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Biomedical subjects

C M Cooper

Publications and source records attributed to C M Cooper.

At least 37 records · Page 2Linked to original sources
PubMed1999

Suspected recurrence of malignant hyperthermia after post-extubation shivering in the intensive care unit, 18 h after tonsillectomy.

A 25-yr-old man, subsequently shown to be malignant hyperthermia (MH) susceptible by in vitro contracture testing, developed MH during anaesthesia for tonsillectomy. Prompt treatment, including dantrolene, led to rapid resolution of the metabolic crisis. Eighteen hours later the patient's trachea was extubated in the ICU, when he had been stable and apyrexial overnight. Twenty minutes after extubation, an episode of shivering was followed by the onset of tachycardia, hypertension, tachypnoea and a rapid increase in temperature. Recurrence of MH was suspected and the patient was given another dose of dantrolene with good clinical effect. Shivering in this patient may have been an indicator or a causative factor of recurrence of MH.

Adult↗
PubMed1998

Selective inhibition of factor Xa in the prothrombinase complex by the carboxyl-terminal domain of antistasin.

Studies of antistasin, a potent factor Xa inhibitor with anticoagulant properties, were performed wherein the properties of the full-length antistasin polypeptide (ATS-119) were compared with the properties of forms of antistasin truncated at residue 116 (ATS-116) and residue 112 (ATS-112). ATS-119 was 40-fold more potent than ATS-112 in prolonging the activated partial thromboplastin time (APTT), whereas ATS-119 inhibited factor Xa 2.2-fold less avidly and about 5-fold more slowly than did ATS-112. The decreased reactivity of ATS-119 suggests that the carboxyl-terminal domain of ATS-119 stabilizes an ATS conformation with a reduced reactivity toward factor Xa. The observation that calcium ion increases the reactivity of ATS-119 but not that of ATS-112 suggests that calcium ion may disrupt interactions involving the carboxyl terminus of ATS-119. Interestingly, ATS-119 inhibited factor Xa in the prothrombinase complex 2-6-fold more potently and 2-3-fold faster than ATS-112. These differences in affinity and reactivity might well account for the greater effectiveness of ATS-119 in prolonging the APTT and suggest that the carboxyl-terminal domain of ATS-119 disrupts interactions involving phospholipid, factor Va, and prothrombin in the prothrombinase complex. The peptide RPKRKLIPRLS, corresponding to the carboxyl domain of ATS-119 prolonged the APTT and inhibited prothrombinase-catalyzed processing of prothrombin, but it failed to inhibit the catalytic activity of isolated factor Xa. Thus, this novel inhibitor appears to exert its inhibitory effects at a site removed from the active site of factor Xa.

Amino Acid Sequence↗
PubMed1998

Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates.

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.

Aminopyridines↗
PubMed1998

Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position.

As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

Administration, Oral↗
PubMed1998

C6 modification of the pyridinone core of thrombin inhibitor L-374,087 as a means of enhancing its oral absorption.

1 (L-374,087) is a potent, selective, efficacious, and orally bioavailable thrombin inhibitor that contains a core 3-amino-2-pyridinone moiety. Replacement of the C6 pyridinone methyl group of 1 by a propyl group gave 5 (L-375,052), which retained all the excellent properties of 1, and also yielded higher plasma levels after oral dosing in dogs and rats.

Administration, Oral↗
PubMed1998

Toxicological evaluation of constructed wetland habitat sediments utilizing Hyalella azteca 10-day sediment toxicity test and bacterial bioluminescence.

A toxicological evaluation was conducted on wetland habitats created as a result of run-off from agricultural areas. These temporary wetlands were created by using drop pipes as a means of reducing erosional cutting in agricultural fields. Toxicity bioassays utilizing bacterial bioluminescence and Hyalella azteca were used to assess sediment pore water and whole sediment, respectively. Inhibition of bacterial bioluminescence was initially used to determine relative toxicities of pore water from ten wetland sites. Constructed wetland sites were compared to the University of Mississippi Biological Field Station, a relatively pristine reference site. The H. azteca ten day sediment toxicity test was utilized to assess sediment from four selected sites using survival and growth as toxicological endpoints. Results from the toxicological evaluation, along with extensive ecological evaluations, were used to assess the best approach for implementation of temporary wetland habitats with existing agricultural practices.

Agriculture↗
PubMed1997

Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position.

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.

Administration, Oral↗
PubMed1997

Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation.

Studies on the transmission of human (Hu) prions to transgenic (Tg) mice suggested that another molecule provisionally designated protein X participates in the formation of nascent scrapie isoform of prion protein (PrPSc). We report the identification of the site at which protein X binds to the cellular isoform of PrP (PrPC) using scrapie-infected mouse (Mo) neuroblastoma cells transfected with chimeric Hu/MoPrP genes even though protein X has not yet been isolated. Substitution of a Hu residue at position 214 or 218 prevented PrPSc formation. The side chains of these residues protrude from the same surface of the C-terminal alpha-helix and form a discontinuous epitope with residues 167 and 171 in an adjacent loop. Substitution of a basic residue at positions 167, 171, or 218 also prevented PrPSc formation: at a mechanistic level, these mutant PrPs appear to act as "dominant negatives" by binding protein X and rendering it unavailable for prion propagation. Our findings seem to explain the protective effects of basic polymorphic residues in PrP of humans and sheep and suggest therapeutic and prophylactic approaches to prion diseases.

Animals↗
PubMed1997

Enzyme-linked immunosorbent assay for the detection of Cryptosporidium parvum IgG in the serum of cats.

The objective was to develop an enzyme-linked immunosorbent assay (ELISA) for the detection of Cryptosporidium parvum IgG in the serum of cats. The ELISA was an indirect ELISA using soluble C. parvum oocyst antigens and a peroxidase-labeled anti-feline IgG secondary antibody. Sera from cats with Toxocara felis, Giardia spp., Aelurostrongylus abstrusus, Isospora felis, Isospora rivolta, Toxoplasma gondii, or Taenia spp. infections were assayed in specificity studies. Following optimization, the ELISA and fecal examination for oocysts were performed on samples from 170 client-owned or humane society source cats and 1 cat inoculated orally with C. parvum oocysts. Cryptosporidium parvum oocysts were detected in feces (4/170; 2.4%), and C. parvum IgG was detected in serum (26/170; 15.3%) from naturally exposed cats. The seroprevalence data suggest that some cats in the geographical area studied were exposed to C. parvum, but persistent oocyst shedding was less common. The ELISA is not useful for predicting oocyst shedding in individual cats.

Animals↗
PubMed1996

Feline ocular and cerebrospinal fluid Toxoplasma gondii-specific humoral immune responses following specific and nonspecific immune stimulation.

Toxoplasma gondii-naive cats and cats previously infected orally with T. gondii tissue cysts were inoculated with soluble tachyzoite antigens plus adjuvant or adjuvant alone. Toxoplasma gondii-specific IgM and IgG were measured in serum, aqueous humor, and cerebrospinal fluid (CSF). The Goldman-Witmer coefficient (C value) for ocular or central nervous system (CNS) antibody production was calculated for aqueous humor or CSF samples positive for T. gondii-specific antibodies. Following inoculation with adjuvant plus soluble tachyzoite antigens, ocular and CNS T. gondii-specific IgG C values increased in the three previously infected cats. Following inoculation with adjuvant, the two previously infected cats had increases in ocular and CNS T. gondii-specific IgG C values. Ocular (2/3 cats) or CNS (1/3 cats) T. gondii-specific IgG C values of over 1 were detected in some T. gondii-naive cats following inoculation with adjuvant plus soluble tachyzoite antigens. The results of this study suggest that T. gondii-specific IgG C values of over 1 in aqueous humor or CSF do not prove active ocular or CNS infection in all cats.

Adjuvants, Immunologic↗
PubMed1996

Toxoplasma gondii antigen recognition by serum immunoglobulins M, G, and A of queens and their neonatally infected kittens.

OBJECTIVE: To evaluate antigen recognition patterns of serum IgM, IgG, and IgA from queens and their kittens as a method of diagnosing neonatal toxoplasmosis. ANIMALS: 5 pregnant queens were inoculated orally with Toxoplasma gondii tissue cysts during gestation (18 to 44 days). On various days after parturition (0 to 97), serum was obtained from queens and kittens (n = 19). PROCEDURE: Tissues from most kittens were assessed for T gondii infection by bioassay in mice. Serum samples were evaluated by IgM, IgG, and IgA western blot immunoassays for the presence of T gondii antibodies. Antigens recognized by kitten serum samples, but not by the corresponding queen serum sample, were considered to indicate neonatal infection with T gondii. RESULTS: Using the results of western blot immunoassay, 8 of 19 kittens (age, 2 to 97 days) were determined to be infected with T gondii. Western blot immunoassay results correlated well with bioassay results, identifying 7 of 8 bioassay-positive kittens. Western blot immuno-assay additionally identified 1 kitten as infected, but tissues from the kitten had not been bioassayed. In each of the 5 kittens that developed clinical signs of toxoplasmosis, the diagnosis of neonatal toxoplasmosis was supported by results of the western blot immunoassays. CONCLUSION AND CLINICAL RELEVANCE: Comparison of queen and kitten T gondii antigen recognition patterns of IgM, IgG, and IgA can be used for antemortem diagnosis of neonatal toxoplasmosis.

Animals↗
PubMed1995

Health promotion in human immunodeficiency virus-infected patients through psychosocial interventions.

The extreme fear, prejudice, and stigmatization associated with human immunodeficiency virus disease make the acquired immune deficiency syndrome epidemic a unique phenomenon of the modern era. A fundamental understanding of the phychosocial issues surrounding the disease is essential, if nurses are to design interventions that promote optimal health among those infected and those at risk for infection.

HIV Infections↗
PubMed1994

Homozygosity for prion protein alleles encoding glutamine-171 renders sheep susceptible to natural scrapie.

Natural scrapie has been viewed both as a recessive trait and as a contagious disease modulated by a host locus. To address this conundrum, we determined the structure of the sheep prion protein (PrP) gene, which contains three exons and extends over 20 kb of DNA. In the United States 86.4% of scrapie cases occur in Suffolk sheep, and within this breed 49 +/- 6% (+/- S.D., n = 69) of healthy animals carry one or more PrP alleles encoding Arg (R)-171. Four scrapie-affected sheep were homozygous for wild-type PrP open reading frames encoding the alternative Gln (Q)-171 allele. Analysis of additional cases revealed that all were Q/Q-171 homozygotes (n = 31), yielding a probability of 0.000004 that PrP genotype is unrelated to susceptibility. These data imply that homozygosity for Q-171 codons is necessary but not sufficient for the development of natural scrapie, echo reports of recessive manifestation, and parallel over-representation of PRNP codon 129 homozygotes in Creutzfeldt-Jakob disease of humans. Whereas progress has been substantial regarding experimental scrapie in rodents, the occurrence and spread of disease in flocks of sheep has remained enigmatic. Appreciation of the relationship between codon 171 genotype and susceptibility may help define the molecular basis of natural scrapie.

Alleles↗
PubMed1994

Toxoplasma gondii-specific antibodies in the aqueous humor of cats with toxoplasmosis.

We decided to determine whether Toxoplasma gondii-specific IgM or IgG is produced locally or is deposited in the aqueous humor of T gondii-naive cats after primary or secondary inoculation with T gondii. Cats were orally inoculated with T gondii tissue cysts during weeks 0 and 36. Aqueous humor and serum T gondii-specific IgM and IgG were measured, using ELISA, during weeks 0, 2, 4, 6, 8, 12, 16, 20, 26, 34, 38, 40, 42, 44, 48, 56, 62, 66, and 72 after primary oral inoculation. Total immunoglobulin-based Goldmann-Witmer coefficients were calculated to verify intraocular antibody production. Toxoplasma gondii-specific IgM was not detected in the aqueous humor of any cat. Data indicate that cats have transient local production of T gondii-specific IgG in the aqueous humor after primary and secondary oral inoculations with T gondii tissue cysts. The intraocular immune response to systemic T gondii infection may signal ocular recruitment of antigen-specific lymphocytes that function independently from the general humoral response to T gondii infection. Cautious interpretation of results that suggest intraocular production of T gondii-specific IgG in cats with uveitis is warranted.

Animals↗
PubMed1992

Cutaneous cryptococcosis: recurrence following oral fluconazole treatment.

A case of recurrent cutaneous cryptococcosis in an immunocompromised patient is described. The patient presented with a non-healing cutaneous ulcer due to infection with Cryptococcus neoformans. Extensive investigation failed to reveal any evidence of associated systemic cryptococcosis. Treatment with oral fluconazole resulted in complete resolution of the ulcer but after several months a second cutaneous cryptococcal lesion appeared, strongly suggesting dissemination from an underlying systemic focus. This case illustrates the hazards associated with making a diagnosis of isolated cutaneous cryptococcosis and the necessity for prolonged follow-up of patients who present in this way.

Administration, Oral↗
PubMed1991

Serum F-protein concentration following halothane or isoflurane anaesthesia.

We have investigated the prevalence of hepatic injury following uncomplicated anaesthesia using a sensitive and specific marker of hepatic damage, the serum F-protein concentration. The median variation in serum F-protein in fit adults over six days is 16 ng/ml, minimum 0 ng/ml, maximum 36 ng/ml. A significant rise in serum F-protein was demonstrated six days following anaesthesia and surgery, but not earlier after 3 or 24 h. There was no significant difference between patients who received halothane (n = 12) or isoflurane (n = 13). These changes were not related to duration of anaesthesia, quantity of delivered volatile agent or mode of ventilation. Hepatocellular damage may occur following anaesthesia for minor surgery.

Adult↗
PubMed1989

Multicenter evaluation of TDx test for assessing fetal lung maturity.

"TDx Fetal Lung Maturity," an automated assay that measures the relative concentrations of surfactant and albumin in amniotic fluid, was compared with the lecithin/sphingomyelin (L/S) ratio and phosphatidylglycerol determination at five clinical sites. A total of 695 amniotic fluid samples were analyzed, of which 312 were followed by delivery of the infant within three days of sample collection. Of these 312, 24 developed respiratory distress syndrome and seven developed transient tachypnea. With the cutoff for maturity set at a surfactant/albumin value of 50 mg/g, the assay showed a sensitivity of 0.96 and a specificity of 0.88 for all samples, compared with a sensitivity of 0.96 and a specificity of 0.83 for the L/S ratio. The combination of rapid assay (30 min), accurate results, and uniformity among testing centers makes the TDx assay a very promising method.

Albumins↗