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Biomedical subjects

K Holmes

Publications and source records attributed to K Holmes.

At least 37 records · Page 2Linked to original sources
PubMed1995

Agonist action of (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) in the amygdala.

Glutamatergic excitatory postsynaptic potentials (EPSPs) in the basolateral amygdala (BLA) are reduced in amplitude following agonist activation of presynaptic metabotropic glutamate receptors (mGluR). In this study, the effect of a presumed mGluR antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), was investigated on the EPSP recorded intracellularly in BLA neurons. Superfusion of MCPG (500 microM) significantly reduced the amplitude of evoked EPSPs. In the presence of MCPG, postsynaptic responses to alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA, 1 microM) were unaltered while responses to N-methyl-D-aspartate (NMDA, 3-5 microM) were potentiated. These data suggest that the MCPG-induced reduction of EPSP amplitude is due to a mGluR agonist action at a presynaptic mGluR 'autoreceptor'.

Amygdala↗
PubMed1995

Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency.

Breast milk samples from human immunodeficiency virus type 1 (HIV-1)-seropositive women were analyzed by polymerase chain reaction to determine the prevalence and determinants of HIV-1-infected cells in breast milk. Breast milk samples (212) were collected from 107 women, and 58% of the samples had detectable HIV-1 DNA. The proportion of HIV-1-infected cells in the milk samples ranged from 1 to 3255/10(4) cells. Breast milk samples with detectable HIV-1 DNA were more likely to be from women with absolute CD4 cell counts of < 400 (odds ratio, 3.1; 95% confidence interval [CI], 1.5-7.0). Severe vitamin A deficiency (< 20 micrograms/dL) was associated with a 20-fold increased risk of having HIV-1 DNA in breast milk among women with < 400 CD4 cells/mm3 (95% CI, 2.1-188.5). Women with CD4 cell depletion, especially those with vitamin A deficiency, may be at increased risk of transmitting HIV-1 to their infants through breast milk.

Adolescent↗
PubMed1994

B cells from M167 mu kappa transgenic mice fail to proliferate after stimulation with soluble anti-Ig antibodies. A model for antigen-induced B cell anergy.

The transgenic (TG) mouse strain 207-4, carries mu a + kappa transgenes ligated to the anti-phosphocholine (PC) VH1 and V kappa 24 V region genes from the MOPC-167 myeloma. Although B cells from mice carrying these transgenes respond both in vivo and in vitro to thymus-dependent Ags, they failed to proliferate in response to soluble goat anti-mu Ab or other soluble anti-Ig reagents. On the other hand, B cells from the Sp6 mu kappa anti-trinitrophenyl TG mouse line proliferated normally after stimulation with soluble anti-mu. However, the 207-4 anti-PC transgene positive (TG+) splenic B cells proliferated when stimulated with anti-mu, anti-idiotype, anti-allotype, or PC-conjugated to Sepharose beads. TG+ B cells were also induced to proliferate when stimulated with anti-Lyb-2; thus, their defect may be restricted to signaling through sigM. The lack of response to soluble anti-mu could not be reversed by addition of IL-4, by removal of T cells, by addition of anti-FcR Ab, or by stimulation with F(ab')2 anti-mu. Thus, the failure to proliferate was not caused by active T cell suppression or FcR-mediated inhibition. In mixed cultures of TG+ and transgene negative (TG-) spleen cells, the TG- cells were able to proliferate normally to soluble anti-mu, indicating that suppressive factors were not involved in the unresponsiveness of the TG+ anti-PC-specific B cells. These studies suggest that B cells in the 207-4 anti-PC TG mice exhibit a defect in activation through their sIgM receptors, and this unresponsiveness may reflect a form of Ag-induced tolerance.

Animals↗
PubMed1994

Integrating ergonomics and engineering in the technical design process.

Leyland DAF and the University of Nottingham collaborated in establishing an ergonomics team to support the truck design and development process in the company. The project was planned within the framework of a Teaching Company Scheme funded jointly by Leyland DAF and the UK government. This framework provided a training environment in which the team, which was formed of young professional ergonomists and engineers, could quickly acquire the specialist skills needed for work in the automotive industry in addition to gaining practical experience in applying ergonomics, and the programme was structured to promote the integration of ergonomics and engineering considerations within the technical design process. The experience gained in this project has shown the benefits of such an approach to implementing ergonomics in product design, and provided an insight into the ways in which ergonomists and designers can communicate more effectively in a manufacturing organization.

Journal Article↗
PubMed1994

Peptidoglycan isolated from nontypeable Haemophilus influenzae induces experimental otitis media in the chinchilla.

Bacterial cell wall components induce a number of biologic effects and promote inflammatory changes in a variety of hosts. Peptidoglycan isolated from Streptococcus pneumoniae can induce inflammation in the middle ear; however, an analogous role for peptidoglycan derived from gram-negative otitis media pathogens has not been described. Peptidoglycan isolated from nontypeable Haemophilus influenzae (NTHi), a major cause of otitis media, was evaluated in a chinchilla model. The direct injection of the middle ear with 3-300 micrograms of peptidoglycan resulted in tympanic membrane inflammation, abnormal pressure in the middle ear, leukocytosis, and histopathologic changes in the middle ear mucosa that included marked edema, osteoneogenesis, focal hemorrhage, and a mononuclear infiltration into the subepithelial space. These data indicate that NTHi peptidoglycan induced inflammation and histopathologic changes in the tympanic membrane and middle ear mucosal epithelium and may contribute to the pathogenesis of otitis media.

Animals↗
PubMed1994

Preparation for AIDS vaccine evaluation in Mombasa, Kenya: establishment of seronegative cohorts of commercial sex workers and trucking company employees.

In preparation for human immunodeficiency virus (HIV) prophylactic vaccine trials, prospective cohorts of HIV seronegative female commercial sex workers and male trucking company employees were established in Mombasa, Kenya, with the aims of defining HIV seroincidence and correlates of HIV seroconversion. Female and male cohorts were followed at 1- and 3-month intervals, respectively, with questionnaires, physical examinations, evaluation for sexually transmitted diseases, and HIV serologic testing. Between February and September, 1993, 1,277 women and 748 men were tested for antibodies to HIV-1. Seroprevalence was 55.4% among commercial sex workers and 17.7% among trucking company employees. Three hundred fifty-two HIV-seronegative women and 507 seronegative men were enrolled in the cohort studies. Annualized seroincidence rates of HIV infection were 16.4% (95% CI 8.8-27.0) among commercial sex workers and 6.6% (95% CI 2.5-13.8) among trucking company employees. These cohorts may be valuable resource for evaluating HIV vaccines and other potential preventive interventions.

AIDS Vaccines↗
PubMed1993

Detection and quantitation of cells secreting IL-6 under physiologic conditions in BALB/c mice.

IL-6 is a pleiotropic cytokine involved in the regulation of hematopoiesis and lymphocyte activation. An extremely sensitive ELIspot assay was developed to detect and enumerate individual cells secreting IL-6 in normal BALB/c mice. Under physiologic conditions, the frequency of cells producing IL-6 in the bone marrow, spleen, and mesenteric lymph nodes of normal adult animals was approximately 0.5, 0.1, and 0.01%, respectively. FACS analysis revealed that macrophages and Mac1- B220- cells accounted for the vast majority of IL-6 production in the bone marrow, whereas T and B lymphocytes accounted for 4% and 38% of IL-6 production in the spleen. Simultaneous studies comparing cell number with IL-6 levels indicated that the average activated cell produced approximately 85 molecules of IL-6/s.

Animals↗
PubMed1993

Long-term urodynamic effects of finasteride in benign prostatic hyperplasia: a pilot study.

A group of 69 men with bladder outflow obstruction due to benign prostatic hyperplasia (BPH) were treated in a double-blind placebo-controlled study with finasteride (Proscar), a 5 alpha-reductase inhibitor, 5 mg or 10 mg/day, or an identical placebo for 3 months; subsequently, 20 patients received finasteride 5 mg/day in an open extension study. Ten of these patients have now completed 3 years of therapy and have been reevaluated with pressure/flow urodynamics. In finasteride-treated patients dihydrotestosterone (DHT) declined by over 60%, remaining unchanged with placebo. Symptom scores fell in both groups of patients, maximum flow rate values decreased on placebo but improved by a mean of 1.5 ml/s in the 10-mg group and 3.3 ml/s in the 5-mg group. After 1 year of therapy, the reduction in symptom score was well maintained and the flow rate had increased by a mean of 2.7 ml/s; the mean prostate volume was reduced by 14% and prostate-specific antigen (PSA) had declined by 28%. In the 10 patients treated for 3 years who consented to further urodynamic study, the maximum urinary flow rate had improved from a mean baseline value of 8.7 ml/s to a mean of 13.8 ml/s, while maximum subtracted voiding pressure had decreased from a mean baseline value of 72 cm H2O to an unobstructed mean value of 44 cm H2O. Side effects were minimal and reversible on stopping the medication.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗
PubMed1993

Lack of short-term effect of the thromboxane synthetase inhibitor UK-38,485 on airway reactivity to methacholine in asthmatic subjects.

Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.

Adult↗
PubMed1992

Effect of diethyl maleate on glutathione, hepatic and renal cortical perfusion, and portal 6-ketoPGF1 alpha and TxB2 levels in swine.

1. Effects of diethyl maleate (DEM) mediated glutathione (GSH) depletion on hepatic and renal cortical blood flow (perfusion), plasma GSH, and portal prostacyclin (6-ketoPGF1 alpha) and thromboxane (TxB2) were determined in anaesthetized swine. 2. Although DEM depleted hepatic GSH to 25% of control, plasma GSH increased 10-fold in comparison to controls. DEM caused a drop in blood pressure and renal cortical perfusion but had no effect on hepatic perfusion or portal 6-ketoPGF1 alpha or TxB2 levels. 3. Possibly, the unexpected rise in plasma GSH may have inhibited prostanoid synthesis, preventing any alterations in tissue perfusion that may have occurred following tissue GSH depletion.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Dual mechanism for catecholamine secretion in the dogfish shark Squalus acanthias.

Both 1,1-dimethyl-4-phenylpiperazinium iodide, a ganglionic stimulating drug (DMPP), and potassium ion (K+) cause a pressor response when injected into Squalus acanthias, an elasmobranch. The pressor responses are due to increased secretion of epinephrine and norepinephrine. The pressor response to DMPP can be blocked by prior infusion of hexamethonium, a ganglionic blocking drug. However, ganglionic blockade does not inhibit the pressor response to K+. Plasma catecholamine concentrations do not increase significantly in response to challenge with DMPP after hexamethonium infusion, but exceedingly high levels of plasma catecholamines quickly appear after K+ injection following hexamethonium infusion. It is concluded that there are at least two mechanisms controlling catecholamine secretion in the dogfish, one of which involves the ganglion cells that are intimately associated with chromaffin cells in the chromophil bodies that are so characteristic of this species and elasmobranchs in general.

Animals↗
PubMed1983

Effect of ganglionic blockade on catecholamine secretion in exercised dogfish.

A brief bout of vigorous exercise results in significant increases in plasma epinephrine (E) and norepinephrine (NE) in the dogfish, Squalus acanthias. Since the presence of a functioning sympathetic nervous system in dogfish is in doubt, experiments were undertaken to show whether or not exercise-induced catecholamine (CA) secretion is under autonomic neurogenic control. Changes in plasma E and NE in a control group of exercised fish were compared with changes in fish exercised while under the influence of ganglionic blockade. Ganglionic blockade was induced in dogfish by hexamethonium infusion before exercise. CA secretion in response to a subsequent bout of exercise was significantly reduced without impairment of the ability of the fish to exercise. The pattern of systemic arterial pressure response to exercise and recovery (initial decrease during exercise followed by a prompt recovery to control level) was not significantly altered by ganglionic blockade. It is concluded that in dogfish some fraction of CA secretion capacity is possibly or potentially under neurogenically related control. Apparently the fraction of CA secretion under such control is not essential for performing exercise. The pattern of CA secretion accompanying the events of exercise and recovery in dogfish suggests that CA may play a more important role in recovery from exercise than in its performance.

Animals↗
PubMed1983

Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism.

The metabolism of exogenously infused porcine insulin and glucagon was assessed concurrently in normal fasted dogs under anaesthesia. Hepatic and renal extraction of glucagon were 25.6 +/- 2.3 and 43.7 +/- 3.9%, respectively, and its metabolic clearance 16.5 +/- 0.8 ml/kg/min. Hepatic and renal extraction accounted for 28.5 +/- 4.2 and 28.7 +/- 3.7% of total glucagon clearance, respectively. Insulin MCR was 18.3 +/- 1.5 ml/kg/min and its hepatic and renal extraction were 49.6 +/- 3.4 and 41.7 +/- 4.4% accounting for 51.9 +/- 4.4 and 27.3 +/- 3.9% of total insulin clearance, respectively. Neither total glucagon metabolic clearance nor its hepatic or renal components saturated even in the face of circulating glucagon levels extending into the pharmacologic range up to 14 ng/ml. In contrast however, with increasing arterial concentrations of insulin, saturability of metabolism was apparent as evidenced by significant reductions in MCR as well as hepatic and renal extraction. This demonstration of saturability of hepatic insulin metabolism occurred at levels encountered in the portal vein after meals and is compatible with the concept that the hepatic capacity for extraction of this hormone may be an important site of control of the proportion of secreted insulin reaching the periphery. The metabolic handling of each hormone was shown to be independent of the other. Despite similarities in the interaction of insulin and glucagon with the target cell, there are important differences in the mechanisms of metabolism of these peptides as the major degradative sites.

Animals↗