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Biomedical subjects

W Ryan

Publications and source records attributed to W Ryan.

At least 19 recordsLinked to original sources
PubMed2005

Trismus: or is it tetanus? A report of a case.

Tetanus is a life-threatening infection that is rare in the developed world. Trismus and dysphagia are the most common presenting symptoms, and thus oral and maxillofacial surgeons may be involved in the early stages of evaluation of the patient. Early diagnosis helps initiate prompt management and referral for intensive therapy. This article is a case report of severe generalized tetanus with a discussion of its diagnosis, pathophysiology, and management.

Amputation, Surgical↗
PubMed2002

Evaluation of therapeutic effectiveness using MR imaging in a rabbit model of anterior uveitis.

Magnetic resonance imaging (MRI) has been used to examine conditions that alter the permeability of the blood-retinal barrier. Our goal was to determine if blood-aqueous barrier permeability could be similarly assessed, because MRI offers the theoretical advantage of providing quantitative data directly from inflamed uveal tissues rather than from the aqueous humor into which the inflammatory reaction spills. As an additional challenge, we sought to use MRI to measure differences between the inflamed uveal tissues of corticosteroid-treated and placebo-treated uveitic eyes. Anterior uveitis was induced in one eye of eight rabbits by subcutaneous injection of Mycobacterium tuberculosis, followed after 10 days with intravitreal challenge. One rabbit of each pair was treated with topical 1% prednisolone acetate while control rabbits were treated with artificial tears. Contrast-enhanced MRI studies were performed prior to uveitis induction, one day after induction and then weekly for at least 2 weeks. MR image data were analyzed to determine percent change in peak enhancement of the ciliary body and anterior chamber. The initial rate of change of enhancement of the anterior chamber was also measured. Extensive contrast agent-induced MR image enhancement of both the anterior chamber and the ciliary processes was measured following the induction of uveitis. More rapid improvement was measured for the 1% prednisolone acetate-treated rabbit eyes (P < 0.001). MR signal enhancement data obtained from the ciliary processes proved to be the most reliable indicator of disease activity in this rabbit model of uveitis. Such data can only be obtained using MRI.

Animals↗
PubMed2000

Comprehensive review of the psychiatric uses of valproate.

The therapeutic effects of valproate in psychiatric conditions are most substantially recognized in bipolar disorder. However, this well-tolerated medication may be beneficial in the treatment of other mental illnesses. In this article, the authors comprehensively review studies of valproate as treatment for psychiatric conditions, including bipolar, depressive, anxiety, and psychotic disorders; alcohol withdrawal and dependence; tardive dyskinesia; agitation associated with dementia; and borderline personality disorder. Valproate shows the most promising efficacy in treating mood and anxiety disorders, with possible efficacy in the treatment of agitation and impulsive aggression, and less convincing therapeutic response in treating psychosis and alcohol withdrawal or dependence. The authors conclude with a brief summary of its mechanism of action and therapeutic spectrum.

Anticonvulsants↗
PubMed1998

Clinical symptom presentation in suspected malingerers: an empirical investigation.

To empirically investigate the usefulness and validity of clinical presentation and recent history variables in the detection of malingered psychiatric disorder, 30 criminal defendants involved in forensic evaluations, who had a documented history of psychiatric hospitalization preceding their arrest on the instant offense (low risk of malingering group) and 30 defendants who complained of psychiatric difficulties but had no history of psychiatric hospitalization or treatment (suspected malingering group) were studied. Each subject's mental status was rated, blind to psychiatric history, diagnosis, and psycholegal opinions, on a Likert-like scale for the uncommon nature of their symptom presentation. In addition, the final outcome of the court cases, whether they were found competent to stand trial, not guilty by reason of insanity, or evidenced diminished capacity was determined by obtaining the court disposition in each case. Based on the unusual nature of their presentation, the defendants suspected of malingering were discriminated from the low risk of malingering defendants with a 90 percent rate of correct classification. Suspected malingerers were found to evidence current psychiatric presentations inconsistent with their recent Global Assessment of Functioning, unusual symptom presentation, and hallucinatory experiences rated as atypical for psychiatric disorder. A high proportion of suspected malingerers were found competent to proceed. The results are discussed in terms of the usefulness of clinical identification of malingering.

Adult↗
PubMed1997

Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs).

Several novel 4-alkyloxy-aminoalkyl indole derivatives 3 were synthesized from 4-benzyloxyindole (1). Alkylation of 1 with 4-(2-chloroethyl)morpholine (NaH/HMPA) formed 2. Deprotection using palladium hydroxide on carbon/hydrogen followed by alkylation with the appropriate alkyl bromide gave the target compounds 3b-3j. In the synthesis of 3i and 3j, the appropriate alkyl bromides 13 and 17 were prepared from the commercially available 1-naphthylethyl bromide 9 using the chain lengthening sequences as shown in Scheme 3. In receptor binding assay and in vivo testing, the long chain alkoxy compounds 3g and 3h (Ki = 127 nM) showed affinity for the CB1 receptor which was approximately 16-35-fold less than that of WIN 55,225. However, the pharmacological profile of 3h mimics that of WIN 55,212. An examination of the SAR of these analogues shows that translocating the napthyl group in AAIs from the C-3 position to C-4 via an oxygen (ether linkage) decreases activity which is in contrast to previous findings that a naphthylcarbonyl at C-4 retains activity. The present work points to the importance of the role of a keto group in the interaction with the receptor. Molecular modeling work suggests that, although reasonable superposition of key structural features between delta 9-THC and AAIs can be made, the overlay is not straightforward. The present study also illustrates the difficulty in accommodating AAIs into the cannabinoid pharmacophore and it seems likely that a unique pharmacophore will need to be developed. Only then will the similarities to and differences from the classical cannabinoid pharmacophore be clearly delineated.

Analgesics↗
PubMed1996

Agonist-antagonist characterization of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol in two isolated tissue preparations.

This investigation was directed at characterizing some of the pharmacological properties of 6'-cyanohex-2'-yne-delta 8-tetrahydrocannabinol (O-823), a compound with high affinity for cannabinoid binding sites (Ki = 0.77 nM). In mouse vasa deferentia, O-823 behaved as a potent partial cannabinoid CB1 receptor agonist (EC50 = 0.015 nM). In the guinea-pig myenteric plexus preparation, it antagonized WIN 55.212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholino)methyl]pyrrolo-[1,2,3-de ]-1, 4-benzoxazin-6-yl](1-naphthyl)methanone] and CP 55.940 [(-)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl ) cyclohexan-1-ol] with Kd values of 0.65 and 0.27 nM, respectively. After in vivo delta 9-tetrahydrocannabinol pretreatment. the sensitivity of vasa deferentia to O-823-induced inhibition of electrically evoked contractions was reduced by 127-fold. 3.162 nM O-823 was inhibitory in unpretreated vasa deferentia but antagonized CP 55,940 in pretreated tissues (Kd = 0.26 nM). O-823 is probably an antagonist in the myenteric plexus preparation and delta 9-tetrahydro-cannabinol pretreated vasa deferentia but a partial agonist in unpretreated vasa deferentia because the first two of these preparations contain fewer receptors than the third.

Analgesics↗
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↗