PubMed Health⌕ Search

Biomedical subjects

W Ryan

Publications and source records attributed to W Ryan.

At least 19 recordsLinked to original sources
PubMed1995

A novel class of potent tetrahydrocannabinols (THCS): 2'-yne-delta 8- and delta 9-THCS.

A series of 3-alkyl-2'-yne (side chain) acetylenic analogs of delta 9-THC were synthesized and evaluated for in vitro and in vivo activity. Analogs were evaluated for receptor affinity in a [3H]CP-55,940 displacement assay and for in vivo pharmacological activity in a mouse procedure utilizing a tetrad of measures. These compounds represent a preliminary exploration of the consequences of restricting the flexibility of the side chain regarding cannabimimetic activity. All analogs proved to have receptor affinities (4-11 nM) that were five to ten times greater than that observed for delta 9-THC. However, the in vivo activities of these compounds varied greatly. All analogs proved to possess the greatest potency for production of antinociception, with activity similar to or less than that observed for the production of hypomotility, hypothermia, and catalepsy. The most potent analog 11b exhibited an ED50 of 0.031 mg/kg in the tail-flick procedure, with values in other measures being between 0.5 and 1.0 mg/kg. The least active compound (11c), though still possessing a KI of 11 nM, exhibited ED50 values of 3.1 and 9.3 mg/kg for tail-flick and temperature procedures, as well as 41 and 48 mg/kg for ring-immobility and spontaneous locomotor activity, respectively. This profile (high receptor affinity but low in vivo potency) would normally be suggestive of a compound with antagonist properties (at least for immobility and activity measures). It is unclear why these acetylenic analogs were so potent in vitro, while only one (11b) exhibited the degree of in vivo potency anticipated based upon comparison to values for delta 9-THC. It is possible these side chain modifications do not interfere with receptor recognition, but limit receptor activation or second messenger signal transduction. Regardless, it is clear these novel analogs provide a basis for the further exploration of the cannabinoid receptor pharmacophore.

Analgesics↗
PubMed1995

Pharmacological and behavioral evaluation of alkylated anandamide analogs.

Anandamide (arachidonylethanolamide), isolated from porcine brain, has been shown to bind to the cannabinoid receptor and also to produce cannabimimetic activity in pharmacological assays. This study examined structure-activity relationships in alkylated anandamide analogs. The analogs were evaluated for their ability to displace [3H]CP-55,940 in a filtration binding assay using rat brain membranes in the presence and absence of the enzyme inhibitor phenylmethylsulfonyl fluoride (PMSF). Behavioral activity was assessed by the ability of the analogs to produce hypomotility and antinociception. Methylations at carbons 2 and 1 produced compounds stable in the absence of PMSF with similar affinities and behavioral activity as anandamide. Addition of larger alkyl groups at these positions or nitrogen methylation reduced receptor affinity and behavioral potency. These results indicate that methylations at specific carbons of anandamide confer stability in vitro.

Alkylation↗
PubMed1995

Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs.

Recent evidence implicates anandamide as the endogenous ligand for the cannabinoid receptor. One purpose of this study was to determine the structural requirements for anandamide's receptor interaction and the influence of phenylmethylsulfonyl fluoride (PMSF), an enzyme inhibitor, on receptor affinity. A second objective was evaluation of the correlation between affinities of the analogs and in vivo pharmacological activities. The ability of anandamide and analogs to displace [3H]CP-55,940 ([3](-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3- hydroxylpropyl]cyclohexan-1-ol) was determined by a filtration assay. Displacement curves for anandamide in the presence of PMSF produced a Ki of 89 +/- 10 nM; without PMSF the Ki increased to 5400 +/- 1600 nM. Anandamide analogs were evaluated for their ability to produce antinociception and hypomotility. The levels of saturation of the anandamide structure were critical to receptor affinity and in vivo potency, with complete saturation and hydroxyl substitution with a fluorine moiety resulting in a compound with increased potency in the spontaneous activity and antinociception assays. Substitution of the hydroxyl with a fluorine atom increased affinity only in the presence of PMSF and reduced potency in the antinociception assay. Ethanolamide substitution with bromobenzenesulfonamide produced an inactive compound in all assays. Increasing the length of the N-substituent by one or two carbons decreased receptor binding affinity and potency in the tail-flick assay only. Certain structural modifications, such as methylations, allowed the analogs to retain affinity without the addition of PMSF. Linear correlation between the behavioral and binding assays were performed, and the greatest correlation was obtained with compounds that were either very potent or inactive.

Animals↗
PubMed1994

Characteristics of a two-site immunoradiometric assay for human skeletal alkaline phosphatase in serum.

This two-site IRMA includes specific monoclonal antibodies for measuring skeletal alkaline phosphatase (B-ALP) in human serum. Assay calibration is based on mass units (micrograms per liter) and was established with purified B-ALP from a human osteosarcoma cell line, SAOS-2. Precision studies demonstrated intra- and interassay CVs of 3-5% and 5-7%, respectively. Relative reactivity studies showed that the assay has a sevenfold preference for detecting B-ALP compared with the liver isoenzyme in serum. The normal reference interval for 478 healthy adults was 5-22 micrograms/L. Method comparison studies showed good correlation between this B-ALP assay (y) and commercially available electrophoretic methods (x) (y = 0.3540x + 20.5, R2 = 0.929) in a pagetic population. Temporal profiles for total ALP, this IRMA B-ALP assay, and B-ALP by electrophoresis in three pagetic patients were parallel. We conclude that this assay demonstrates good analytical performance and would be useful for the clinical assessment of metabolic bone disorders.

Adult↗
PubMed1992

Complications of metalwork removal.

A total of 188 patients who had metalwork removed were reviewed. There was an overall 20 per cent complication rate. The highest complication rate of 42 per cent was seen with forearm fractures. Infection was the most common complication, and was particularly high in those fractures which were originally open (43 per cent) and where infection developed after the initial internal fixation (32 per cent). We suggest using prophylactic antibiotics for these two groups. All nerve injuries were permanent and were produced by junior surgeons.

Adolescent↗
PubMed1990

Variation of oxygen requirement with plasmid size in recombinant Escherichia coli.

We have previously found an inverse relationship between certain cell growth parameters and plasmid size for a series of recombinant Escherichia coli strains containing pUC8 or one of a series of pUC8 recombinant derivatives. To extend these results we investigated whether there was a similar variation among our strains in oxygen requirement, which might be related to the differences in growth. During logarithmic growth in shake flasks, oxygen uptake by E. coli strain JM103 containing an 8.7-kb pUC8 derivative (pBS5) was 2.5 times that of JM103 harboring pUC8 (2.7 kb) and 7.5 times that of plasmid-free JM103. Supplementing the medium with acetate eliminated both the growth disadvantage of and the increased oxygen uptake by the strain harboring pBS5 compared with that containing pUC8. In all cases oxygen consumption decreased drastically as cells began and then continued into stationary phase, and no significant difference was seen among the three strains at these times. When the three strains were grown in a fermentor with continuous monitoring of oxygen levels, plasmid-free JM103 outgrew JM103 containing pUC8 or pBS5 at three levels of aeration. The latter two strains grew identically when aeration was high; their growth curves diverged, however, when aeration was low. In the fermentor experiments the point at which the growth of the three strains diverged was coincident with the point of oxygen depletion in the cultures.

Escherichia coli↗
PubMed1990

Effects of tamoxifen treatment on plasma lipids and lipoprotein lipid composition.

Concern has been raised that long term treatment with the antiestrogen tamoxifen might predispose women to the rapid development of cardiovascular disease. Since estrogen-induced changes in plasma lipids confer protection to females from coronary heart disease, we have examined the impact of tamoxifen on lipoprotein levels and composition on eight posmenopausal women. After 3 months of tamoxifen treatment (10 mg, twice daily), no significant changes were observed in either whole plasma triglyceride (pre-Rx, 137 +/- 59; post-Rx, 157 +/- 110 mg/dL) or cholesterol (pre-Rx, 193 +/- 23; post-Rx, 204 +/- 14 mg/dL); plasma free (unesterified) cholesterol (FC), however, fell significantly (pre-Rx, 66.5 +/- 6.5; post-Rx, 59.6 +/- 4.6 mg/dL; P less than 0.05). Since plasma lecithin (L) was unchanged, the FC/L ratio declined significantly to levels observed in healthy menstruating women (pre-Rx, 95 +/- 0.16; post-Rx, 0.74 +/- 0.12 molar ratio; P less than 0.025). In low density lipoprotein (LDL), the concentrations of cholesterol and FC and the FC/L ratio all fell significantly (P less than 0.025, P less than 0.05, and P less than 0.025, respectively). Despite a tendency for high density lipoprotein2 cholesterol (HDL2-C) to increase (pre-Rx, 9.7 +/- 3.6; post-Rx, and 14.4 +/- 13.3 mg/dL; P less than 0.4) and phosphoinositol to fall, there were few clear-cut alterations in either HDL2 or HDL3 surface or core lipid composition. The combination of reduced HDL3 lysolecithin (P less than 0.025) associated with a posttreatment trend toward increased triglyceride/cholesterol esters ratios in both HDL subfractions are findings consistent with tamoxifen-induced inhibition of hepatic lipase. These changes in lipoprotein composition together with the fall in LDL cholesterol and increase in sex hormone-binding globulin (P less than 0.005) indicate that tamoxifen acts as an estrogen agonist on the liver. Since elevated LDL cholesterol levels and qualitatively altered lipoproteins enriched in FC are both associated with increased coronary risk, the improvement noted in these parameters after tamoxifen should allay to some degree anxiety about its use with regard to cardiovascular risk.

Cholesterol, HDL↗
PubMed1989

Evaluation of factors affecting the performance of enzymatic SPan-1 immunoassays for pancreatic cancer.

An avidin-biotin complex (ABC) sandwich enzymatic immunoassay was developed utilizing SPan-1, a murine monoclonal antibody of the IgM isotype. Biotin was attached to the epsilon-amino group of lysines of SPan-1 using biotin-N-hydroxysuccinimide esters with or without a spacer (aminohexane). Addition of biotin to carbohydrates was with biotin hydrazide after periodate oxidation of the immunoglobulin. The resultant assays were compared to a sandwich radioimmunoassay and to another form of the SPan-1 enzymatic immunoassay in which oxidized horseradish peroxidase had been directly conjugated to SPan-1. Comparable antigen detection limits were obtained regardless of whether biotin was added to the peptide or carbohydrates or whether a spacer was used or not. The ABC assay had approximately the same SPan-1 antigen detection limit as the radioimmunoassay. 90.6% of the human pancreatic cancer sera tested positive in the ABC assay as compared to a previously reported 93% positive rate with a radioimmunoassay.

Antibodies, Monoclonal↗
PubMed1988

Mucin-like antigens in a human pancreatic cancer cell line identified by murine monoclonal antibodies SPan-1 and YPan-1.

The antigenic determinant recognized by monoclonal antibody SPan-1 is greatly elevated in sera of patients with pancreatic cancer but not in sera of normal individuals. Here we describe the mucin-like characteristics of the SPan-1 antigen isolated from culture medium and xenografts of the human pancreatic cancer cell line SW-1990. YPan-1, another pancreatic cancer associated monoclonal antibody, also reacts with the SPan-1 antigen. The SPan-1/YPan-1 antigens have densities of 1.4-1.5 g/ml and elute in the void volume of Sepharose CL-2B columns. They are resistant to degradation by chondroitinase ABC, nitrous acid, and hyaluronidase but susceptible to protease digestion and reductive beta-elimination. All these characteristics suggest that the SPan-1 and YPan-1 determinants are carried on mucinous antigens. Both SPan-1 and YPan-1 immunoreactivities are unaffected by boiling or by alkylation and reduction of the mucins while they are abolished by mild periodate oxidation or neuraminidase and are markedly decreased by wheat germ agglutinin. Thus, their antigenic determinants are composed principally of carbohydrates with sialic acid, an absolute requirement for reactivity. However, the epitope specificities of SPan-1 and YPan-1 are different since YPan-1 does not compete with SPan-1 for binding to antigen. Moreover, YPan-1 and SPan-1 can be distinguished from several other sialic acid requiring, cancer associated antibodies such as B72.3, CSLEX-1, DU-PAN-2, OC-125, and 19-9 by either their epitope characteristics or their tissue reactivity patterns.

Animals↗
PubMed1988

A district general hospital experience of surgical treatment of gastric and duodenal ulcer from 1970 to 1982.

Seven hundred and thirteen patients who had undergone 793 operations for peptic ulcer disease during the years 1970 to 1982 were subsequently referred to a gastric follow-up clinic. The indications for initial elective surgical treatment (514) were failed medical management (448), recent hemorrhage (32) and obstruction of gastric outflow (34); for initial emergency surgical treatment (199), the indications were hemorrhage (97) and perforation (102). Reoperation was required in 80 patients-previous perforation (40), recurrent ulcer (32), reperforation (three), hemorrhage (three) and obstruction of gastric outflow (two). The over-all postoperative mortality rate was 4.2 per cent (33 of 713); 15 deaths occurred after elective surgical treatment (2.5 per cent) and 18 after emergency surgical treatment (8.6 per cent). The postoperative morbidity expressed in terms of duration of postoperative stay was unaltered for each procedure throughout the study period. Follow-up attendance rates at one, three, five and ten years were 86, 85, 74 and 28 per cent, respectively. Iron deficiency anemia was detected in 13.6 per cent of gastric resection procedures and 1.6 per cent of vagotomy and drainage procedures. No instances of macrocytic anemia and only two instances of asymptomatic metabolic bone disease were recorded. By providing accurate data for surgical audit, which suggested that screening for metabolic sequelae in the first decade after surgical treatment is not indicated and which resulted in alteration of policy toward peptic ulcer perforation, a specific follow-up clinic has proved valuable in formulating the over-all management policy regarding surgical treatment for peptic ulcer.

Adult↗
PubMed1986

Metabolic emergencies in cancer medicine.

This article describes the many metabolic complications encountered in the management of cancer patients. Pathogenetic mechanisms and therapy are discussed, with special emphasis on hypercalcemia, the most common of these disorders.

ACTH Syndrome, Ectopic↗
PubMed1986

Duodenal ulcer perforation: the effect of H2 antagonists?

One hundred and two patients with perforated duodenal ulcers over a 13 year period (1970 to 1982) have been prospectively followed-up at a special gastric clinic. Of the 37 patients with perforation of their acute ulcer, 34 were treated by oversew and three had an initial definitive operation (vagotomy and drainage). The remaining 65 patients presented with perforation of a chronic ulcer and 54 were treated by oversew and 11 underwent definitive surgery--nine had vagotomy and drainage and two had partial gastrectomies. Seven of the 34 patients (20.5%) with acute ulcer perforation treated by simple oversew subsequently required definitive ulcer surgery at a mean 17.5 months after perforation and 31 of the 54 patients (57.4%) with chronic ulcer perforations required definitive surgery at a mean 27.4 months after perforation. The introduction of H2 antagonists in 1977 did not alter the re-operation rate in patients with chronic ulcer perforation managed by oversew. Results of this study provide further evidence in favour of treating patients with perforation of their chronic duodenal ulcer by definitive surgery whenever possible.

Acute Disease↗
PubMed1985

The effect of alcohol intoxication on inflammation of the cornea.

New Zealand albino rabbits received daily intraperitoneal injections of alcohol (ethyl alcohol), 1.6 g/kg and the effect of short-term (three days) and long-term (six weeks) administration on corneal inflammation was studied. Both regimens produced an average peak serum concentration of more than 0.200 g/dL, a level consistent with gross intoxication in the majority of humans. Clinical signs of intoxication were present in all animals, manifested by a gross disturbance of equilibrium and gait. Neither regimen produced measurable liver damage. Nonetheless, following both regimens of alcohol administration, significantly fewer polymorphonuclear leukocytes invaded the corneas of animals receiving alcohol than invaded the corneas of simultaneously run controls receiving intraperitoneal saline. These data provide a mechanism to explain why an alcoholic individual might not cope with a corneal infection as well as a nonalcoholic person, an observation long thought to be true clinically.

Alcoholic Intoxication↗
PubMed1985

A prospective randomised controlled trial of mezlocillin versus netilmicin in biliary surgery.

A prospective randomised controlled trial of mezlocillin versus netilmicin in 133 patients undergoing biliary surgery at a district hospital is reported. Sixty-four patients received mezlocillin and 69 received netilmicin. The two groups of patients were comparable with regard to age, sex, underlying pathology and operative procedures performed. The incidence of infected bile at operation was 14.2% and both antibiotics were equally effective in reducing postoperative bacteraemia (0.75%) and wound infection (4.5%) to acceptable levels. It is concluded that netilmicin is a more cost-effective antibiotic in biliary surgery than mezlocillin.

Aged↗
PubMed1984

Thalamic kindling: electrical stimulation of the lateral geniculate nucleus produces photosensitive grand mal seizures.

Kindling is traditionally viewed as a chronic, focal epilepsy model which consistently induces complex partial seizures from limbic structures in animals. This study revealed that primary or exceedingly rapid secondary generalized seizures could also be kindled when stimulation was applied to the lateral geniculate nucleus, a thalamic region involved in sleep regulation and possibly also photosensitive epilepsy. Two experiments were conducted in cats. Experiment 1 compared the development of generalized tonic-clonic convulsions and associated sleep disorders following electrical stimulation of the lateral geniculate nucleus (N = 4) and the amygdala (N = 4). Experiment 2 described the effects of intermittent light stimulation on seizure thresholds in both groups. Three primary findings distinguished the epileptogenic process in those two brain regions. First, generalized electroencephalographic and clinical seizures accompanied the first afterdischarge obtained with thalamic stimulation. In contrast, focal seizures with secondary generalization appeared during a 3- to 4-week period of afterdischarge elicitations from the amygdala. Second, amygdala-kindled cats showed fewer sleep spindles during slow-wave sleep whereas cats kindled in the lateral geniculate nucleus had abnormal sleep spindles approaching spike wave-like activity. Third, only the latter cats showed reduced seizure thresholds in response to photic stimulation. Based on the anatomic substrates involved, the clinical and electrographic profiles observed during kindling and the type of sleep disturbance shown, we concluded that lateral geniculate nucleus kindling may represent primary generalized epilepsy, possibly of a photosensitive nature; alternatively, the rapid propagation of abnormal discharge was also consistent with the important role of the thalamus in secondary seizure generalization.

Amygdala↗
PubMed1982

Penetrating injuries of the Iliac vessels. Early recognition and management.

Exsanguination due to hemorrhage caused death in 18 percent of patients with penetrating iliac vessel trauma. Improved survival demands earlier recognition and expedient operative control. One hundred fourteen patients were treated at a single institution during an 11 year period. Gunshot wounds were the predominant cause of injury and combined arteriovenous injury was present in 40 percent of the patients. Twenty-one of the 28 deaths were directly related to vascular injury. All deaths occurred in patients who were initially hypotensive. Seventy-six percent of patients presented with entry wounds below the umbilicus, positive abdominal examination, and hypotension. Earlier recognition is based on this triad. Failure to respond to volume repletion portends a grave prognosis, but it is often reversed by rapid operative intervention. All hypotensive patients with entry wounds below the umbilicus and positive abdominal examination should be taken immediately to the operating room for resuscitation and operation.

Humans↗