP1, and CPX-2. In the present report, we describe mouse CPX-1, another novel member of this gene family. Like AEBP1 and CPX-2, CPX-1 contains an N-terminal region of 160 amino acids with sequence similarity to the discoidin domain of a variety of proteins. The 410-residue CP-like domain of CPX-1 has 54% to 62% amino acid sequence identity with AEBP1 and CPX-2 and 33% to 49% amino acid identity with other members of the CPE subfamily. However, several active-site residues that are important for catalytic activity of other CPs are not conserved in CPX-1. Furthermore, CPX-1 expressed in either the baculovirus system or the mouse AtT-20 cell line does not cleave standard CP substrates. Northern blot analysis showed the highest levels of CPX-1 mRNA in testis and spleen and lower levels in salivary gland, brain, heart, lung, and kidney. In situ hybridization of CPX-1 mRNA in embryonic and fetal mouse tissue showed expression throughout the head and thorax, with abundance in primordial cartilage and skeletal structures. In the head, high levels of CPX-1 mRNA were associated with the nasal mesenchyme, primordial cartilage structures in the ear, and the meninges. In the thorax, CPX-1 mRNA was expressed in multiple developing skeletal structures, including chondrocytes and perichondrial cells of the rib, vertebral, and long-bone primordia. Taken together, these findings suggest that it is unlikely that CPX-1 functions in the processing of neuroendocrine peptides. Instead, CPX-1 may have a role in development, possibly mediating cell interactions via its discoidin domain.

Amino Acid Sequence↗
PubMed1999

An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity.

UNLABELLED: We examined the effects of several opioids that vary in intrinsic efficacy at the mu-opioid receptor alone and in combination with morphine in a rat warm water tail withdrawal procedure using 50 degrees C and 52 degrees C water (i.e., low- and high-stimulus intensities). Morphine, levorphanol, dezocine, and buprenorphine produced dose-dependent increases in antinociception using both stimulus intensities. Butorphanol produced maximal levels of antinociception at the low, but not at the high, stimulus intensity, whereas nalbuphine failed to produce antinociception at either stimulus intensity. For cases in which butorphanol and nalbuphine failed to produce antinociception alone, these opioids dose-dependently antagonized the effects of morphine. When levorphanol, dezocine, and buprenorphine were combined with morphine, there was a dose-dependent enhancement of morphine's effects. Similar effects were obtained at the low-stimulus intensity when butorphanol was administered with morphine. In most cases, the effects of these combinations could be predicted by summating the effects of the drugs when administered alone. These results indicate that the level of antinociception produced by an opioid is dependent on the intrinsic efficacy of the drug and the stimulus intensity. Furthermore, the level of antinociception produced by the opioid, not necessarily the opioids' intrinsic efficacy, determines the type of interaction among opioids. IMPLICATIONS: Compared with high-efficacy opioids, lower efficacy opioids produce lower levels of pain relief, especially in situations of moderate to severe pain. When opioids are given in combination, the effects can only be predicted on the basis of the antinociception obtained when the drugs are administered alone.

Analgesics, Opioid↗
PubMed1999

Sensitivity to the discriminative stimulus and antinociceptive effects of mu opioids: role of strain of rat, stimulus intensity, and intrinsic efficacy at the mu opioid receptor.

Effects of low (butorphanol, nalbuphine)-, intermediate (buprenorphine)-, and high (morphine, levorphanol)-efficacy mu opioids were examined in F344, Sprague-Dawley (SD), Long-Evans (LE), and Lewis rats using a tail withdrawal and a drug discrimination procedure. In the tail withdrawal procedure using low (50 degrees C), intermediate (52 degrees C), and high (56 degrees C) water temperatures, morphine and levorphanol produced maximal effects in each of the strains and were most potent in F344 and least potent in Lewis. Similar differences across strains were obtained with buprenorphine, and at the high intensity, maximal effects were not obtained in Lewis. At the low intensity, butorphanol produced maximal effects in F344 and SD at relatively low doses, half-maximal effects in LE at very high doses, and no effect in Lewis. Nalbuphine produced near maximal effects in F344 and SD when tested with the low intensity and no effect in the LE and Lewis. Similar results were obtained at the intermediate intensity for these opioids, although the absolute level of antinociception was lower. These results indicate that there are profound differences to the antinociceptive effects of mu opioids across rat strains. The magnitude of these differences increased with higher stimulus intensities and when tested with lower efficacy opioids. In rats trained to discriminate morphine (3.0 or 5.6 mg/kg) from water, there were no consistent differences across rat strains to the effects of these mu opioids. Possible reasons for differences between the results obtained in the tail withdrawal and drug discrimination procedures are discussed.

Analgesics, Opioid↗
PubMed1999

The admission of Alzheimer's patients to hospital inpatient psychiatric units.

Alzheimer's Disease presents extreme challenges not only to the individuals afflicted with it and their families, but also to both our legal and healthcare systems. The nature of the disease is such that current legal standards and requirements simply fail to function in an appropriate manner. So too, the health system currently is not in a position to handle the anticipated influx of Alzheimer's patients over the next several decades. This Article examines some of the challenges presented by this disease, and suggests several possible methods to improve our response to it.

Aged↗
PubMed1998

Impaired spatial navigation learning in transgenic mice over-expressing heme oxygenase-1.

Transgenic mice expressing heme oxygenase-1 (HO-1) using the neuron-specific enolase promoter were impaired in learning the Morris water maze compared to nontransgenic littermates. The memory of the HO-1 mice for the location of the platform was similarly impaired when tested using a probe trial after 7 training blocks, but performance on visible platform trials was similar for both groups of mice. Importantly, both HO-1 and nontransgenic mice had normal sensorimotor function, and performed the same on a Y-maze alternation task, highlighting the specificity of memory deficit in the spatial navigation task. These results suggest that carbon monoxide, one product of HO-1 activity, interferes in the development of spatial navigation memory, and may play a role in normal memory function.

Animals↗
PubMed1998

Translocation (1;22) in refractory anemia and the prognostic significance of karyotypic abnormalities in refractory anemia.

The most common cytogenetic abnormalities associated with myelodysplastic syndromes are deletions of chromosomes 5 and 7 and trisomy 8. Reciprocal translocation is relatively uncommon in refractory anemia. We describe a case of refractory anemia associated with trisomy 8 and a derivative chromosome 22 resulting from t(1;22)(q11;q11.2). The diseases and the role of the various genes that are mapped to these breakpoints are discussed. The prognostic significance of karyotypic abnormalities in refractory anemia are reviewed.

Aged↗
PubMed1998

Cellular immune response to adenoviral vector infected cells does not require de novo viral gene expression: implications for gene therapy.

Replication-defective adenoviral (RDAd) vectors can be generated at high titers and infect both dividing and nondividing cells. Long term expression in the transduced tissue, however, has been a problem because of the cellular immune responses against the infected cells. We demonstrate that mice injected with RDAd vectors containing mouse leptin gene reduce food intake and lose weight for only 7 to 10 days. Splenocytes obtained from infected mice are able to lyse target cells infected with RDAd vectors. Surprisingly, target cells infected with psoralen-treated, UV-crosslinked, biologically inactive RDAd also were lysed efficiently by the effector cells. Furthermore, splenocytes obtained from mice injected with inactive RDAd vectors efficiently lysed target cells infected with RDAd vectors. Whether RDAd vectors were injected i.m. or i.v. or through an i.p. route, the extent of lysis was similar. We propose that cells infected with RDAd vectors present antigens for recognition by class 1 major histocompatibility complex-restricted cytotoxic T lymphocytes by a mechanism that does not require viral replication or de novo protein synthesis. These results should prompt reevaluation of the use of RDAd vectors for gene therapy when long-term expression is required.

Adenoviridae↗
PubMed1998

Loop III region of platelet-derived growth factor (PDGF) B-chain mediates binding to PDGF receptors and heparin.

Site-directed mutagenesis of the platelet-derived growth factor (PDGF) B-chain was conducted to determine the importance of cationic amino acid residues (Arg160-Lys161-Lys162; RKK) located within the loop III region in mediating the biological and cell-association properties of the molecule. Binding to both PDGF alpha-and beta-receptors was inhibited by the conversion of all three cationic residues into anionic glutamates (RKK-->EEE), whereas an RKK-->SSS mutant also exhibited a modest loss in affinity for beta-receptors. Replacements with serine at either Arg160 (RKK-->SKK) or at all three positions (RKK-->SSS) had little effect on binding to alpha-receptors. Replacements with either glutamic or serine residues at any of the three positions also resulted in significant inhibition of heparin-binding activity. Furthermore, the RKK-->EEE mutant exhibited decreased association with the cell surface and accumulated in the culture medium as 29-32 kDa forms. Stable transfection of U87 astrocytoma cells with RKK-->EEE mutants of either the A-chain or the B-chain inhibited malignant growth in athymic nude mice. Despite altered receptor-binding activities, each of the loop III mutants retained full mitogenic activity when applied to cultured Swiss 3T3 cells. CD spectrophotometric analysis of the RKK-->EEE mutant revealed a secondary structure indistinguishable from the wild type, with a high degree of beta-sheet structure and random coil content (50% and 43% respectively). These findings indicate an important role of the Arg160-Lys161-Lys162 sequence in mediating the biological and cell-associative activities of the PDGF-BB homodimer, and reveal that the mitogenic activity of PDGF-BB is insufficient to mediate its full oncogenic properties.

Animals↗
PubMed1998

Attenuation of ischemia-induced activation of cardiac sympathetic afferents following brief myocardial ischemia in cats.

OBJECTIVE: We have previously shown that brief myocardial ischemia impairs neural conduction in cardiac sympathetic efferent fibers. However, attenuation of the activity of afferent sympathetic nerves, which may contribute to impaired ischemic nociception and reflex hemodynamic responses, is not well understood. Therefore, we studied the electrophysiological effects of brief myocardial ischemia on the mechano-, chemo- and ischemia-sensitive properties of cardiac sympathetic afferent fibers. METHODS: Single unit activity of sympathetic afferent A delta and C fibers innervating the left ventricle (LV) was recorded from the thoracic chain or rami communicantes in 16 anesthetized cats. We tested the response of impulse activity to (1) mechanical LV probing, (2) epicardial application of bradykinin (10 microg), H2O2 (1.5%) or adenosine (500 microg), and (3) 1 min of coronary occlusion. Repeat tests were performed in 11 of 16 fibers after 15 min of coronary occlusion and 15 min of reperfusion. Control responses were measured in five fibers before and after a 30-min interval without ischemia. RESULTS: Afferent fibers responded with increased activity to LV probing (16/16 fibers), bradykinin (13/16 fibers), H2O2 (7/11 fibers), adenosine (1/11 fibers), and to a 60 s period of coronary occlusion (11/16 fibers). The unit impulse activity to 1 min of coronary occlusion was markedly attenuated after 15 min of myocardial ischemia and 15 min of reperfusion (P < 0.05). This attenuation was associated with reduced sensitivity to mechanical and chemical stimuli, while in separate time-control studies (n = 5) no attenuation was observed in absence of ischemia. CONCLUSION: A brief period of myocardial ischemia is capable of attenuating mechano-, chemo- and ischemia-sensitive activity of cardiac afferent sympathetic nerves. This may have important implications for the mechanism of silent myocardial ischemia.

Adenosine↗
PubMed1998

Regulation of interleukin-13 receptor constituents on mature human B lymphocytes.

Human B cells stimulated through both their immunoglobulin and CD40 receptors up-regulate 745 +/- 51 interleukin (IL)-13 ligand binding sites with an affinity of 0.91 +/- 0.08 nM within 24 h. IL-13 binds primarily to the IL-13Ralpha1 with subsequent sequestration of the IL-4Ralpha into the complex. IL-13Ralpha1 may also be found in those receptors capable of binding IL-4. gamma chain (gammac) participates in receptors capable of binding IL-4 but is not found in association with bound IL-13. Dimeric receptors composed of the IL-4Ralpha complexed with either the IL-13Ralpha1 or gammac occur simultaneously within defined B cell populations. mRNAs for all receptor constituents are increased subsequent to immunoglobulin stimulation alone, while maximal expression of IL-13Ralpha1 is more dependent upon co-stimulation of immunoglobulin and CD40 receptors. mRNA levels for IL-13Ralpha1 vary over a wider range subsequent to surface stimulation than other receptor components. Although gammac is not bound to IL-13 in B cells under the conditions evaluated, it may influence IL-13 binding by competing with IL-13Ralpha1 for association/sequestration with the IL-4Ralpha chain. IL-13Ralpha2 does not participate in the IL-13 receptor that is up-regulated upon activation of quiescent tonsillar B lymphocytes, although mRNA for the protein may be found in the centroblastic fraction of tonsillar cells.

B-Lymphocytes↗
PubMed1998

Early manifestations (pre-AIDS) of HIV-1 infection in Uganda.

OBJECTIVES: To describe the early manifestations of HIV-1 infection before the development of AIDS, in a rural Ugandan population. METHODS: Three monthly follow-up of HIV-1-infected and uninfected participants in an HIV-1 natural history cohort from the start of the cohort in 1990 to the end of 1996. RESULTS: A total of 107 persons with prevalent infection and 104 persons with incident infection were enrolled. Eighty (75%) prevalent and 89 (86%) incident individuals were asymptomatic on enrollment. Of the 91 persons with incident infection seen within 2 years of their estimated date of seroconversion, 51% [95% confidence interval (CI), 40-61] were still asymptomatic 2 years after seroconversion. At 4 and 5 years after seroconversion, only 26% (95% CI, 17-36) and 11% (95% CI, 4-22), respectively, remained asymptomatic. A total of 89 participants entered World Health Organization (WHO) stage 2, and their main stage-defining conditions were weight loss <10% (and > 5%) and minor mucocutaneous manifestations. The median CD4 lymphocyte count for participants entering WHO stage 2 was 516 x 10(6) cells/l (interquartile range, 360-884 x 10(6)/l). A total of 94 participants entered WHO stage 3 and the main reasons were weight loss >10%, unexplained chronic diarrhoea, fever for more than 1 month, and severe bacterial infection. The median CD4 lymphocyte count for participants entering WHO stage 3 was 428 x 10(6) cells/l (interquartile range, 276-736 x 10(6)/l). The rates of all conditions reported under the WHO staging system were significantly more frequent in HIV-positive persons than HIV-negative controls with the exception of fever for more than 1 month and oral hairy leukoplakia (which was seen in only three individuals). CONCLUSION: These are the first data from a non-selected African population describing the early manifestations of HIV infection. The main early manifestations were weight loss, minor mucocutaneous features, chronic diarrhoea, chronic fever and severe bacterial infections. The apparent rapid development of HIV-related signs and symptoms is probably indicative of the high background level of these conditions in our study area, as reflected by the rates of these conditions in the HIV-negative controls.

Adult↗
PubMed1998

The mu opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the mu opioid receptor.

The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.

Animals↗
PubMed1998

Plasma leptin in diabetic and insulin-treated diabetic and normal rats.

Adipose tissue leptin mRNA levels are decreased by food deprivation or induction of insulin-deficient diabetes. To determine whether plasma leptin concentrations are similarly affected, whether treatment of diabetes with insulin restores plasma leptin, and whether this requires restoration of body weight (lost as a result of diabetes) and/or normalization of glycemia, we measured plasma leptin concentrations in control, untreated streptozotocin (STZ)-diabetic, and insulin-treated STZ-diabetic rats. Plasma leptin was markedly reduced in untreated STZ-diabetic rats. Insulin treatment for 4 to 17 days increased plasma leptin approximately twofold above control levels. However, despite the hyperleptinemia, insulin-treated diabetic rats gained weight at a rate equal to that of sham-treated controls. Epididymal adipose tissue leptin mRNA levels in 17-day insulin-treated diabetic rats were equal to but did not exceed sham-control levels, unlike plasma leptin. Plasma glucose concentrations in insulin-treated STZ-diabetic rats were lower than in sham controls. Therefore, to determine whether hypoglycemia may be important in increasing plasma leptin, we measured plasma leptin levels in diabetic rats infused with insulin for 3 hours along with a variable-rate glucose infusion targeting glycemia to 200 or 40 mg/100 mL. Plasma leptin rapidly increased in these rats irrespective of target glycemia. Plasma leptin also increased rapidly in normal rats infused with insulin and glucose (target glycemia, 200 mg/100 mL). We conclude that plasma leptin concentrations are markedly reduced under conditions of insulin deficiency and rapidly increased by insulin treatment. The increase in plasma leptin does not require restoration of body weight and, under glucose clamp conditions, does not depend on target glycemia. Hyperleptinemia in insulin-treated diabetic rats is not explained on the basis of steady-state leptin mRNA levels, at least as reflected in epididymal fat.

Adipose Tissue↗
PubMed1998

Setting up wound dressing guidelines: avoiding the pitfalls.

Wound dressings guidelines promote rational prescribing. The development of such guidelines is described, including how to get started, the collection of data, format, contents and avoiding the pitfalls. After implementation, the guidelines require on-going monitoring, review, updating and audit.

Bandages↗
PubMed1998

Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse.

Visceral left-right asymmetry occurs in all vertebrates, but the inversion of embryo turning (inv) mouse, which resulted following a random transgene insertion, is the only model in which these asymmetries are consistently reversed. We report positional cloning of the gene underlying this recessive phenotype. Although transgene insertion was accompanied by neighbouring deletion and duplication events, our YAC phenotype rescue studies indicate that the mutant phenotype results from the deletion. After extensively characterizing the 47-kb deleted region and flanking sequences from the wild-type mouse genome, we found evidence for only one gene sequence in the deleted region. We determined the full-length 5.5-kb cDNA sequence and identified 16 exons, of which exons 3-11 were eliminated by the deletion, causing a frameshift. The novel gene specifies a 1062-aa product with tandem ankyrin-like repeat sequences. Characterization of complementing and non-complementing YAC transgenic families revealed that correction of the inv mutant phenotype was concordant with integration and intact expression of this novel gene, which we have named inversin (Invs).

Amino Acid Sequence↗
PubMed1998

Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes.

Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.

Alzheimer Disease↗