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Biomedical subjects

C Lynch

Publications and source records attributed to C Lynch.

At least 37 records · Page 2Linked to original sources
PubMed2000

Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels.

BACKGROUND: Volatile anesthetics produce differing degrees of myocardial protection in animal models of ischemia. The purpose of the current investigation was to determine the influence of isoflurane and halothane on myocardial protection in a human model of simulated ischemia and the role of adenosine A1 receptors and adenosine triphosphate-sensitive potassium (KATP) channels in the anesthetic pathway. METHODS: Human atrial trabecular muscles were superfused with oxygenated Krebs-Henseleit buffer and stimulated at 1 Hz, with recording of maximum contractile force. Fifteen minutes before a 30-min anoxic insult, muscles were pretreated for 5 min with either anoxia, the A1 agonist N6-cyclohexyladenosine, 1% halothane or 1.2% isoflurane. These treatments were also performed in the presence of either the KATP channel antagonist glibenclamide or the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Anesthetic effects were also determined on KATP currents in isolated whole cell voltage-clamped human atrial myocytes. RESULTS: Recovery of force (recorded 60 min after anoxia) in isoflurane-pretreated muscles was reduced from 76.6 +/- 7.5% of baseline to 43.7 +/- 7.1% by pretreatment with glibenclamide, and to 52.5 +/- 6.2% by pretreatment with DPCPX. Halothane treatment provided no cardioprotection and seemed to inhibit protection by anoxic preconditioning. Halothane decreased whole cell KATP currents in atrial myocytes, whereas isoflurane had no effects. CONCLUSIONS: This study demonstrates the cardioprotective effects of isoflurane in contrast to the effects of halothane. Furthermore, A1 receptors and KATP channels seem to mediate the beneficial effects of anoxia and isoflurane in human myocardium.

Adenosine Triphosphate↗
PubMed2000

Clevidipine blockade of L-type Ca2+ currents: steady-state and kinetic electrophysiological studies in guinea pig ventricular myocytes.

Steady-state and transient effects of clevidipine, a rapidly degraded dihydropyridine (DHP) L-type Ca2+ channel antagonist, were examined on I(Ca) in guinea pig ventricular myocytes. When myocytes were voltage-clamped with holding potential (V(H)) at -80 mV, 10 nM clevidipine decreased I(Ca) at 0 mV by approximately 30%, but >50% when V(H) was -40 mV. Rapid (<50 ms) perfusion switching and repeated depolarizations delivered at 0.5-2 Hz were used to determine the time constants of onset (tau(on)) and recovery from (tau(off)) clevidipine inhibition of I(Ca). The tau(on) and tau(off) were monoexponential functions of time. The tau(on) of I(Ca) inhibition decreased from 21.5 +/- 1.2 to 9.9 +/- 0.9 s when the rapidly applied [clevidipine] was increased from 10 to 100 nM at V(H) = -80 mV; tau(off) was independent of the applied [clevidipine] and was 23.9 +/- 1.1 s. The dissociation constant (K(D)) calculated for clevidipine at V(H) = -80 mV was 65 +/- 3 nM, similar to the IC50 of 78 nM determined in steady-state measurements. Decreasing V(H) to -40 mV increased tau(off) more than threefold to 81 +/- 6 s, and K(D) was markedly decreased to 9.0 +/- 0.8 nM (IC50, 7.1 nM at V(H) = -40 mV). The increased affinity at depolarized V(H) may contribute to the varying concentration-effect relation observed in vivo.

Animals↗
PubMed2000

Comprehensive theory of Alzheimer's disease. The effects of cholesterol on membrane receptor trafficking.

Neurotrophic factors (NTFs), once known for their role in development, have recently been shown to contribute to the maintenance and plasticity of the adult nervous system. This knowledge has provoked hypotheses implicating NTFs in neurodegenerative conditions, particularly Alzheimer's disease (AD). Many of these hypotheses, however, fail to place the possibility of trophic factor dysfunction in the context of recent advances in the molecular pathogenesis of AD. Most notable has been the discovery of several genetic risk factors and three causative Alzheimer's genes. Genetic advances, in turn, have not yet shed much light on an important pathological feature of AD, synaptic loss. We propose here an hypothesis based on recent cell biological research that attempts to integrate findings in these areas. Our hypothesis states that AD pathogenesis results from disruption of cholesterol uptake and metabolism and that this in turn results in abnormal trafficking of membrane proteins critical to normal neuronal function and synaptic plasticity.

Alzheimer Disease↗
PubMed2000

Effects of volatile anesthetics on the direct and indirect protein kinase C-mediated enhancement of alpha1E-type Ca(2+) current in Xenopus oocytes.

The effect of the volatile anesthetics (VAs) halothane (0.59 mM) and isoflurane (0.70 mM) on protein kinase C (PKC)-mediated modulation of alpha1E type of high-voltage-gated Ca(2+) channels was examined in Xenopus oocytes coexpressing m1 muscarinic acetylcholine receptors. Phorbol-12-myristate-13-acetate (PMA) or 1, 2-dioctanoyl-sn-glycerol (DOG) was used to activate PKC directly, whereas indirect activation was induced with acetyl-beta-methylcholine (MCh). The interaction between PKC activators and VAs was examined by perfusing either VA before, during, or after the administration of PMA, DOG, or MCh. In addition, the effect of VAs was studied after the down-regulation of PKC. The application of VAs inhibited Ba(2+) current (I(Ba)), whereas PMA (500 nM), DOG (100 microM), or MCh (1 and 10 microM) markedly potentiated I(Ba). VAs inhibited PMA- or DOG-enhanced I(Ba) to the same extent as seen in controls. The inhibition of I(Ba) induced by VAs was not reversed by PMA or DOG. The administration of VAs in combination with PMA, DOG, or MCh (1 microM) led to the inhibition of I(Ba). MCh (10 microM) counteracted the inhibitory effect of VAs when administered together and reversed the inhibition of I(Ba) produced by VAs. These differences in the responses between PMA and MCh (10 microM) may be based on the involvement of various pools of PKC. It is suggested that VAs act directly at the membrane, because they blocked the membrane-based action of PMA, whereas the receptor-based action of MCh was only partially blocked. It is possible that some PKC isoforms may not be a direct target of VAs.

Anesthetics, Inhalation↗
PubMed2000

Perioperative blood pressure control: a prospective survey of patient management in cardiac surgery.

OBJECTIVE: To conduct a survey of current cardiac anesthetic practice in Europe and the United States, as a first step toward establishing guidelines for the management of perioperative hypertension. DESIGN: Prospective, multicenter study. SETTING: University hospitals. PARTICIPANTS: Unselected patients (n = 1,930) requiring cardiac surgery. INTERVENTIONS: Data extending from the preoperative evaluation to 120 hours or more after surgery were collected from all patients. MEASUREMENTS AND MAIN RESULTS: Only the data from patients undergoing coronary artery bypass surgery, valve surgery, or combined procedures were analyzed, leaving a final total of 1,660 patients from the original 1,930. Of these, 88% were treated at least once perioperatively to lower arterial blood pressure. Deepening of anesthesia was the most commonly used antihypertensive measure (68%), regardless of the ongoing anesthetic regimen, and was usually combined with vasodilator therapy, most frequently nitroglycerin (53%) or sodium nitroprusside (28%). Reported perioperative mean arterial pressure (MAP) was 15 to 20 mmHg lower than MAP before anesthesia induction, regardless of the use of antihypertensive therapy. The MAP at which antihypertensive treatment was initiated varied markedly among the various phases of surgery and showed no clear correlation with preoperative MAP. CONCLUSIONS: The results of this survey show that current anesthetic practice tries to prevent perioperative hypertension wherever possible during cardiac surgery. Blood pressure measurements taken before surgery have little influence on the development of hypertension intraoperatively, and the main determinants of perioperative blood pressure control and the need for therapeutic intervention are factors arising from the surgical procedure itself, such as aortic cross-clamping and activation of adrenergic mechanisms.

Blood Pressure↗
PubMed2000

Primary non-Hodgkin's lymphoma of bone.

We describe a patient with hip pain who had a painful solitary pelvic bone lesion with a lytic, permeative appearance and minimal periosteal reaction, despite a relatively large soft tissue mass. Histologic examination and thorough evaluation revealed this solitary tumor to be a primary non-Hodgkin's lymphoma of the bone.

Aged↗
PubMed1999

Mapping the active site topography of the NAD-malic enzyme via alanine-scanning site-directed mutagenesis.

The NAD-malic enzyme cDNA has been subcloned into the pQE expression vector, expressed with a six-His tag, and purified. The His-tagged enzyme is purified by a combination of Ni-NTA and orange A agarose column chromatography with a yield of 45% and an estimated purity of >90%. The tag and linker have no effect on the kinetic parameters of the enzyme compared to the wild-type enzyme. Alanine-scanning site-directed mutagenesis has been carried out on all of the conserved neutral acid residues of the NAD-malic enzyme from Ascaris suum. Data obtained confirm the predicted role of D178 and D295 in metal ion binding, the likely role of D294, D361, and E440 in the NAD binding site, and the role of E58 and D272 in malate binding. Decreases in V/E(t) by 10(4)-fold and in V/K(malate)E(t) by 10(7)-fold, when D295 is changed to alanine, suggest that it is a likely candidate for the general base that accepts a proton from the malate hydroxyl in the oxidation step.

Alanine↗
PubMed1999

Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes.

The genes encoding the alpha(1A), alpha(1B), alpha(1C) and alpha(1E) subunits of neuronal high voltage-gated Ca channels (HVGCCs) were separately expressed with beta(1B) and alpha(2)/delta subunits in Xenopus oocytes to determine the effects of volatile anesthetics (VAs) on currents through each specific channel. VA effects were determined on currents carried by Ba(2+) (I(Ba)) using the two electrode voltage clamp technique. Although time to peak was unaffected, both halothane (0.59 mM) and isoflurane (0.70 mM) reversibly inhibited peak I(Ba) by 25-35% and late current (at 830 ms) by 50-60%. A hyperpolarizing shift in steady-state inactivation of alpha(1E)-current was found which could contribute up to one third of observed decrease in the peak current. The rate of inactivation of I(Ba) seen with alpha(1A), alpha(1B) and alpha(1E)-type Ca channels was consistently increased by halothane and isoflurane. To more clearly quantify these effects, I(Ba) inactivation was fit by a single exponential function. The anesthetics depressed both the inactivating and non-inactivating residual components of I(Ba) and decreased the time constant of inactivation. In the case of I(Ba) through alpha(1C)-type channels, inactivation was minimal; however, the average current was inhibited by VAs. Similar inhibition of all these HVGCCs by halothane and isoflurane suggests that a common structural component may be involved. Furthermore, the inhibition of such neuronal HVGCCs in situ could alter synaptic neurotransmitter release and contribute to the anesthetic state.

Anesthetics, Inhalation↗
PubMed1999

Identification of multiple Gypsy LTR-retrotransposon lineages in vertebrate genomes.

Gypsy LTR-retrotransposons have been identified in the genomes of many organisms, but only a small number of vertebrate examples have been reported to date. Here we show that members of this family are likely to be widespread in many vertebrate classes with the possible exceptions of mammals and birds. Phylogenetic analyses demonstrate that although there are several distinct lineages of vertebrate gypsy LTR-retrotransposons, the majority clusters into one monophyletic clade. Groups of fungal, plant, and insect elements were also observed, suggesting horizontal transfer between phyla may be infrequent. However, in contrast to this, there was little evidence to support sister relationships between elements derived from vertebrate and insect hosts. In fact, the majority of the vertebrate elements appeared to be most closely related to a group of gypsy LTR-retrotransposons present within fungi. This implies either that at least one horizontal transmission between these two phyla has occurred previously or that a gypsy LTR-retrotransposon lineage has been lost from insect taxa.

Animals↗
PubMed1999

Injury of the rectum during vaginal surgery.

OBJECTIVE: We sought to report our experience with injury of the rectum during vaginal surgery. STUDY DESIGN: A retrospective chart review of a vaginal surgery database was performed. RESULTS: Nine injuries were identified. Four patients with posthysterectomy vault prolapse incurred a rectal laceration just above the perineum during an attempt to develop the rectovaginal space. Another rectal laceration occurred just above the perineum during an attempt to develop the rectovaginal space during vaginectomy-hysterectomy for gender dysphoria. Three other injuries occurred between the vaginal cuff and peritoneum while posterior culdotomy for vaginal hysterectomy was attempted. The remaining injury was in a Schuchardt incision. All 9 injuries were recognized, repaired, and healed without complication. CONCLUSIONS: Laceration of the rectum is an uncommon complication of vaginal surgery. Prompt recognition and repair result in uncomplicated primary healing.

Female↗
PubMed1999

A homolog of the fungal nuclear migration gene nudC is involved in normal and malignant human hematopoiesis.

The filamentous fungus Aspergillus nidulans nudC gene has an essential function in movement of nuclei following mitosis and is required for normal colony growth. Here, the molecular cloning and role in hematopoiesis of a human gene (designated HnudC) homologous to A. nidulans nudC is reported. The amino terminus of the larger human protein (HNUDC = 45 kDa) does not overlap with A. nidulans NUDC (22 kDa). However, NUDC and the C-terminal 94 amino acids of HNUDC are 67% identical. The C-terminal region of the HnudC gene fully complements the A. nidulans temperature-sensitive nudC3 mutation, suggesting that nudC has an essential function in cell growth that is conserved from filamentous fungi to humans. In initial studies, HNUDC levels were much higher in erythroid precursors compared to most other human tissues. Therefore, the potential role of HnudC in hematopoiesis was explored. In normal human bone marrow, HNUDC protein and mRNA are highly expressed in early myeloid and erythroid precursors and decline as these cells terminally differentiate. To determine whether hematopoietic growth factors induce HnudC expression, TF-1 cells were stimulated by granulocyte-macrophage colony-stimulating factor. This induced a significant increase in HNUDC protein and HnudC mRNA, suggesting that enhancement of HnudC expression in response to growth factor stimulation may be mediated at the transcription level. Furthermore, HNUDC was significantly enhanced in lysates of bone marrow aspirates from patients with acute myelogenous and acute lymphoblastic leukemia compared to aspirates from normal controls, suggesting that HnudC is involved in malignant hematopoietic cell growth as well. These data demonstrate that HNUDC is highly expressed in normal and malignant human hematopoietic precursors and suggest it is of functional importance in the proliferation of these cells.

Antibody Specificity↗
PubMed1999

The magnetless Clarion cochlear implant in a patient with neurofibromatosis 2.

We present our experience using the Clarion magnetless multichannel cochlear implant with a woman profoundly deafened following bilateral acoustic neuromata as a consequence of neurofibromatosis 2 (NF2). The right neuroma had been previously removed without an attempt at neural preservation. On the left, however, a posterior fossa approach had been taken with the aim of preserving hearing. Although the left cochlear nerve appeared to be undamaged at the end of the operation, no hearing thresholds could be elicited on post-operative audiometry, because of damage either to the cochlear nerve or to the blood supply to the cochlea. Round window electrical stimulation subsequently produced a perception of sound, confirming that the cochlear nerve was capable of functioning and that a cochlear implant would be effective. Because she would need regular magnetic resonance imaging (MRI) to monitor existing and future NF2 lesions, it was decided to use a magnetless Clarion implant, which has been shown to be MRI compatible. We report our experience of using the device in this case and discuss some of the issues related to the provision of cochlear implants to patients with NF2.

Adult↗
PubMed1999

Characterization of the pharmacological-sensitivity profile of neoglycoprotein-induced acrosome reaction in mouse spermatozoa.

Mammalian spermatozoa undergo the acrosome reaction (AR) in response to the interaction of a carbohydrate-recognizing molecule(s) on the sperm plasma membrane (sperm surface receptor) and its complementary glycan (ligand) moiety(ies) on the zona pellucida (ZP). Previously, we demonstrated that a hexose (mannose) or two amino sugars (glucosaminyl or galactosaminyl residues) when covalently conjugated to a protein backbone (neoglycoproteins) mimicked the mouse ZP3 glycoprotein and induced the AR in capacitated mouse spermatozoa (Loeser and Tulsiani, Biol Reprod 1999; 60:94-101). To elucidate the mechanism underlying sperm-neoglycoprotein interaction and the induction of the AR, we have examined the effect of several AR blockers on neoglycoprotein-induced AR. Our data demonstrate that two known L-type Ca(2+) channel blockers prevented the induction of the AR by three neoglycoproteins (mannose-BSA, N-acetylglucosamine-BSA, and N-acetylgalactosamine-BSA). The fact that the L-type Ca(2+) channel blockers (verapamil, diltiazem) had no inhibitory effect on sperm surface galactosyltransferase or alpha-D-mannosidase, two carbohydrate-recognizing enzymes thought to be sperm surface receptors, suggests that the reagents block the AR by a mechanism other than binding to the active site of the enzymes.

Acrosome Reaction↗
PubMed1999

Volatile anesthetic sensitivity of T-type calcium currents in various cell types.

UNLABELLED: We evaluated the effects of volatile anesthetics on T-type calcium current (ICa,T) present in four different cell types using the whole cell version of the patch clamp technique. In dorsal root ganglion neurons and in two neuroendocrine cells--adrenal glomerulosa cells (AG) and thyroid C-cells--ICa,T was reversibly decreased by volatile anesthetics at clinically relevant concentrations, with isoflurane and enflurane being more potent that halothane. In AG cells, the most sensitive cell type tested, ICa,T was reduced 47%+/-4% (n = 6) by isoflurane (0.7 mM) and 56%+/-2% (n = 5) by enflurane (1.2 mM), but by only 24%+/-1% (n = 5; P < 0.05) by halothane (0.7 mM). Isoflurane caused a significant increase in the rate of deactivation of ICa,T in AG cells. In ventricular myocytes, however, ICa,T was much less sensitive to both isoflurane and halothane. The differential sensitivity of ICa,T in various cell types to the anesthetics may reflect differences in the channels expressed in these tissues or differences in the cellular intermediates involved in anesthetic action. Depression of ICa,T in neuronal cells may contribute to anesthetic action through decreases in cellular excitability. IMPLICATIONS: Using the patch clamp technique, we showed that T-type calcium channels, which promote cellular excitability, are inhibited by volatile anesthetics in neuronal and neuroendocrine cells, but not in ventricular myocytes. Inhibition of neuronal T-type channels may contribute to the mechanism of action of volatile anesthetics.

Anesthetics, Inhalation↗