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Biomedical subjects

F M Cowan

Publications and source records attributed to F M Cowan.

83 records · Page 5Linked to original sources
PubMed1979

Suppression of DNA synthesis in mitogen stimulated leukocytes with partial trypsin digests of Staphylococcus aureus protein A.

Staphylococcus aureus protein A (SPA) acts as a mitogen stimulating DNA synthesis and is not antagonistic to the mitogenic activity of other mitogens. The mitogenicity of SPA is due to the protein's multivalent Fc antibody receptors. Partial trypsin digestion of SPA yields monovalent Fc antibody receptors which are not mitogenic. Using a thymidine incorporation assay, results indicated that tryptic digests of SPA added to mouse splenic leukocytes 12 hours after stimulation with either concanavalin A, lipopolysaccaride or SPA suppressed the DNA synthesis normally elicited by these mitogens. SPA was digested with 1% trypsin at pH 8 for varying periods of time. As the digestion time increased from 0 to 60 minutes the mitogenicity of the SPA-trypsin digests decreased indicating cleavage from multivalent to monovalent SPA Fc antibody receptors. The decrease in mitogenicity of the SPA digests was directly associated with increased ability to inhibit DNA synthesis in mitogen stimulated leukocytes. A proposed mechanism for the inhibition of DNA synthesis suggests that SPA-monovalent Fc antibody receptors mimic cellular Fc receptor function thereby influencing cellular gene expression.

Animals↗
PubMedDate not supplied

Hypothesis for synergistic toxicity of organophosphorus poisoning-induced cholinergic crisis and anaphylactoid reactions.

The neurotoxicity of organophosphorus (OP) compounds involves the inhibition of acetylcholinesterase (AChE), causing accumulation of acetylcholine (ACh) at synapses. However, cholinergic crisis may not be the sole mechanism of OP toxicity. Adverse drug reactions caused by synergistic toxicity between drugs with distinct pharmacological mechanisms are a common problem. Likewise, the multiple pharmacological activities of a single molecule might also contribute to either toxicity or efficacy. For example, certain OP compounds (e.g. soman) exhibit anti-AChE activity and also act as secretagogues by inducing mast cell degranulation with associated autacoid release and anaphylactoid reactions. Anaphylactoid shock can produce a lethal syndrome with symptoms of respiratory failure and circulatory collapse similar to the physiological sequelae observed for OP poisoning. Moreover, the major classes of drugs used as antidotes for OP intoxication can affect anaphylaxis. Acetylcholine can act as an agonist of autacoid release, and autacoids such as histamine can augment soman-induced bronchial spasm. In concert with the demonstrably critical role of cholinergic crisis in OP toxicity, the precepts of neuroimmunology indicate that secondary adverse reactions encompassing anaphylactoid reactions may complicate OP toxicity.

Anaphylaxis↗
PubMedDate not supplied

Protective action of the serine protease inhibitor N-tosyl-L-lysine chloromethyl ketone (TLCK) against acute soman poisoning.

Soman-poisoned rats display cholinergic crisis, a systemic mast cell degranulation characteristic of anaphylactic reactions and an excitotoxin-like sequential seizure and neuronal degeneration. The protection of guinea pigs from soman lethality by prophylactic administration of the serine protease inhibitor suramin suggests a possible proteolytic component in soman poisoning. The present study tested the effect of N-tosyl-L-lysine chloromethyl ketone (TLCK), an inhibitor of trypsin-like serine proteases, on soman-induced toxic signs (convulsions, righting reflex) and survival time. Nine control guinea pigs receiving 2 x LD(50) (56 microg kg(-1), s.c.) of soman immediately followed by a therapeutic dose of atropine sulfate (17.4 mg kg(-1) i.m.) experienced severe convulsions, and 8/9 lost the righting reflex. Six of these nine animals expired within 65 min; the three remaining animals survived 24 h to termination of the experiment. When a second group of animals were given TLCK (12 mg kg(-1), i.p.) 30 min prior to a 2 x LD(50) soman challenge and atropine-sulfate therapy, 5/9 experienced convulsions and only 3/9 lost the righting reflex. All nine animals survived beyond 4 h, with six surviving to 24 h. Compared with soman controls, prophylaxis with TLCK significantly prevented the loss of righting reflex (P = 0.05) and enhanced 4-h survival (P = 0.005). Although, convulsions were reduced and 24-h survival was improved in TLCK-treated animals, these results were not statistically significant. The protection from soman toxicity by chemically distinct protease inhibitors such as suramin and TLCK suggests a role for pathological proteolytic pathways in soman intoxication.

Animals↗
PubMedDate not supplied

Putative role of proteolysis and inflammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi-threat medical countermeasures.

Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and inflammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal-epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2'-dichlorodiethyl sulfide) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and inflammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-inflammatory pharmacology. Accordingly, we hypothesize that drugs with anti-inflammatory actions against either nerve or blister agent might also display multi-threat efficacy for the inflammatory pathogenesis of both classes of chemical warfare agent.

Animals↗
PubMedDate not supplied

Inhibition of sulfur mustard-increased protease activity by niacinamide, N-acetyl-L-cysteine or dexamethasone.

The pathologic mechanisms underlying sulfur mustard-induced skin vesication remain undefined. Papirmeister et al. (1985) have postulated a biochemical mechanism for sulfur mustard-induced cutaneous injury involving DNA alkylation, metabolic disruption, and enhanced proteolytic activity. We have previously utilized a chromogenic peptide substrate assay to establish that human peripheral blood lymphocytes exposed to sulfur mustard exhibited enhanced proteolytic activity. In this study, compounds known to alter the biochemical events associated with sulfur mustard exposure or to reduce protease activity were tested for their ability to block the sulfur mustard-increased proteolysis. Treatment of cells with niacinamide, N-acetyl-L-cysteine, or dexamethasone resulted in a decrease of sulfur mustard-increased protease activity. Complete inhibition of sulfur mustard-increased proteolysis was achieved by using protease inhibitors (antipain, leupeptin, and 4-(2-aminoethyl)-benzenesulfonylfluoride). These data suggest that therapeutic intervention in the biochemical pathways that culminate in protease activation or direct inhibition of proteolysis might serve as an approach to the treatment of sulfur mustard-induced pathology.

Acetylcysteine↗
PubMedDate not supplied

Sulfur mustard-increased proteolysis following in vitro and in vivo exposures.

The pathologic mechanisms underlying sulfur mustard (HD)-induced skin vesication are as yet undefined. Papirmeister et al. (1985) postulate enhanced proteolytic activity as a proximate cause of HD-induced cutaneous injury. Using a chromogenic peptide substrate assay, we previously reported that in vitro exposure of cell cultures to HD enhances proteolytic activity. We have continued our investigation of HD-increased proteolytic activity in vitro and have expanded our studies to include an in vivo animal model for HD exposure. In vitro exposure of human peripheral blood lymphocytes (PBL) to HD demonstrated that the increase in proteolytic activity is both time- and temperature-dependent. Using a panel of 10 protease substrates, we established that the HD-increased proteolysis was markedly different from that generated by plasminogen activator. The hairless guinea pig is an animal model used for the study of HD-induced dermal pathology. When control and HD-exposed PBL and hairless guinea pig skin where examined, similarities in their protease substrate reactivities were observed. HD-exposed hairless guinea pig skin biopsies demonstrated increased proteolytic activity that was time-dependent. The HD-increased proteolytic response was similar in both in vitro and in vivo studies and may be useful for elucidating both the mechanism of HD-induced vesication and potential treatment compounds.

Animals↗
PubMedDate not supplied

Proton MR spectroscopy of the brain in infants.

Proton magnetic resonance spectroscopy (MRS) was used to study the brain of 2 normal and 15 abnormal infants aged from 33 weeks postmenstrual age (PMA) to 14 months postnatal age. Eleven of the infants were examined on at least two occasions. The principal clinical diagnoses in the abnormal infants were perinatal ischemic and hemorrhagic brain injury. All proton spectra demonstrated peaks that were assigned to N-acetylaspartate (NAA), choline containing compounds (Cho), and creatine plus phosphocreatine (Cr). The NAA/Cho and NAA/Cr ratios increased with age, while the Cho/Cr ratio decreased with age in the majority of infants. The NAA/Cho ratio was generally lower in abnormal infants, but the difference was not apparent before 40 weeks (PMA). This ratio was lowest in infants with the severest degree of neurological abnormality. Proton and phosphorus MRS was compared in seven infants. In those with severe brain lesions, early phosphorus spectra were abnormal. On follow-up the phosphorus spectra became normal, but the proton spectra showed persistently low NAA/Cho and NAA/Cr ratios. Proton MRS provides new information that may be complementary to phosphorus MRS in the diagnosis and monitoring of brain development in normal and neurologically damaged infants.

Asphyxia Neonatorum↗
PubMedDate not supplied

MR imaging of anisotropically restricted diffusion in the brain of neonates and infants.

Brain MR examinations were performed on one normal and 30 abnormal neonates and infants with a variety of clinical problems using pulsed gradient spin echo (PGSE) sequences sensitized in different directions to detect changes due to anisotropically restricted diffusion of water within the brain. Anisotropically restricted diffusion was demonstrated within white matter, which appeared to be myelinated with T1-weighted inversion recovery or spin echo sequences and within white matter where the presence of myelin was not demonstrated with these sequences. Cysts and fluid collections were recognised by their low signal intensity using PGSE sequences in the subcortical regions, lentiform nuclei, and periventricular regions. An intracerebral hematoma and a subdural hematoma showed a high signal intensity with PGSE sequences consistent with isotropically restricted diffusion. Chronic infarction displayed a low signal intensity consistent with relatively free isotropic diffusion. Patients with leukodystrophy associated with congenital muscular dystrophy showed an anisotropic pattern with different components of the abnormality present on images with sensitization in different directions. The corticospinal tracts failed to show highlighting in three cases where conventional imaging was normal. In several patients with a history of birth asphyxia, asymmetry and a relative reduction in signal intensity were seen in the corticospinal tracts.

Asphyxia Neonatorum↗
PubMedDate not supplied

High signal regions in normal white matter shown by heavily T2-weighted CSF nulled IR sequences.

Inversion recovery (IR) sequences with an inversion time (TI) designed to markedly reduce or null the signal from CSF (TI of approximately 2,100 ms at 1.0 T) and a very long echo time (TE) of 240 ms were used to image the brain of two normal adult volunteers, one 34-year-old man with an intrinsic tumor, and one 3-month-old infant with an infarct. Using these very heavily T2-weighted pulse sequences, adult gray and white matter showed similar signal intensity in many areas of the brain, but normal white matter in regions of the centrum semiovale, posterior internal capsule, parietopontile tract, occipitothalamic radiation, and brain stem showed a much higher signal intensity than surrounding gray or white matter. The infant displayed a low signal intensity in myelinated regions in the internal capsule and occipitothalamic radiation and a high signal in unmyelinated white matter. In many of the images there were strong similarities to the distribution of high signal within white matter seen with pulsed gradient spin echo sequences (TE 130 ms) designed to demonstrate effects due to anisotropic diffusion. Arguments are advanced to support the view that the high signal intensity in white matter tracts is due to one or more long T2 components that may be associated with unmyelinated or sparsely myelinated fibres within white matter. The resemblance to diffusion weighted images may reflect the fact that both employ long TEs and both produce a low signal from CSF. If myelin possessed a different susceptibility from axoplasm so that magnetic field gradients were generated around nerve fibres when their orientation was not parallel to B0, diffusion of water might then produce the observed dependence on fibre direction. The high signal regions in white matter are a potential source of confusion in image interpretation, and measurements of T2 in white matter need to be made with these regional variations in mind. The concept of normal appearing white matter also needs to be applied with a knowledge of these differences. The IR sequences used in this study provide a very high T2 dependence with a low signal from CSF and may be useful for detecting disease in the CNS of adults and children.

Adult↗
PubMedDate not supplied

Inpatient health care utilization for patients with HIV and AIDS in the Edinburgh City Hospital.

A retrospective analysis of HIV-positive patients admitted to the City Hospital, Edinburgh by 31st December 1992, 7 years after the inception of the HIV clinic, revealed that 373 patients, 72% of them injection drug users (IDUs), had required 2069 admissions (5.5/admitted patient, 3.3/clinic patient or 0.5/clinic patient/year) and had utilized 21,934 bed days (59 bed days/admitted patient, 35 days/clinic patient or 5 bed days/clinic patient/year). The average length of stay (ALOS) was significantly longer for AIDS than HIV (non-AIDS) admissions (14.0 vs 9.5, P < 0.0001) as it was for admissions with a CD200 diagnosis (a CD4 count below 200 cells per mm3 on two consecutive occasions) compared to those without (12.1 vs 10.0 days, P = 0.004). There was no gender effect on ALOS but there was a significant effect of risk activity; homo/bisexuals had a significantly longer ALOS than drug users (P < 0.0001). Homo/bisexual patients with AIDS or a CD200 diagnosis had longer ALOS than drug users (15.7 vs 13 days and 15.8 vs 10.8). By 1992 each member of the clinic was on average utilizing one admission per year and 11.6 bed days per year. The number of admissions in that year for patients without a CD200 or AIDS diagnosis was however low (0.5 and 0.75 admissions/patient/year) compared to patients with an AIDS or CD200 diagnosis (2.6 and 1.6 admissions/patient/year). The annual number of occupied bed days/living patient was greatest for those with AIDS (60 vs 5 days) or with a CD200 diagnosis (23.5 vs 4.1 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗