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Biomedical subjects

M Nugent

Publications and source records attributed to M Nugent.

At least 19 recordsLinked to original sources
PubMed2006

Vitamin D and fractures in people with intellectual disability.

BACKGROUND: People with intellectual disability (ID) are thought to be at an increased risk of fractures. The extent of this increase in risk has been incompletely documented in the literature, and the underlying reasons remain to be elucidated. METHODS: The aims of our study were to document the vitamin D status and fracture incidence in an intellectually disabled population, to test for associations between vitamin D status and possible risk factors for reduced vitamin D levels, and to determine the efficacy of oral vitamin D supplementation in restoring appropriate vitamin D levels in those found to be vitamin D insufficient. A 5-year retrospective audit of fractures in 337 individuals with ID receiving health care at a residential facility was performed. Data analysed included age, gender, mobility, dietary status, incident fractures, medications and 25-hydroxyvitamin D levels. Vitamin D insufficient individuals received oral vitamin D supplementation, and had repeat testing to assess treatment efficacy. RESULTS: In total, 57% of individuals tested were found to be vitamin D insufficient. Vitamin D insufficiency was strongly correlated with reduced mobility (P < 0.001) and difficulty with consuming solids (P < 0.001). However, the correlation between vitamin D levels and fractures was not significant (P = 0.3). Oral vitamin D supplementation using cholecalciferol (vitamin D3) 100,000 IU every 4 months was effective in correcting vitamin D insufficiency. Sixty-eight fractures occurred over the study period in 52 individuals, a rate of 1 fracture every 23.8 person years. A total of 55% of these fractures involved the extremities. Fractures were more common in men than in women. Peripheral fractures (hand, foot, wrist, ankle) accounted for 54% of all fractures, and were particularly prevalent in the most mobile individuals. CONCLUSIONS: Fractures and vitamin D insufficiency are relatively common in people with ID. This study did not find a significant association between vitamin D insufficiency and fractures in the study population. Oral vitamin D supplementation is effective in restoring normal vitamin D levels, and should be considered routinely for those at the highest risk.

Adult↗
PubMed2004

Oral transmucosal fentanyl citrate in the management of breakthrough pain in cancer: an open, multicentre, dose-titration and long-term use study.

Sixty-six patients with cancer-related pain entered an open multicentre study to examine the safety and efficacy of oral transmucosal fentanyl citrate (OTFC) in the treatment of breakthrough pain. Patients were eligible for the study if they were stabilized on a long-acting opioid but were experiencing up to four episodes of breakthrough pain a day and achieving at least partial relief from breakthrough pain using conventional medication (normal release oral morphine in the majority of patients). The efficacy of the conventional medication was documented in a run-in phase and patients then changed to OTFC. All patients were treated initially with a 200 mcg unit of OTFC and the dose was increased if necessary to a level that produced relief of breakthrough pain without troublesome adverse effects. Fifty-eight patients completed the run-in phase using their usual medication and entered the dose titration phase with OTFC and 57 patients received at least one dose of OTFC. Forty-two patients (72%) found a successful dose of OTFC. The primary outcome measures were the Summed Pain Intensity Differences (SPID) and Total Pain Relief (TOTPAR) scores at 60 min. There was a significant difference in both measures in favour of OTFC compared with conventional medication in these patients. Twenty-eight of the 42 patients (67%) preferred OTFC to their usual medication. The most common adverse effects attributed to OTFC were nausea, stomatitis, vomiting and dizziness but there were no unpredicted or severe problems. Thirty-seven patients continued into the long-term study and 12 of these completed six months treatment. Most drop-outs in this phase were associated with progression of the underlying disease. No patient stopped using OTFC because of dissatisfaction with the drug. OTFC appears to be a safe and effective treatment for breakthrough pain in cancer patients and may have advantages over currently available opioid formulations.

Administration, Buccal↗
PubMed2001

Long-term observations of patients receiving transdermal fentanyl after a randomized trial.

We observed 73 cancer patients receiving transdermal fentanyl for 1-29 (mean 5.5) months immediately after participation in a randomized clinical trial. Of these, 32 received fentanyl until death, 18 were lost to follow-up, 11 required alternative analgesia, and 12 withdrew for other reasons. The median first recorded dose (not necessarily the patient's first fentanyl dose) was 75 microg/h. The median final dose was 100 microg/h. All but 3 patients required <300 microg fentanyl/h. In the 16 who received fentanyl for > or =3 months until death, the median dose was unchanged (100 microg/h) 3 months before death and at death; 8/16 required no dosage change. The incidence of constipation, skin reactions, nausea, and vomiting was low. No significant respiratory depression was associated with fentanyl. Most patients (85%) and investigators (86%) rated the treatment as good or excellent. We conclude that long-term treatment with transdermal fentanyl is safe and acceptable to many cancer patients.

Administration, Cutaneous↗
PubMed1999

Basic fibroblast growth factor decreases elastin gene transcription through an AP1/cAMP-response element hybrid site in the distal promoter.

Previous studies demonstrated that basic fibroblast growth factor (bFGF) decreases elastin gene transcription in pulmonary fibroblasts. In this study we pursue the identification of the element and the trans-acting factors responsible. Gel shift analyses show that bFGF increases protein binding to a sequence located at -564 to -558 base pairs (bp), which possesses homology to both AP1 and cAMP-response consensus elements yet displays a unique affinity for heterodimer binding. Site-directed mutation of the -564- to -558-bp sequence results in an increase in promoter activity and abrogates the effect of bFGF. Western blot analysis shows that bFGF induces a sustained increase in the steady-state levels of Fra 1, and co-transfection of a Fra 1 expression vector with an elastin promoter reporter construct results in an inhibition of elastin promoter activity. Overall the results suggest that bFGF represses elastin gene transcription by increasing the amount of the Fra 1 that subsequently binds to the -564- to -558-bp as a heterodimer with c-Jun to form an inhibitory complex. We propose that the identified bFGF response element can serve to down-regulate elastin transcription in elastogenic cells and, conversely, can serve to up-regulate elastogenesis in cells where endogenous bFGF signaling is attenuated or altered.

Animals↗
PubMed1999

Transforming growth factor-beta1 (TGF-beta1) is sufficient to induce fibrosis of rabbit corpus cavernosum in vivo.

PURPOSE: The pleotropic cytokine TGF-beta1 which induces connective tissue synthesis, and inhibits the growth of smooth muscle cells, has been implicated in corpus cavernosum fibrosis. The objective of this study was to determine the dose and time dependence of TGF-beta1 as an active agent in penile corporal fibrosis in an animal model. MATERIALS AND METHODS: A time release method of delivery was developed using sodium alginate microspheres containing recombinant human (rh) TGF-beta1. New Zealand White rabbits were injected intracorporally with a single alginate microsphere either with or without rh-TGF-beta1. Dosage was varied from 325 to 1500 ng./bead. Animals were sacrificed at either three or five days post injection and the penises removed en bloc, examined, and processed for quantitative histomorphometric analysis, staining the sections with Masson's trichrome. RESULTS: Alginate microspheres containing [125I]-rh-TGF-beta1 showed slow-release kinetics (t1/2 = 10.5 hours). Histomorphometric analysis of 60 sets of high powered fields/treatment/ animal showed dose dependent decreases in percentage of corporal smooth muscle with TGF-beta1 treatment (750 to 1500 ng./bead). Placebo (alginate microspheres alone) had trabecular smooth muscle content comparable to values previously reported for untreated rabbit corpus cavernosum. CONCLUSIONS: This study confirms that TGF-beta1 induces fibrosis in situ by altering connective tissue synthesis and hence the structure of the corpus cavernosum. Injection of rh-TGF-beta1 impregnated alginate microspheres into the corpus cavernosum resulted in dose-dependent decreases in percentage of corporal smooth muscle.

Animals↗
PubMed1997

Human platelet Ca2+ mobilization, glycoprotein IIb/IIIa activation, and experimental coronary thrombosis in vivo in dogs are all inhibited by the inotropic agent amrinone.

BACKGROUND: Inotropic drugs are often used to treat acute, severe heart failure resulting from acute myocardial infarction and other unstable coronary artery syndromes. However, catecholamine inotropic agents may potentiate coronary thrombosis via a platelet alpha2-adrenergic mechanism, thus exacerbating the original problem. The present studies were designed to determine whether the nonadrenergic inotropic and vasodilator drug amrinone, which elevates platelet cAMP levels, would both inhibit human platelet Ca2+ mobilization and adhesion molecule expression ex vivo and protect against experimental coronary thrombosis in vivo in dogs. METHODS AND RESULTS: Human platelets in suspension were preincubated with amrinone 2.5 to 15 microg/mL; stimulated with the agonists thrombin 0.1 U/mL, ADP 10(-6) mol/L, or arginine vasopressin 10(7) mol/L; and studied for Ca2+ mobilization, glycoprotein IIb/IIIa activation, and P-selectin expression by fluorescent flow cytometry methods. Experimental coronary thrombosis in vivo was studied in an open-chest dog model with critical coronary artery stenosis and deep vessel wall injury. Results showed that at the cellular level, amrinone inhibited agonist-induced Ca2+ mobilization and had modest inhibitory effects on adhesion molecule expression. In vivo in dogs, intravenous amrinone 2 mg/kg plus infusion at 20 microg x kg(1) x min(-1) completely abolished coronary thrombosis. CONCLUSIONS: The fact that amrinone inhibited human platelet activation at the cellular level and protected against experimental coronary thrombosis in vivo in dogs suggests a potentially advantageous antithrombotic action for this inotropic and vasodilator drug.

Amrinone↗
PubMed1996

Mechanisms of venous leakage: a prospective clinicopathological correlation of corporeal function and structure.

PURPOSE: We investigated the pathophysiology of structurally based corporeal veno-occlusive dysfunction. MATERIALS AND METHODS: We prospectively evaluated 24 impotent patients (mean age plus or minus standard error 46 +/- 3 years) who had exposure to vascular risk factors and/or disorders inducing diffuse trabecular structure alterations and who underwent penile prosthesis insertion. Preoperative indexes of veno-occlusive function (flow to maintain, venous outflow resistance and pressure decay measurements using repeat dosing pharmacocavernosometry) were correlated with postoperative erectile tissue computer assisted color histomorphometry (percent trabecular smooth muscle to total erectile tissue area). To develop further study findings and correlate histomorphometric findings with molecular biological properties molecular biological studies (ribonuclease protection analysis, reverse transcription-polymerase chain reaction assay for expression of transforming growth factor-beta 1 messenger [m] ribonucleic acid [RNA] and protein affinity labeling techniques for specific transforming growth factor-beta receptors) were performed in representative patients with high (39 to 43%), intermediate (30 to 37%) and low (13 to 29%) trabecular smooth muscle content (normal 42 to 50%). RESULTS: Flow to maintain, venous outflow resistance and pressure decay values significantly correlated with trabecular smooth muscle cell content (r = -0.89, 0.82 and -0.85, respectively). In the high, intermediate and low smooth muscle content subgroups flow to maintain, venous outflow resistance and pressure decay values were 1 to 5, 9 to 30 and 50 to 120 ml. per minute, 17 to 84, 3 to 9 and 1 to 2 mm. Hg/ml. per minute, and 40 to 60, 48 to 80 and 110 to 120 mm. Hg decrease in 30 seconds from 150 mm. Hg, respectively. There were no significant differences in patient age or prevalence of risk factors among the 3 subgroups. Patients representative of all 3 subgroups had transforming growth factor-beta 1 mRNA, auto-induction of transforming growth factor-beta 1 mRNA and induction and/or increased availability of all 3 types of transforming growth factor-beta receptors. CONCLUSIONS: The pathophysiology of structurally based corporeal veno-occlusive dysfunction is related to elevated corporeal connective tissue content. Based on our data and those in the literature corporeal fibrosis is hypothesized to develop secondary to abnormalities in the regulation of normal collagen synthesis and degradation, most likely associated with adverse influences of chronic ischemia.

Adult↗
PubMed1994

ASA monitoring standards and magnetic resonance imaging.

Some patients, often because of age or altered mental state, require general anesthesia or monitored anesthesia care and sedation if adequate magnetic resonance imaging (MRI) is to be accomplished. This study evaluated whether patients can be monitored during MRI with 1.5-tesla scanners in a manner which complies with ASA monitoring standards without causing degradation of image quality. Ten volunteers were scanned in the MRI without sedation. Monitors meeting ASA standards were placed and electronic artifact produced by the magnetic resonance (MR) scanner was evaluated, after which two scans of the head and two of the chest were performed. One of each pair of scans was obtained with the monitors functioning and one with them turned off. Four radiologists, blinded as to whether the monitors were turned on or off, independently evaluated the 20 pairs of scans. Differences in diagnostic quality and image degradation between the scans were evaluated and scores assigned. All monitors functioned appropriately during the scans, with the exception of the electrocardiogram (ECG) which was grossly distorted to the extent that only ventricular rate could be evaluated. None of the head or body scans was nondiagnostic; however, images with the monitors off were of better quality overall than with them on. Two types of noise were generated and are described. During the head scans, three of seven monitoring combinations caused degradation of the images, while four were judged clinically adequate. During the body scans, two of six monitoring combinations created noticeable noise, while four introduced no significant noise. Ungated cardiac scans were nondiagnostic.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesiology↗
PubMed1993

Characterization of the apurinic endonuclease activity of Drosophila Rrp1.

Drosophila Rrp1 (Recombination repair protein 1) belongs to a family of DNA repair nucleases that includes Escherichia coli exonuclease III, Streptococcus pneumoniae exonuclease A, bovine BAP, mouse APEX endonuclease, and human APE. Within a 252 amino acid region, colinear homology is shared between all members. Rrp1 is unique in that it includes a 427 amino acid N-terminal region not related to any known sequence. The protein copurifies with an apurinic endonuclease and a double-stranded DNA 3'-exonuclease. In this study, a 5'-end-labeled 37 base pair oligonucleotide substrate containing a single apurinic site was used to characterize the endonuclease activity of Rrp1. This substrate is utilized efficiently by Rrp1: the specific activity observed is 1 x 10(5) units/mg. The abasic double-stranded DNA oligonucleotide is cleaved only at the abasic site to create a single-strand break. Strand breaks are not detected in the complementary strand, in the single-stranded DNA oligonucleotide, or in the base-paired control substrate. After endonucleolytic cleavage at the abasic site, exonucleolytic processing at the nick is slow and requires a molar excess of Rrp1, while exonuclease III degrades the nicked substrate more efficiently. The Rrp1 cleavage product comigrates with a DNaseI cleavage product, and the newly formed terminus supports DNA synthesis by DNA polymerase. Therefore, Rrp1 cleaves the phosphodiester backbone at one position 5' to the apurinic site and leaves a 3'-hydroxyl terminus. Rrp1 is a class II apurinic endonuclease and is likely to be important in DNA repair in Drosophila.

Animals↗
PubMed1990

Side effects of nalbuphine while reversing opioid-induced respiratory depression: report of four cases.

Nalbuphine hydrochloride, an agonist-antagonist opioid, is reported to reverse the respiratory depression of moderate doses of fentanyl (20 micrograms.kg-1) and still provide good analgesia. We report four patients having abdominal aortic aneurysm repair in which we attempted to reverse the respiratory depression of large doses of fentanyl (50-75 micrograms.kg-1) with nalbuphine (0.3 mg.kg-1, 0.1 mg.kg-1 or 0.05 mg.kg-1). Nalbuphine reversed respiratory depression in all four patients and the respiratory rate increased from 10 to 23 breaths per minute, end-tidal CO2 decreased from 7.0 +/- 0.3 per cent to 5.6 +/- 0.7 per cent, and peak inspiratory pressure after 0.1 seconds increased from 4 +/- 1.4 to 13 +/- 2.6 mmHg. However, hypertension, increased heart rate, and significant increase in analogue pain scores accompanied reversal of respiratory depression. Agitation, nausea, vomiting, and cardiac dysrhythmias also were observed frequently. We do not recommend the use of nalbuphine to facilitate early extubation of the trachea after large doses of fentanyl for abdominal aortic surgery.

Analgesia↗
PubMed1990

Sodium nitroprusside decreases spinal cord perfusion pressure during descending thoracic aortic cross-clamping in the dog.

Paraplegia is a devastating complication of surgery on the descending thoracic aorta. During surgical repair, the aorta is cross-clamped, and nitroprusside is often used to treat arterial hypertension that can occur above the cross-clamp. Twenty-one dogs were studied to determine the effects of nitroprusside on intraspinal pressures, mean aortic pressures below the cross-clamp, and spinal cord perfusion pressure. Perfusion pressure in spinal radicular arteries originating below the aortic cross-clamp was estimated as the distal aortic pressure minus intraspinal pressure. Nitroprusside was used to return the mean arterial pressure above the cross-clamp to values similar to the pre-cross-clamp levels in 7 dogs. Fourteen animals did not receive sodium nitroprusside. Aortic cross-clamping resulted in small but significant increases in intraspinal pressure (4.3 +/- 0.8 to 7.5 +/- 0.9 mm Hg in non-nitroprusside-treated dogs, and 3.4 +/- 1.0 to 5.6 +/- 1.5 mm Hg in the nitroprusside group before nitroprusside). Nitroprusside caused a further increase in intraspinal pressure (5.6 +/- 1.5 to 8.3 +/- 2.2 mm Hg) and a decrease in aortic pressure below the cross-clamp (26 +/- 5 to 18 +/- 4 mm Hg). The increase in intraspinal pressure and the decrease in aortic pressure below the cross-clamp after nitroprusside resulted in a decrease in spinal cord perfusion pressure from 19 +/- 5 mm Hg to 11 +/- 4 mm Hg. Because nitroprusside decreases spinal cord perfusion pressure and may increase the risk of spinal cord ischemia, the avoidance of large doses of nitroprusside to arbitrarily return mean arterial pressure above the cross-clamp to pre-cross-clamp levels is recommended.

Animals↗
PubMed1990

Isoflurane and halothane attenuate coronary artery constriction evoked by serotonin in isolated porcine vessels and in intact pigs.

Serotonin is a vasoconstrictor thought to cause coronary artery constriction in humans. The purpose of this study was to determine if isoflurane and halothane each attenuated coronary artery constriction evoked by serotonin in pigs. Both in vitro and in vivo experimental methods were used. Isolated coronary arteries with an without endothelium were studied in organ chambers in the presence and absence of 2.5% concentrations of the anesthetics. In intact pigs serotonin was infused directly into the left anterior descending coronary arteries to induce constriction. The vasodilator effects of 0.5%, 1.25%, and 2.0% isoflurane and halothane were determined using quantitative angiography. Contractile responses of isolated coronary arteries were depressed by the two anesthetics. Maximum contractile responses to serotonin were as follows: rings with endothelium 45 +/- 5% untreated versus 29 +/- 5% with isoflurane 2.5% (difference between dose-response curves, P less than 0.01) and without endothelium 67 +/- 5% untreated versus 51 +/- 6% with isoflurane 2.5% (P less than 0.001); with endothelium 52 +/- 7% untreated versus 28 +/- 7% with halothane 2.5% (P less than 0.001) and without endothelium 65 +/- 5% untreated versus 40 +/- 6% with halothane 2.5% (P less than 0.001). In intact pigs isoflurane and halothane dilated constricted coronary arteries with and without endothelium at all anesthetic concentrations tested, including concentrations as low as 0.5%. Isoflurane 1.25% increased diameter of vessels with endothelium from 1.5 +/- 0.1 mm to 1.7 +/- 0.1 mm (P less than 0.02) and halothane 1.25% increased diameter from 1.6 +/- 0.1 mm to 1.7 +/- 0.1 mm (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pseudoseizures caused by hyperventilation resembling absence epilepsy.

During the 4-year period, 1982-1986, 18 patients presented to the Children's Hospital, Camperdown, Sydney, with the following features: (1) Recurrent "absences" clinically indistinguishable from childhood absence epilepsy, (2) Normal clinical examination, (3) Electroencephalogram (EEG) demonstrating normal waking background and sleep activity. On hyperventilation, "absences" occurred, characterized on EEG by a marked build-up of paroxysmal slow-wave activity unassociated with evidence of epileptic activity. We designate these attacks "pseudoseizures caused by hyperventilation resembling absence epilepsy." Individual cases demonstrated a variety of other symptoms consistent with the hyperventilation syndrome. There was an identifiable environmental stress in 13 of the 18 cases. Follow-up of 13 patients after a mean period of 20 months revealed that only two children continued to have occasional absences, associated with a clear history of breathing up when upset. Treatment did not influence outcome. On repeat hyperventilation with EEG and respiratory monitoring, five of the 13 had pseudoseizures. There was no indication that susceptibility to these episodes was associated with an abnormal CO2 response. It is postulated that the occurrence of pseudoseizures is related to cerebrovascular immaturity and an excessive vasoconstrictor response to a given level of CO2.

Adolescent↗
PubMed1989

Halothane, but not isoflurane or enflurane, protects against spontaneous and epinephrine-exacerbated acute thrombus formation in stenosed dog coronary arteries.

Occlusive platelet thrombi periodically form in mechanically stenosed dog coronary arteries producing cyclical blood flow reductions occurring over 4-7 min. Cyclical coronary flow reductions are exacerbated by IV epinephrine 0.4 microgram.kg-1.min-1 for 15 min. These flow reductions can be abolished by known inhibitors of platelet function. This study assesses the effect of halothane, isoflurane, and enflurane on spontaneous- and epinephrine-exacerbated cyclical coronary flow reductions. Twenty-three open-chest dogs [1% halothane (n = 5), 0.5% halothane (n = 5), 0.25% halothane (n = 3), 1.5% isoflurane (n = 5), and 2.0% enflurane (n = 5)] with a mechanically stenosed coronary artery showed cyclical blood flow reductions. With 1.0% halothane administration, spontaneous cyclical blood flow reductions were abolished (n = 5), whereas during administration of isoflurane 1.5% (n = 5) and enflurane 2.0% (n = 5) cyclical flow reductions and myocardial ischemia continued. Subsequent administration of halothane in the isoflurane and enflurane groups showed abolition of coronary flow reductions in all animals (n = 10). In eight animals a 15-min epinephrine infusion (0.4 microgram.kg-1.min-1) was given following a control period and again following abolition of coronary flow reductions by halothane 0.5% (n = 5) and halothane 0.25% (n = 3). The magnitude of cyclical blood flow reductions (difference between initial and final coronary flow level of each flow reduction) changed from 52 +/- 11 to 61 +/- 12 ml/min (NS), and frequency increased from 0.37 to 0.57/min (P less than 0.05, n = 8) during epinephrine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Paraplegia after thoracic aortic occlusion: influence of cerebrospinal fluid drainage. Experimental and early clinical results.

Paraplegia occurs in 6.5% to 40% of patients after repair of extensive thoracoabdominal aortic aneurysms requiring aortic clamping. This study aimed to determine whether drainage of cerebrospinal fluid (CSF) done before aortic cross-clamping could decrease the incidence of paraplegia in dogs. The descending thoracic aorta was clamped distal to the left subclavian artery for either 40 minutes (group I) or 60 minutes (group II). All control animals in group I (10) and group II (10) showed evidence of spinal cord injury with paraparesis or paraplegia. In contrast, 9 of 10 animals (90%) in group I and 7 of 10 animals (70%) in group II that had CSF drainage before aortic cross-clamping were neurologically normal (p less than 0.001 and p less than 0.01, respectively). Aortic pressure distal to the aortic cross clamp was the same in all groups; however, spinal cord perfusion pressure (distal aortic pressure minus CSF pressure) was significantly higher in neurologically normal animals (34 +/- 5 mm Hg, n = 15) compared with those with paraparesis (26 +/- 4 mm Hg, n = 8) or paraplegia (19 +/- 5 mm Hg, n = 8) (r = 0.871, p less than 0.001). This study demonstrates that drainage of CSF before thoracic aortic occlusion significantly increases spinal cord perfusion pressure and decreases the incidence of paraplegia. Limited early clinical experience suggests that CSF drainage may be a useful adjunct to prevent paraplegia in patients who are having repair of thoracoabdominal aortic aneurysms.

Animals↗