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Biomedical subjects

J P McGrath

Publications and source records attributed to J P McGrath.

At least 19 recordsLinked to original sources
PubMed2006

Fractures of the sternum: the influence of non-invasive cardiac monitoring on management.

Management of sternal fractures often involves a protracted hospital stay. This is often based on serial electrocardiography (ECG) and cardiac enzyme measurement (AST, CK, LDH). This retrospective study examined all cases of sternal fracture presenting to our institution between October 1998 and February 2003. Seventy-two cases were identified, 52 of which had isolated sternal fractures. Of these, 11 (21%) patients had an elevation in all cardiac enzymes. Twenty-three (44%) had an increase in some but not all. A single patient with ECG changes had no elevation in cardiac enzymes. Those patients with elevated cardiac enzymes had a significantly longer stay of 5.5 days compared with 3.7 days (P < 0.05). No adverse outcome was recorded in either group. We conclude that ECG and estimation of cardiac enzymes in these patients are of limited benefit and, when abnormal, appear to be associated with a significantly protracted and probably unnecessary hospitalisation.

Accidents, Traffic↗
PubMed2001

Oestrogen receptor status determines oncological benefits of laparoscopic oophorectomy.

A meta-analysis of over 3000 patients in 1992 demonstrated that ovarian ablation in women less than 50 years of age produces a highly significant reduction in both disease recurrence and mortality. Laparoscopic ovarian ablation has been offered to premenopausal women at the University College Hospital in Galway for 12 years. A review of 136 cases with follow-up and examination of disease-free survival and mortality is presented. The influence of oestrogen receptor status on response and long-term outcome is examined. Premenopausal women over the age of 40 years were offered bilateral laparoscopic oophorectomy. This procedure was well tolerated with no serious morbidity. A significant difference in disease-free survival and reduction in mortality was observed in the oestrogen receptor positive group when compared with women with oestrogen receptor negative disease. No significant difference in disease-free survival or mortality was observed between the oestrogen receptor negative group and a comparable control group. These results have influenced our patient selection for this adjuvant treatment. A controlled prospective trial is now necessary to examine the role of laparoscopic oophorectomy in oestrogen receptor negative, premenopausal women with breast cancer.

Journal Article↗
PubMed2001

Expandable metal stents in the palliation of malignant dysphagia and oesophageal-respiratory fistulae.

The use of self expandable metal stents in the palliation of malignant dysphagia and oesophago-respiratory fistulae has increased in recent years. The aim of this study was to report a comprehensive 4 year audit of a Specialist Unit's experience with the expandable stent. 200 expandable metal stents were deployed for palliation of non operable malignant dysphagia or fistulae. Per-operative, early (<30 days) and late (>30 days) complications specific to the stent were documented. Stents were successfully positioned in all patients. There was no mortality associated with the insertion and no perforation. Dysphagia was palliated initially in 93 per cent of cases. The mean dysphagia score improved significantly from 3.2 to 1.5 (p<0.01). This significant benefit persisted at 3 months and 6 months of follow-up. The commonest complication was stent migration (5.5%) and 23 patients (11%) required a second stent insertion. Oesophago-respiratory fistulae were successfully palliated in all cases. This study demonstrates the effectiveness of self expandable metallic stents in the palliation of non operable malignant dysphagia and oesophago-respiratory fistulae. The minimal risk of significant complications and low incidence of reintervention should establish this approach as first line palliation in these patients.

Aged↗
PubMed1999

Highly purified recombinant adeno-associated virus vectors are biologically active and free of detectable helper and wild-type viruses.

Gene transfer vectors based on the replication-defective human parvovirus, adeno-associated virus type 2 (AAV-2), are viable candidates for in vivo and ex vivo human use. However, widespread testing of AAV vectors has been limited by difficulties in generating pure, high-titer vector stocks that are fully characterized. To address these issues, we have developed a single-step purification scheme using heparin affinity chromatography. Recovery from the crude lysate starting material exceeds 70%, and the end product rAAV vector is highly purified and appears to be free of adenovirus and cellular contaminates. Importantly, purified vectors retain predicted in vivo biologic activity. Concurrently, we have developed simple and rapid approaches for vector quantification using real-time PCR. These new methods, combined with the use of stable producer cell lines for rAAV production, make the commercial production of rAAV vectors for human use truly viable and pragmatic.

Chromatography, Affinity↗
PubMed1998

Production and characterization of fusion proteins containing transferrin and nerve growth factor.

To explore the ability to use genetic fusions of transferrin as a carrier for brain targeting and delivery, a series of fusion proteins containing both human nerve growth factor (NGF) and human transferrin was produced in mammalian cells. A protein in which the hinge region from human IgG3 joined the carboxyl terminus of NGF and the amino terminus of transferrin formed a covalent homodimer, bound human transferrin receptor, and retained full NGF in PC12 cells. In contrast, proteins in which polypeptide dimerization was not induced or in which NGF was fused through its amino terminus had greatly reduced NGF activity. The ability to maintain both biologically active NGF and transferrin as part of a fusion protein may offer a novel way to deliver NGF and other neurotrophic factors to the central nervous system.

Blood-Brain Barrier↗
PubMed1997

Bifunctional fusion between nerve growth factor and a transferrin receptor antibody.

The cDNAs encoding the variable regions of the heavy and light chains of a murine antibody specific for the human TfR were cloned and a human chimera (gamma1, kappa) was produced. A gene fusion was created by joining the 3' end of the coding region of the human nerve growth factor (NGF) precursor to the 5' end of the heavy chain variable region of the chimeric antibody. When expressed with the unmodified light chain in mammalian cells, the protein fusion is properly processed, assembled, and secreted. Subsequent purification and characterization established the uncompromised bifunctional activities of the protein, relative to the unmodified components, as demonstrated by its ability to both bind to the human TfR and induce neurite outgrowth in primary sympathetic or spinal ganglia and in trkA-transfected pheochromocytoma cells. The ability to generate biologically active NGF fused to a TfR targeting antibody, which was previously shown to cross the blood-brain barrier, may offer a novel way to deliver NGF and other neurotrophic factors to the central nervous system.

Animals↗
PubMed1997

Acute food bolus impaction: aetiology and management.

A prospective study into the aetiology of acute food bolus obstruction (AFBO) was carried out on 17 consecutive patients who presented with this complaint. There were nine males and eight females. Twelve patients (71 per cent) had symptoms of oesophageal disease and 10 patients (59 per cent) had prior food bolus obstruction. Investigations included endoscopy, barium swallow, oesophageal pH and manometry studies. Evidence of oesophageal pathology was found in 12/14 (86 per cent) of patients investigated. No patients had malignancy and the most common abnormality, gastroesophageal reflux (GOR) was found in eight out of 14 (57 per cent) of cases. Oesophageal dysmotility was seen in five out of 12 (42 per cent) patients who had manometric studies. With such a high incidence of recurrence of AFBO, we suggest that patients with this condition be investigated to exclude malignancy and to identify benign oesophageal pathology using techniques such as oesophageal pH and manometry. Appropriate treatment of oesophageal disease may help prevent recurrence of this distressing condition.

Adult↗
PubMed1996

'Booboos': the study of everyday pain among young children.

Three- to 7-year olds were observed in their day cares to determine the prevalence and nature of incidents of everyday pain (e.g. bumps, cuts, and scrapes). An observational checklist was used to record information on the behavioral responses of child and caregiver. The checklist showed excellent interrater reliability and supported the validity of the pain measure used. No age or sex differences in the incidence or severity of everyday pain were found. However, girls engaged more often in distress responses and received more physical comfort from adult caregivers. It was concluded that girls have a vocal response style which elicits responses from adult caregivers. No significant effect of age was found on intensity or duration of distress or on adult response, but frequency of help-seeking behaviors was found to decrease with age. Limited effects of age may be due to the age range restriction of 28-81 months. Analyses of temperment indicated that less adaptive children were more agitated prior to a pain incident. Analysis of behavioral context demonstrated that larger groups of children display a higher level of activity and individuals in the group display higher levels of agitation. Personal control of the child during a pain incident decreased within larger groups and increased with a high level of activity. Finally, it was found that children who experienced 'booboos' most often also responded to them most strongly, suggesting that increased exposure to this type of pain may lead to sensitization, rather than desensitization.

Chi-Square Distribution↗
PubMed1996

Upper oesophageal sphincter function during general anaesthesia.

The effect of anaesthesia on the upper oesophageal sphincter response to acid in the distal oesophagus and hypopharynx, and the effect of atracurium besylate on acid migration into the hypopharynx, was studied in 102 patients undergoing elective varicose vein surgery. Group 1 (n = 48) received a general anaesthetic and the muscle relaxant atracurium besylate whereas group 2 (n = 54) received a general anaesthetic without relaxation. Upper oesophageal sphincter tone was significantly lower in patients receiving muscle relaxants ('sphinctometer output', eight versus 14, P < 0.05). Sixteen patients (16 per cent) had reflux into the distal oesophagus during anaesthesia (nine in group 1 and seven in group 2, P not significant), of whom seven had reflux to the hypopharynx. There was no difference in incidence of hypopharyngeal acid exposure between groups. Upper oesophageal sphincter tone did not alter in response to reflux into the distal oesophagus or hypopharynx in either group. The upper oesophageal sphincter fails to protect the hypopharynx under general anaesthesia even if patients do not receive a muscle relaxant.

Adult↗
PubMed1995

An essential yeast gene encoding a homolog of ubiquitin-activating enzyme.

Ubiquitin (Ub) activation by the Ub-activating (E1) enzyme is the initial and essential step common to all of the known processes that involve post-translational conjugation of Ub to itself or other proteins. The "activated" Ub, linked via a thioester bond to a specific cysteine residue in one of several Ub-conjugating (E2) enzymes, which catalyze the formation of isopeptide bonds between the C-terminal glycine of Ub and lysine residues of acceptor proteins. In the yeast Saccharomyces cerevisiae, a 114-kDa E1 enzyme is encoded by an essential gene termed UBA1 (McGrath, J.P., Jentsch, S., and Varshavsky, A. (1991) EMBO J. 10, 227-236). We describe the isolation and analysis of another essential gene, termed UBA2, that encodes a 71-kDa protein with extensive sequence similarities to both the UBA1-encoded yeast E1 and E1 enzymes of other organisms. The regions of similarities between Uba1p and Uba2p encompass a putative ATP-binding site as well as a sequence that is highly conserved between the known E1 enzymes and contains the active-site cysteine of E1. This cysteine is shown to be required for an essential function of Uba2p, suggesting that Uba2p-catalyzed reactions involved a transient thioester bond between Uba2p and either Ub or another protein. Uba2p is located largely in the nucleus. The putative nuclear localization signal of Uba2p is near its C terminus. The Uba1p (E1 enzyme) and Uba2p cannot complement each others essential functions even if their subcellular localization is altered by mutagenesis. Uba2p appears to interact with itself and several other S. cerevisiae proteins with apparent molecular masses of 52, 63, 87, and 120 kDa. Uba2p is multiubiquitinated in vivo, suggesting that at least a fraction of Uba2p is metabolically unstable. Uba2p is likely to be a component of the Ub system that functions as either an E2 or E1/E2 enzyme.

Amino Acid Sequence↗
PubMed1994

Chronic toxicity, metabolism, and pharmacokinetics of the 5-HT3 receptor antagonist zatosetron (LY277359) in Fischer 344 rats.

Studies were done to characterize the chronic toxicity, metabolism, and pharmacokinetics of a 5-HT3 receptor antagonist in Fischer 344 rats. Animal were given daily gavage doses of 10, 30, or 90 (females only were increased from 90 to 120 mg/kg for months 7-12) mg/kg of zatosetron for 1 year. Treatment-related histologic changes occurred primarily in the liver and kidney of rats given 30 or 90/120 mg/kg and consisted of hepatocellular fatty change (males only), hepatic granuloma formation, and histiocytosis (females only), and renal pigment deposition (both sexes), lesions not previously described in animals treated with 5-HT3 receptor antagonists. Decreased erythrocyte parameters, increased total leukocyte, lymphocyte, and neutrophil counts, and increased serum alkaline phosphatase, gamma glutamyltransferase, alanine transaminase, and liver weights in females were most likely related to the chronic inflammatory process in the liver. Increased alanine transaminase and transiently increased alkaline phosphatase with increased liver weights in males were likely related to the hepatocellular fatty change. Increased renal tubular epithelial pigment deposition (lipofuscin and hemosiderin) was observed in males and females in the high-dose group and in females in the middle-dose group. Both had increased kidney weights and increased serum inorganic phosphorus. Females in the high-dose group had increased urine volume, decreased pH, and increased total excretion of sodium, potassium, chloride, and creatinine. These changes may have been a reflection of tubular dysfunction associated with excessive pigment deposition. No toxicologically significant effects occurred in rats treated with 10 mg/kg/day for 1 year. Plasma concentrations of zatosetron and its 3-hydroxy metabolite increased with increasing dose and duration of dosing in both males and females during the first 6 months of dosing. Subsequent values measured at 12 months showed no substantive increases except in males given the highest dose. At comparable doses, consistent sex differences (F > M) in mean 1-hr plasma content of parent compound were evident across dose and time. Zatosetron-induced hepato- and nephrotoxicity seems to be peculiar to the rat and is observed only at very high doses relative to the proposed human clinical dose.

Animals↗
PubMed1993

Assessment of hemolytic and hemorrhagic anemias in preclinical safety assessment studies.

The general characteristics of anemia and the distinguishing features of hemolytic, hemorrhagic, hypoproliferative, maturation abnormality, and iron-deficiency anemias are described. Hemolytic anemias are differentiated initially from hemorrhagic anemias by excluding hemorrhage on clinical, necropsy, or histologic examination. Next, they are distinguished from the remaining types of anemia on the basis of higher reticulocyte counts or, in some instances, by the very rapid rate of decline of the PCV. Hemolytic anemias are distinguished from each other on the basis of incidence and the presence or absence of a dose-response (idiosyncratic vs toxic) and by the cause of hemolysis (oxidative, nonoxidative, or immune-mediated). Hemorrhagic anemias are subclassified on the basis of single- and multiple-site hemorrhage. The causes of multiple-site hemorrhage (hemostasis dysfunction) are established by first- and second-line tests, the type of bleeding, clinical data, and the information gained from an evaluation of the structure, activity, and metabolism of the compound.

Anemia↗
PubMed1991

UBA 1: an essential yeast gene encoding ubiquitin-activating enzyme.

All known functions of ubiquitin are mediated through its covalent attachment to other proteins. The post-translational formation of ubiquitin--protein conjugates is preceded by an ATP-requiring step in which the carboxyl terminus of ubiquitin is adenylated and subsequently joined, through a thiolester bond, to a cysteine residue in the ubiquitin-activating enzyme, also known as E1. We report the isolation and functional analysis of the gene (UBA1) for the ubiquitin-activating enzyme of the yeast Saccharomyces cerevisiae. UBA1 encodes a 114 kd protein whose amino acid sequence contains motifs characteristic of nucleotide-binding sites. Expression of catalytically active UBA1 protein in E. coli, which lacks the ubiquitin system, confirmed that the yeast UBA1 gene encodes a ubiquitin-activating enzyme. Deletion of the UBA1 gene is lethal, demonstrating that the formation of ubiquitin--protein conjugates is essential for cell viability.

Amino Acid Sequence↗
PubMed1991

Vancomycin-induced release of histamine from rat peritoneal mast cells and a rat basophil cell line (RBL-1).

Rapid intravenous administration of the glycopeptide antibiotic, vancomycin, may cause a hypotensive reaction which can usually be prevented by infusing vancomycin in dilute solutions. The release of histamine from circulating cells such as basophils and tissue mast cells has been implicated in hypotensive reactions since the effects can be prevented by antihistamine pretreatment. The direct effects of vancomycin on histamine release were therefore investigated in rat peritoneal mast cells and rat leukemic basophils (RBL-1 cells). Suspension cultures of mast cells or RBL-1 cells were exposed to vancomycin for 30-60 minutes at concentrations comparable to those infused clinically (2.28 or 4.56 mg/ml). Vancomycin induced a time- and dose-dependent release of histamine into the culture media from both cell types. The reference degranulating agent, Compound 48/80 (CP 48/80), was also shown to induce histamine release from mast cells and RBL-1 cells. Mast cells were significantly more sensitive to vancomycin and CP 48/80 than RBL-1 cells and, unlike RBL-1 cells, were responsive to the inhibitory effects of cromolyn sodium on histamine release. Cromolyn sodium did not inhibit vancomycin-induced histamine release in RBL-1 or mast cells. Morphologically, mast cells exposed to either vancomycin or CP 48/80 exhibited dose-related degranulation. On the other hand, treatment-related degranulation effects of either vancomycin or CP 48/80 on RBL-1 cells could not be reliably distinguished from controls by qualitative evaluation. Based upon these findings it is concluded that mast cells may represent a more useful model to evaluate the potential of investigational agents to release histamine and to study mechanisms of histamine release than RBL-1 cells.

Animals↗
PubMed1991

Evaluation of flow cytometric counting procedure for canine reticulocytes by use of thiazole orange.

An automated reticulocyte counting method that used a flow cytometer and the nucleic acid staining dye, thiazole orange, was developed. Anticoagulated (EDTA) blood specimens were suitable for flow cytometric reticulocyte counting when stored at 4 C for 96 hours after collection. Thiazole orange-stained samples were stable for 5.5 hours after staining when stored capped at 20 C and protected from light. Flow cytometric and manual microscopic reticulocyte counts were compared for counts in the 0.27 to 5.32% range (as determined by flow cytometry) and 0.10 to 4.90% range (as determined by 1 technician). Although the results of flow cytometric analysis generally correlated well (r = 0.821) with manual counts, there was poor correlation between the procedures for counts less than or equal to 2.0% (r less than or equal to 0.272). Linearity of flow cytometric counts over the range 0.27 to 14.46% was excellent (r = 0.999). Within-run precision of flow cytometric counts (% coefficient of variation [cv] = 3 to 5) was superior to manual microscopic counts obtained by one technician (% cv = 19 to 23) and to manual microscopic counts, which were an average of counts done by 3 technicians (% cv = 8 to 18). Comparable flow cytometric counts were obtained by counting 50,000 or 100,000 blood cells in the flow cytometer.

Animals↗