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Biomedical subjects

R A Nugent

Publications and source records attributed to R A Nugent.

At least 19 recordsLinked to original sources
PubMed1998

Pyrimidine thioethers: a novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-resistant HIV.

A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.

Amino Acid Substitution↗
PubMed1998

Anti-inflammatory/antiarthritic ketonic bisphosphonic acid esters.

Bisphosphonate ester 2 is an inhibitor of inflammation, but is devoid of antiarthritic effects. SAR studies on a series of related bisphosphonate esters resulted in compounds 6e, 6i, 6j, and 6m, which exhibited excellent inhibition of an arthritis model, in addition to potent anti-inflammatory effects.

Animals↗
PubMed1997

In vivo measurement of T2 distributions and water contents in normal human brain.

Using a 32-echo imaging pulse sequence, T2 relaxation decay curves were acquired from five white- and six gray-matter brain structures outlined in 12 normal volunteers. The water contents of white and gray matter were 0.71 (0.01) and 0.83 (0.03) g/ml, respectively. All white-matter structures had significantly higher myelin water percentages (signal percentage with T2 between 10 and 50 ms) than all gray-matter structures. The range in geometric mean T2 of the main peak for both white and gray matter was from 70 to 86 ms. T2 distributions from the posterior internal capsules and splenium of the corpus callosum were significantly wider (width is related to water environment inhomogeneity) than those from any other white- or gray-matter structures. Thus, quantitative measurement and analysis of T2 relaxation reveals differences in brain tissue water environments not discernible on conventional MR images. These differences may make short T2 components reliable markers for normal myelin.

Adult↗
PubMed1997

Circulating insulin-like growth factor I, insulin-like growth factor binding proteins, growth hormone, and resumption of estrus in postpartum cows subjected to dietary energy restriction.

The objective of this study was to determine whether serum concentrations of growth hormone (GH), IGF-I, IGF binding proteins (IGFBP), and glucose at wk 2 and 10 postpartum were associated with the ability of postpartum beef cows to resume cycling when maintained on a limited nutrient environment. Cows (n = 29) were individually fed either 130 or 170 kcal ME x BW-75 x d-1 during nonlactation and 170 or 210 kcal ME x BW-75 x d-1 during lactation for an average of 4.1 yr before sample collection. The proportion of cows that resumed estrus within 20 wk after parturition was less (P < .05) at the lower feeding rate (5 of 14) than at the higher feeding rate (11 of 15). Concentrations of IGF-I increased from wk 2 to 10 in cows that resumed cycling but not in cows that remained anestrous and were less (P < .05) at wk 2 and 10 in cows that remained anestrous compared to cows that resumed cycling. Circulating amounts of IGFBP-2 at wk 2 were greater (P < .05) and IGFBP-3 concentrations were lower (P < .05) in cows that remained anestrous compared to cows that resumed cycling. Cows on the lower feeding rate that did not cycle had lower body condition scores and greater concentrations of GH compared (P < .05) to other cows. At the higher feeding rate, body condition score and concentrations of GH did not differ between cows that did or did not resume cycling. Circulating concentrations of IGF-I and IGFBP-2 and -3 at wk 2 postpartum were indicators of the capacity of energy-restricted cattle to resume cycling after parturition.

Analysis of Variance↗
PubMed1994

Carbonyl-containing bisphosphonate esters as novel antiinflammatory and antiarthritic agents.

A study of the decomposition of the pyrazoline bisphosphonate ester 2 identified 3 as the sole bisphosphonate component. Evaluation in a delayed-type hypersensitivity granuloma model of chronic inflammation in mice (DTH-GRA) showed 3 to be a potent inhibitor of granuloma formation (sc, 10 mg/kg, 45%), but in a murine model of antigen-induced arthritis (AIA), no significant inhibition was observed. As a result, new ketonic bisphosphonate tetraethyl esters were synthesized from vinylidenebisphosphonic acid tetraethyl ester 4 and activated carbonyl compounds in 13-84% yield. 6 significantly inhibited the pathology of both the DTH-GRA (sc, 25 mg/kg, 45%) and AIA models (sc, 25 mg/kg, 55%). Other compounds in the series were not as potent. Our results show that bisphosphonate ester 6 can inhibit the chronic inflammatory response associated with cutaneous granuloma formation and erosive arthritis.

Animals↗
PubMed1993

Pyrazoline bisphosphonate esters as novel antiinflammatory and antiarthritic agents.

Vinylidenebisphosphonic acid tetraethyl ester (1) and diazo ketones 7a-1 in ether at 22 degrees C yield pyrazoline bisphosphonate tetraethyl esters 8a-1 in moderate to good yield. These compounds were evaluated in animal models of arthritis: rat adjuvant-induced polyarthritis (AIP) and murine antigen-induced arthritis (AIA) and a murine model of chronic inflammation, the delayed type hypersensitivity granuloma reaction (DTH-GRA). (5-Benzoyl-2,4-dihydro-3H-pyrazol-3-ylidene)-bisphosphonic acid tetraethyl ester (8a), and [5-(3-fluorobenzoyl)-2,4-dihydro-3H-pyraxol-3-ylidene]- bisphosphonic acid tetraethyl ester (8d) significantly inhibited the arthritis models, AIP (15 mg/kg) and AIA (25 mg/kg), as well as the DTH-GRA (25 mg/kg). Conversion of 8a to the corresponding bisphosphonic acid, 10a, resulted in loss of activity. Compounds with alkyl substituents on the pyrazoline nitrogen, 9a-d, were inactive in the DTH-GRA. These results show that 8a and 8d have novel antiinflammatory activity and are capable of inhibiting chronic arthritis and inflammation in animals. Such compounds might be useful in man for treating chronic tissue injury associated with arthropathies such as inflammatory joint disease as well as other chronic inflammatory diseases.

Animals↗
PubMed1993

Radiotherapy in the management of thyroid orbitopathy. Computed tomography and clinical outcomes.

OBJECTIVE: We investigated the long-term outcome of patients with thyroid orbitopathy treated with orbital radiotherapy using quantitative clinical measurements and orbital computed tomographic morphometric changes. DESIGN: Patients who had undergone orbital radiotherapy for thyroid orbitopathy at least 1 year previously were retrospectively recalled for follow-up examination and computed tomography. Controls were patients with similar disease activity but who had not undergone radiotherapy. SETTING: Subspecialty clinic in a university teaching hospital. PATIENTS: Twenty-one patients (42 orbits) who underwent radiotherapy and six clinically comparable patients who had not undergone radiotherapy (12 orbits). INTERVENTION: Standardized, super-voltage, orbital radiotherapy. MEASUREMENTS: Five clinical indexes of orbitopathy and six computed tomographic indexes were examined for interval changes. RESULTS: The orbital computed tomographic muscle-diameter index enlargement ratio did not change in either group (radiotherapy group, 1.54 to 1.51, not significant; nonradiotherapy group, 1.37 to 1.36, not significant). The mean (+/- SEM) number of muscles with low-density areas increased in both groups (radiotherapy group, 1.1 [+/- 1.9] muscles per orbit; P < .001). Soft-tissue signs improved significantly with lesser improvements in extraocular muscle function in both groups. Proptosis, visual acuity, and intraocular pressure rise on upgaze did not improve significantly in either group. CONCLUSIONS: No changes in muscle size measured with computed tomography were found in either patients undergoing radiotherapy or patients not undergoing radiotherapy after long-term follow-up. Clinical indexes of thyroid orbitopathy, especially soft-tissue signs, improved on follow-up, but this was not influenced by the method of treatment.

Adult↗
PubMed1993

Simulated effects of culling ewes for age and failure to conceive on biological efficiency of an annual lambing production system.

A deterministic computer simulation model was used to estimate the effects of different culling strategies for nonconception and age on the biological efficiency of an annual lambing system. Interaction among culling strategy and genotype for system efficiency was estimated by also varying ewe genetic potentials for fertility, precocity of fertility, and litter size. Biological efficiency was defined as grams of empty body weight equivalent value of market lamb, cull ewe, and wool output per kilogram input of TDN. Pure breeding with random selection of intraflock replacement ewe lambs was assumed. Sheep were fed to maintain normal weight. Maximum allowable ewe age (i.e., time at culling for age) was varied from 2 to 10 yr. The four strategies of culling for nonconception that were simulated ranged from no removal for nonconception to removal of all nonpregnant ewes 15 wk after exposure. During calculation of lamb empty body weight equivalent, relative values per kilogram of output for market lambs, cull ewes, and clean wool were assumed to be 1 to .33 to 2.04 for most simulation runs. In addition, relative value of cull ewes was varied to .01, .16, .50, or .99 for some simulations. The effect of strategy for removal of nonconceiving ewes on system efficiency depended on maximum ewe age and genotype. In general, if relative value per kilogram of cull ewes to market lambs was < or = .50, ewes should be allowed to produce through 4 or 5 yr of age and then be salvaged. Unless salvage value of culled ewes approaches that of market lambs, ewe lambs should not be culled for failure to conceive.

Aging↗
PubMed1993

Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates.

Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Several DP have also been shown to exert significant antiarthritic effects in the rat adjuvant-induced polyarthritis model; however, there is no direct evidence for the anti-inflammatory effects of these compounds. We therefore tested the effects of dichloromethylene diphosphonate on delayed-type hypersensitivity granuloma elicited by s.c. implantation of antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dichloromethylene diphosphonate induced a dose-related inhibition of the delayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/kg/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 were also effective in the same dose range. In contrast, all DP failed to suppress 24-hr delayed-type hypersensitivity paw edema in mice. In addition to rat adjuvant-induced polyarthritis, mouse antigen-induced erosive arthritis was also significantly suppressed by s.c. administration of all four DP. Toxicity was minimal for each DP (> 600 mg/kg p.o. or s.c.). We conclude that DP represent a novel class of anti-inflammatory agents with excellent therapeutic potential for chronic inflammatory diseases including rheumatoid arthritis.

Animals↗
PubMed1992

Canine in vivo tracheal chemotaxis of eosinophils to antigen in sensitized dogs: inhibition by a steroid, a systemic lazaroid U-78517F, and several topical H1 antihistamines.

Inflammation of the airways contributes to the multicomponent disease known as asthma. The primary cells that infiltrate the airway in response to antigen exposure are neutrophils and eosinophils. Eosinophils have been implicated in much of the histopathology of the airway following infiltration and degranulation. We used topical antigen exposure in the trachea of sensitized beagle dogs to study the kinetics of eosinophil infiltration with a modified double balloon endotracheal tube technique. After establishment of the eosinophilia, we used inhibitors with known actions to implicate certain mediators in the cellular response. Beagle dogs were sensitized to ascaria ova by feeding them orally by gavage. After 6 wk, challenge with 2.0 micrograms/ml ascaris antigen protein via the tracheal chamber resulted in a rapid (maximal in 4 h) and repeatable influx (p less than 0.05 versus vehicle) of eosinophils that was faster and larger than that of exogenously added LTB4 or PAF exposure. After 4 to 6 separate (every 2 wk) antigen challenges in which the response varied by (SEM +/- 13 to 50%), the individual dogs were rechallenged in the presence of various inhibitors administered either topically in the perfusate or systemically. The inhibitors that were effective in blocking the eosinophil influx by a statistically significant amount were: (1) the lazaroid U-78517F orally 0.5 to 30 mg/kg-18 h (2) Medrol acetate 5 mg/kg intramuscularly-18 h, (3) H1-antihistamines topically (10(-6) M) Astemizole, Cetirizine, and Mepyramine, also orally 30 mg/kg, and Azelastine. Inhibitors falling to inhibit influx topically were a LTB4 receptor antagonist (U-75302) and U-80271 (Merck L-652731), a PAF antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

Effects of alternative lamb production systems, maternal line, and culling strategy on flock age structure.

The 5-yr attrition of 1/4 (n = 411) or 1/2 (n = 403) Finnsheep (Finn) ewes exposed to terminal sire breeds in either an accelerated or semi-intensive annual lambing system was recorded to test the effects of system and percentage Finn on flock age structure at equilibrium. Ewes were culled for discernible ailments and failure to lamb after two consecutive non-spring exposures in yr 3, 4, or 5 only. Additionally, four progressively more intensive culling strategies for nonconception were practiced in retrospect. Flock productivity (kilograms of lamb weaned per ewe maintained per year) at age structure equilibrium was estimated for all culling strategies. The majority of all systems (cull strategy x lambing system x percentage Finn combination) were composed of ewes less than or equal to 3 yr old. Replacement requirements ranged from 24 to 38% in the accelerated system and 22 to 26% in the annual system. Quarter-Finns yielded greater replacement needs and shorter productive lives in accelerated lambing but fewer replacement requirements and longer productive lives than 1/2 Finns in annual lambing. Replacement requirements greatly increased with culling intensity in accelerated lambing (up to 54% above original levels) but only slightly in annual lambing (up to 8% above original levels). Mean (reproductive) lifetime estimated from fitted Weibull survival curves ranged from 3.1 to 5.1 yr in accelerated lambing and 4.5 to 5.4 yr in annual lambing. Increased culling for non-lambing decreased productivity at flock age structure equilibrium in accelerated lambing but did not change productivity in annual lambing. Repeatability of ewe effects on conception was generally low. Overall, system, percentage Finn, and culling strategy interact to influence system productivity through flock age structure. Intensive culling for non-lambing and replacement with ewe lambs of equal genetic merit should not be practiced in accelerated lambing systems.

Age Factors↗
PubMed1992

Granulomatous orbital lesions: computed tomographic features.

Orbital lesions exhibiting granulomatous inflammation represent a heterogeneous group of diseases characterized by infiltration with epithelioid cells. The authors retrospectively reviewed the orbital computed tomography (CT) scans of 39 patients who had biopsy-proven lesions with granulomatous inflammation and found that diagnosis on the basis of CT was possible in only a few patients, those with a lesion of characteristic location and attenuation (such as a dermoid cyst) or characteristic distribution (such as bilateral enlargement of the lacrimal gland occurring in orbital sarcoidosis). In patients with multicompartmental disease exhibiting bone and extraorbital involvement the site of origin of the mass, the pattern of bone involvement and the clinical findings helped in classifying the cause of the lesion as Wegener's granulomatosis, a foreign body or mucormycosis. CT was crucial in determining the intraorbital and extraorbital extent of the lesion before excision or biopsy.

Adolescent↗
PubMed1991

Intracranial extramedullary hematopoiesis. CT and bone marrow scan findings.

This case concerns a patient with intracranial extramedullary hematopoiesis (EH) suspected on a CT scan and subsequently confirmed with In-111 chloride and Tc-99m SC bone marrow scans. The bone marrow scans also provided additional information by demonstrating other sites of EH in the paravertebral tissues and bone marrow expansion into the distal extremities.

Adult↗
PubMed1991

Carotid and vertebral artery trauma: clinical and angiographic features.

Injury to the carotid or vertebral artery is an important clinical entity that requires angiography for definitive diagnosis and evaluation. The common carotid artery may be injured by penetrating trauma while the internal carotid artery is usually damaged by either trivial or blunt trauma. With trivial trauma extracranial internal carotid artery dissection should be considered if there is unilateral headache, Horner's syndrome or delayed transient ischaemic attack, and intracranial dissection if a profound neurological defect occurs immediately following trauma. Injury to the internal carotid artery following blunt trauma includes dissection of the extracranial internal carotid artery, carotid-cavernous fistula and pseudoaneurysm formation. These should be considered in a patient with delayed neurological deficit, mandibular or skull fracture, a constellation of orbital signs or diffuse subarachnoid haemorrhage, respectively. Vertebral artery injury is less frequent. Dissection typically follows abrupt cervical rotation and occurs at C1-2, whereas penetrating trauma may involve either the proximal or distal vertebral artery and occlusion, arteriovenous fistula or pseudoaneurysm may be found. Endovascular techniques may be used in either the carotid or vertebral artery to close fistulae or occlude an extensively damaged vessel.

Adult↗