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Biomedical subjects

A Fisher

Publications and source records attributed to A Fisher.

At least 55 records · Page 3Linked to original sources
PubMed2000

Expert and layperson perceptions of ecosystem risk.

This research examines and compares perceptions held by laypeople and ecologists about risks to ecosystems, particularly risk from global climate change (GCC). A survey elicited perceptions of 31 risk characteristics for 13 GCC and 12 non-GCC risks to ecosystems. Factor analysis was used to examine the structure of layperson and expert risk perceptions. Both experts and laypeople tend to perceive GCC risks to ecosystems as less avoidable and more acceptable than risks from other causes. Compared to laypeople's perceptions, though, experts perceived GCC risks to have slightly lower impacts, be less avoidable, more acceptable, and less understandable than non-GCC risks to ecosystems. These findings may help guide efforts to communicate with laypeople about ecological risks from climate change.

Adult↗
PubMed2000

M1 muscarinic agonists as potential disease-modifying agents in Alzheimer's disease. Rationale and perspectives.

A cholinergic hypofunction in Alzheimer's disease (AD) may lead to formation of beta-amyloids that might impair the coupling of M1 muscarinic ACh receptors (mAChRs) with G proteins. This disruption in coupling can lead to decreased signal transduction, to a reduction in levels of trophic amyloid precursor proteins (APPs), and to generation of more beta-amyloids that can also suppress ACh synthesis and release, aggravating further the cholinergic deficiency. These "vicious cycles," a presynaptic and a postsynaptic one, may be inhibited, in principle, by M1 selective agonists. Such properties can be detected in the functionally selective M1 agonists from the AF series [e.g., project drugs, AF102B, AF150(S)]. These M1 agonists promote the nonamyloidogenic APP processing pathways and decrease tau protein phosphorylation. The effects on tau proteins suggest a link between M1 mAChR-mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule-associated protein. This may indicate a dual role for M1 agonists: as inhibitors of two "vicious cycles," one induced by beta-amyloids, and the other due to overactivation of certain kinases (e.g., glycogen synthase kinase-3, GSK-3) or downregulation of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E-knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-affinity binding site to M1 mAChRs. Except M1 agonists, there are no reports of compounds having such combined effects, for example, amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable, yet unexplored, clinical value of such compounds.

Alzheimer Disease↗
PubMed2000

Amino acid residue 147 of human aldosterone synthase and 11beta-hydroxylase plays a key role in 11beta-hydroxylation.

A number of amino acids differ between aldosterone synthase and 11beta-hydroxylase. To assess their importance in determining the different functional specificities, we substituted aldosterone synthase-specific (aspartate D147, isoleucine I248, glutamine Q43, and threonine T493) with 11beta-hydroxylase-specific amino acids (glutamate E147, threonine T248, arginine R43, and methionine M493), respectively. I248T, Q43R, and T493M had no effect on steroid production compared to wild-type aldosterone synthase. However, CYP11B2-D147E caused a significant increase in corticosterone production and a smaller increase in aldosterone production from 11-deoxycorticosterone (DOC). This appeared to be predominantly due to an increase in the 11beta-hydroxylation of DOC to corticosterone mediated by a decrease in Km, which was 1.4 micromol/L for the mutant compared with 5 micromol/L for the wild-type enzyme. CYP11B2-D147E had no effect on the conversion of 11-deoxycortisol to cortisol. The reverse construct (CYP11B1-E147D), substituting the 11beta-hydroxylase residue with the aldosterone synthase equivalent, decreased the conversion of DOC to corticosterone, which was mediated by an increase in Km that was 7.5 micromol/L for the mutant compared with 2.5 micromol/L for the wild-type enzyme. Again, the conversion of 11-deoxycortisol to cortisol was unimpaired. Thus, amino acid 147 is involved in the transformation of the 17-deoxysubstrate, but not the 17alpha-hydroxysubstrate. The results demonstrate that a conservative change in amino acid, even at some linear distance from known active centers, can significantly affect enzyme substrate affinity and subsequent steroid hormone production.

Amino Acids↗
PubMed2000

Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists.

The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.

Alzheimer Disease↗
PubMed2000

Functional correlation in amino acid residue mutations of yeast iso-2-cytochrome c that is consistent with the prediction of the concomitantly variable codon theory in cytochrome c evolution.

Fitch and Markowitz' theory of concomitantly variable codons (covarions) in evolution predicted the existence of functional correlation in amino acid residue mutations among present-day cytochromes c. Mutational analysis was carried out on yeast iso-2-cytochrome c, where hydrophobic core residues I20, M64, L85, and M98 and surface residue L9 were mutated, in selected combinations, to those found in mammalian and bird cytochromes c. The functionality assay is based upon the ability of yeast cells to grow in YPGE medium. Furthermore, experiments on the single M64L and M98L mutations as well as the double M64L/M98L mutation using NMR showed that the effects of these mutations are to perturb the structural integrity of the protein. We identified functional correlation in two cases of a pair of residue mutations, the I20-->V and M98-->L pair and the L9-->I and L85-->I pair. In both cases, only one of the two alternative, putative evolutionary pathways leads to a functional protein and the corresponding pairs of residue mutations are among those found in present-day cytochromes c. Since valine is predicted to be at position 20 in the ancestral form of cytochrome c, the present data provide an explanation for the ancient requirement of leucine rather than methionine in position 98. The present data provide further evidence for the role of those specific atom-atom interactions in directing a pathway in the evolutionary changes of the amino acid sequence that have taken place in cytochrome c, in accordance with Fitch and Markowitz.

Amino Acid Substitution↗
PubMed1999

Depletion of alloreactive T cells by a specific anti-interleukin-2 receptor p55 chain immunotoxin does not impair in vitro antileukemia and antiviral activity.

The success of bone marrow transplantation (BMT) from HLA-disparate donors depends on the development of new strategies able, on one hand, to efficiently prevent graft-versus-host disease (GVHD) and, on the other hand, to protect leukemic patients from relapse and infections. Using an immunotoxin (IT) directed against the alpha chain (p55) of the human interleukin-2 receptor (RFT5-SMPT-dgA), we previously showed that it is possible to kill mature T cells activated against a specific HLA complex by a one-way mixed lymphocyte culture (MLC). The present study was performed to investigate whether this protocol of allodepletion affects the capacity of residual T cells to display antileukemia and antiviral activity evaluated by limiting dilution assays (LDA), measuring the frequency of cytotoxic T-lymphocyte precursors (CTLp) directed against autologous leukemic blasts (LB) and cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-infected target cells. Antileukemia activity was evaluated in peripheral blood mononuclear cells (PBMC) of 3 patients treated for acute myeloid leukemia who had developed a high frequency of LB-reactive CTLp after either autologous or allogeneic BMT. Results demonstrate that (1) depletion with RFT5-SMPT-dgA efficiently inhibited MLC; (2) fresh PBMC of patients yielded a high frequency of LB-reactive CTLp comparable to that of the mock-treated PBMC; and (3) effector cells obtained after allodepletion fully retained the capacity to lyse pretransplant LB. By contrast, the frequency of CTLp directed against patient's pretransplant BM remission cells was always undetectable. Data obtained in 4 healthy donors showed that specifically allodepleted T cells recognized and killed autologous CMV-infected fibroblasts and autologous EBV-B-lymphoblastoid cell lines. In conclusion, our data indicate that allodepletion using RFT5-SMPT-dgA efficiently removed alloreactive cells, while sparing in vitro antileukemic and antiviral cytotoxic responses.

Bone Marrow Cells↗
PubMed1999

Divided attention-enhancing effects of AF102B and THA in aging monkeys.

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.

Aging↗
PubMed1999

Effect on cell kill of addition of multidrug resistance modifiers cyclosporin A and PSC 833 to cytotoxic agents in chronic lymphocytic leukaemia.

Expression of P-glycoprotein (Pgp), the drug efflux pump which mediates multidrug resistance (MDR), has been widely reported in chronic lymphocytic leukaemia (CLL) and improved accumulation of daunorubicin has been reported using the MDR reversing agent cyclosporin A (CSA). We have investigated the effects on cell kill of the addition of CSA and its analogue PSC 833 to daunorubicin, doxorubicin, idarubicin, mitozantrone and fludarabine in samples from 51 patients with CLL using an MTT [3(4,5-dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Pgp expression was assessed by immunocytochemistry using the JSB-1 monoclonal antibody. Of the 51 samples, 10 (20%) were Pgp positive and all of these samples were from treated patients. With the exception of mitozantrone, the addition of CSA and PSC 833 to cytotoxic agents failed to significantly improve cytotoxicity, even in the Pgp positive group. With mitozantrone significant responses were seen in both Pgp positive and negative groups suggesting that the responses were due to direct cytotoxicity of the cytotoxic-modifier combination rather than reversal of MDR. Both CSA and PSC 833 showed significant direct cytotoxicity (P = 0.004 and 0.04 for PSC 833 at 1000 ng/ml and 500 ng/ml respectively; P < 0.001 for both concentrations of CSA). The responses were disappointing compared to the highly significant improvements in cytotoxicity seen using cells from the Pgp positive CEM VLB 100 acute myeloid leukaemia cell line, and it was not possible to demonstrate the superiority of PSC 833 over CSA which is also seen in cell lines. Our data do not support a role for Pgp modifiers in CLL. Further studies using larger numbers of Pgp positive CLL cells and higher doses of PSC 833 would be useful.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment.

Apolipoprotein E (apoE)-deficient mice have memory deficits that are associated with synaptic loss of basal forebrain cholinergic projections and with hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. Furthermore, treatment of apoE-deficient mice with the M1 selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline) [AF150(S)] abolishes their memory deficits and results in recovery of their brain cholinergic markers. In the present study, we used a panel of anti-tau monoclonal antibodies to further map the tau epitopes that are hyperphosphorylated in apoE-deficient mice and examined the effects of prolonged treatment with AF150(S). This revealed that tau of apoE-deficient mice contains a distinct, hyperphosphorylated "hot spot" domain which is localized N-terminally to the microtubule binding domain of tau, and that AF150(S) has an epitope-specific tau dephosphorylating effect whose magnitude is affected by apoE deficiency. Accordingly, epitopes which reside in the hyperphosphorylated "hot spot" are dephosphorylated by AF150(S) in apoE-deficient mice but are almost unaffected in the controls, whereas epitopes which flank this tau domain are dephosphorylated by AF150(S) in both mice groups. In contrast, epitopes located at the N and C terminals of tau are unaffected by AF150(S) in both groups of mice. These findings suggest that apoE deficiency results in hyperphosphorylation of a distinct tau domain whose excess phosphorylation can be reduced by muscarinic treatment.

Animals↗
PubMed1999

V-shaped cushion at the origin of bovine pulmonary supernumerary arteries: structure and putative function.

This study investigates the anatomic structure at the origin of pulmonary supernumerary arteries and their parent conventional artery. Histological examination showed that at the origin of each supernumerary artery the wall of the parent conventional artery is organized into a distinct V-shaped structure, which begins on the hilum side of each supernumerary artery as a funnel-shaped channel running into the supernumerary artery. The base of the channel is particularly thin walled. The lateral walls of the channel are composed of musculoelastic cushions that become more pronounced toward the supernumerary artery and fuse on its distal side, forming a baffle that projects over the supernumerary artery lumen. These V-shaped structures/cushions were observed with video stereo dissecting microscopy in both an open and closed state in isolated arteries in vitro. Pulmonary vasoconstriction of isolated arteries with the thromboxane A(2) mimetic U-46619 increased the number of V-shaped structures in the closed state. These studies indicate the presence of a novel anatomic structure at the origin of pulmonary supernumerary arteries, which may be able to regulate blood flow into the supernumerary artery.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Reduction of motoric agitation and restlessness by AF102B and tacrine in the macaque.

The cholinesterase inhibitor tacrine (THA) and the M1 muscarinic agonist AF102B (cevimeline), both reported to enhance cognition in animals and humans, were tested in 5 macaques for reduction of spontaneous, random movements. Monkeys were videotaped 1 hour after administration of normal saline vehicle, after low- and high-dose intramuscular AF102B, and after low- and high-dose oral THA. Two independent blind judges counted numbers of spontaneous movements made by each monkey over 12 consecutive 15-second segments for each drug condition. Both THA and AF102B reduced movement significantly at high doses without overt side effects, warranting further research on the agitation-reducing potential of cognition-enhancing cholinomimetic drugs.

Alzheimer Disease↗
PubMed1999

Lack of pharmacokinetic and pharmacodynamic interaction between rizatriptan and paroxetine.

Rizatriptan is a potent, oral 5-HT(1B/1D) agonist with a rapid onset of action being investigated for the acute treatment of migraine. This study examined the clinical and pharmacolinetic interaction between rizatriptan and the selective serotonin reuptake inhibitor, paroxetine. In this two-period crossover study, 12 healthy young subjects (6 males and 6 females) received 1 mg rizatriptan following 14 days of treatment with placebo or paroxetine (20 mg once daily). Plasma was sampled for rizatriptan and N-monodesmethyl rizatriptan, a minor but active metabolite of rizatriptan. Safety evaluations included monitoring for adverse events, vital signs, and visual analog scale assessment of mood. Plasma levels of rizatriptan and N-monodesmethyl rizatriptan were not altered when rizatriptan was administered with paroxetine compared to the placebo. Clinically, coadministration of rizatriptan with paroxetine was well tolerated. Blood pressure, heart rate, and temperature changes during the observation period did not differ to a clinically significant degree when rizatriptan was administered with paroxetine compared to the placebo. No effects on mood occurred following treatment with the combination compared to rizatriptan alone. Adverse events following rizatriptan administration with paroxetine were similar to those reported when rizatriptan was given with the placebo.

Adult↗
PubMed1999

Elaeophorosis in bighorn sheep in New Mexico.

Two bighorn sheep (Ovis canadensis) in New Mexico (USA) were found to be naturally infected with Elaeophora schneideri. An adult ram examined in 1997 in the Fra Cristobal Mountains had 26 nematodes in the carotid and iliac arteries, and microfilariae were present in the skin, nasal mucosa, brain, and lungs. This ram was markedly debilitated prior to euthanasia and extensive crusty, scabby lesions were observed on its head. In 1998, a yearling ewe found dead adjacent to Watson Mountain near the Gila Wilderness area was found to have 13 nematodes present in its heart. This is the first report of E. schneideri in bighorn sheep, and we suggest that bighorn sheep are susceptible to E. schneideri infection wherever they coexist with mule deer (Odocoileus hemionus hemionus) and appropriate tabanid vectors.

Animals↗
PubMed1999

Theorizing the knowledge that nurses use in the conduct of their work.

The authors propose a classification of knowledge that they call case, patient, and person and that reflects the content of the knowledge necessary to the conduct of nursing work. This classification represents an attempt to theorize from their respective empirical research data. Case knowledge is general knowledge of pathophysiology, disease processes, pharmacology, and other therapeutic protocols. Patient knowledge is that knowledge that defines the individual within the health care system, the knowledge expressed in the individual's response to therapeutics, and the knowledge that enables nurses to move the recipient of care through the health care system and along the illness trajectory. Person knowledge is knowledge of the individual as a subject with a personal biography who occupies a certain social space and who acts with his or her own desires and intentions for reasons that make sense to him or her. Two types of social knowledge serve as relational knowledge, or a bridge that links case knowledge to patient knowledge and patient knowledge to person knowledge. Each type of knowledge is accessed differently and the extent to which each is attained and used is determined by the circumstances of the patient's illness and his or her location in the health care system. The authors make a case for why this classification might be useful to the discipline.

Clinical Competence↗