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Biomedical subjects

D McNamara

Publications and source records attributed to D McNamara.

At least 19 recordsLinked to original sources
PubMed2000

Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases.

The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more potent Cdk inhibitors. The most potent Cdk4 inhibitors reported in this study inhibit Cdk4 with IC(50) = 0.004 microM ([ATP] = 25 microM). X-ray crystallographic analysis of representative compounds bound to the related kinase, Cdk2, reveals that they occupy the ATP binding site. Modest selectivity between Cdks is exhibited by some compounds, and Cdk4-selective inhibitors block pRb(+) cells in the G(1)-phase of the cell division cycle.

Adenosine Triphosphate↗
PubMed2000

Myocarditis.

Explore the source record for details and available documents.

Animals↗
PubMed2000

True eminectomy for internal derangement of the temporomandibular joint.

We carried out a prospective study to assess the short- and long-term outcomes of true eminectomy in 20 consecutive patients with type III or IV anteriorly displaced discs in whom conventional conservative treatment had failed to resolve the symptoms. Maximum opening was measured preoperatively, 3-6 months postoperatively and at one year postoperatively. Each patient filled out a Mandibular Functional Impairment Questionnaire [MFIQ] and Clinical Dysfunctional Index both preoperatively and one year postoperatively. Imaging records included preoperative and one year postoperative orthopantomograph (OPG) and magnetic resonance imaging (MRI). Maximum mouth opening one year postoperatively had increased in 95% of patients (range 5-20 mm, mean 12 mm). There was an improvement in symptoms, using the MFIQ, in 85% of patients. The Clinical Dysfunctional Index was reduced to Type I in most patients. MRI showed increase in rotation and translatory movement of the condylar head. We conclude that true eminectomy may be used to successfully treat type III and type IV anteriorly displaced discs in patients who have failed to respond to conventional conservative treatment.

Adult↗
PubMed2000

Consensus guidelines: agreement and debate surrounding the optimal management of Helicobacter pylori infection.

Helicobacter pylori is a recognized cause of a variety of gastroduodenal pathology. The high prevalence of both H pylori infection and related diseases within the community warrants its consideration as a public health care issue. The availability of reliable and safe noninvasive diagnostic techniques coupled with the development of effective and tolerable treatments has enabled primary health care personnel to manage this infection actively. The role of the primary care physician in the future management of H pylori infection is thus of central importance. The wealth of evidence produced by over 15 years of research into H pylori has expanded the list of disease associations and treatment benefits as well as elucidated the pathophysiological mechanisms involved. As a result, there has been a growing need to harmonize this information with clinical practice and to provide direction for the appropriate management by both specialists and general practitioners. Several national guidelines have been produced. The areas relating to H pylori infection that they considered and their recommendations vary. In 1994, the National Institutes of Health produced globally accepted recommendations for the management of H pylori-related peptic ulceration. The broader role of H pylori as a gastroduodenal pathogen and a public health care issue was not addressed. Recently, European and Canadian consensus guidelines have been published that identified overall management issues, including the role of primary and specialist care, and considered the appropriateness of employing eradication therapy for the spectrum of conditions in which H pylori has a direct or indirect association based on the available information. These guidelines, while in agreement regarding many issues, differ considerably in their recommendations for primary health care and regarding central issues such as the management of dyspepsia and gastric cancer. Some variations may reflect differing health care structures as well as the prevalence of both infection and associated diseases. However, the interpretation of evidence produced by recent research contributes to their conflicting statements.

Canada↗
PubMed1999

Effects of central and peripheral nicotinic blockade on human nicotine discrimination.

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

Adult↗
PubMed1999

Gastro-oesophageal reflux disease and Helicobacter pylori: an intricate relation.

Heartburn is a common symptom affecting 21-44% of the adult population on a monthly basis. Oesophagitis is less common, affecting 2% of individuals. Epidemiological studies have shown that patients with gastro-oesophageal reflux disease (GORD) have similar incidence rates of Helicobacter pylori infection as do controls. Some groups have reported that there is a lower incidence, deducing that infection does not cause, and in some way confers protection against GORD. Additional supportive evidence is available from reports of GORD development following successful H pylori eradication. The mechanisms involved are complicated. Individuals with H pylori induced pangastritis and subsequent hypochlorhydria may be protected whereas those with an antral predominant gastritis, as in duodenal ulcer disease, with an increased acid output may be prone to development of GORD. Recent evidence has linked H pylori infection with the development of inflammation of the gastric cardia---carditis. Reports are available which show that carditis is a frequent finding in patients with GORD. The incidence of both cardia and oesophageal carcinoma is increasing. The relation between GORD, carditis, intestinal metaplasia, and cardia carcinoma is unclear. Intestinal metaplasia may result from multifocal atrophic gastritis, linked to H pylori infection or from GORD and the development of Barrett's oesophagus. Long term follow up studies will be required to assess the malignant potential of these histological entities and whether or not H pylori infection has an aetiological role.

Gastritis↗
PubMed1998

Helicobacter pylori and gastric cancer.

Gastric cancer despite a declining incidence remains a significant cause of morbidity and mortality world wide. There is strong epidemiological and histological evidence to associate Helicobacter pylori infection with the subsequent development of gastric cancer. The exact pathophysiological mechanisms involved remain to be elucidated. There is evidence to relate Helicobacter pylori infection and subsequent inflammation with an increase in gastric epithelial cell proliferation and with the induction of apoptosis. Such alterations in cellular dynamics may promote the development of mitogenic cell lines by inducing DNA damage. Studies have shown that following successful treatment, proliferation rates return to normal. At what histological stage, eradication is of benefit is less clear. It is likely that following the development of atrophy or intestinal metaplasia eradication will only slow progression. It would, therefore, seem logical, that to establish any benefit for a population, treatment should be employed at an earlier stage. As yet, an at risk group has not been identified, and as such population screening cannot be advised, mainly as a result of financial implications and the risk of promoting the development of resistant strains. Recent studies have explored the rules of bacterial factors, CagA and VacA status, host factors, HLA type, and environmental factors as determinants of outcome. Results have been variable. The establishment of an at risk group would enable selective screening and treatment, and thus prevent the development of gastric carcinoma as a result of Helicobacter pylori infection in the long-term.

Adenocarcinoma↗
PubMed1996

Comparisons between SPECT and quantitative EEG measures of cortical impairment in mild to moderate Alzheimer's disease.

This study aimed at examining correlations between quantitative REM sleep EEG, regional cerebral blood flow measured by single photon emission computerized tomography (SPECT) and global cognitive functioning in nine patients with mild to moderate Alzheimer's disease. REM sleep EEG was not correlated with SPECT measures in any of the 6 regions studied. However, degrees of interhemispheric asymmetry calculated by both measures were concordant for the parieto-occipital region. Mini-mental state score correlated with REM sleep EEG slowing for left frontal, left and right parieto-occipital and left temporal regions but was not correlated with SPECT measures for any of the six regions. These results suggest that quantitative REM sleep EEG would be more useful than SPECT for evaluating cerebral dysfunctions in mild to moderate Alzheimer's disease.

Aged↗
PubMed1996

Left ventricular dysfunction after heart transplantation: incidence and role of enhanced immunosuppression.

BACKGROUND: The purpose of this study was to examine the incidence, natural history, and outcome of left ventricular dysfunction in 102 consecutive heart transplant recipients. Left ventricular dysfunction (defined as a decline in the echocardiographic ejection fraction to < 0.45) occurred in 16 of 102 transplant recipients (16%) at a mean of 9.7 +/- 8.6 (standard deviation) months after transplantation. METHODS: Diagnostic evaluation included right heart catheterization and endomyocardial biopsy in all patients and coronary angiography in 13 patients. RESULTS: Four patients were found to have moderate cellular rejection (International Society for Heart and Lung Transplantation grade 2 or higher) and were treated with enhanced immunosuppression. Two patients had angiographically apparent coronary allograft vasculopathy; both died of electromechanical dissociation within 4 months. The remaining ten patients had no or mild cellular rejection (International Society for Heart and Lung Transplantation grade 0 or 1). Therapy in these ten patients included corticosteroids (n = 8). OKT3 (n = 5), and plasmapheresis (n = 2). Three patients died within 2 months of diagnosis, two from undetected severe coronary allograft vasculopathy and one from unrecognized constrictive pericarditis. The echocardiographic ejection fraction improved in the surviving patients after enhanced immunosuppressive therapy (0.33 to 0.53, p < 0.005). With the benefit of long-term clinical follow-up and autopsy data, the origins of left ventricular dysfunction in the 16 patients included moderate cellular rejection (n = 4), vascular rejection (n = 1), coronary allograft vasculopathy (n = 3), intercurrent cytomegalovirus infection (n = 1), constrictive pericarditis (n = 1), and either mild or no evident rejection (n = 6). Survival of the 16 patients with left ventricular dysfunction was similar to that of the 86 patients without left ventricular dysfunction. CONCLUSIONS: The cause of left ventricular dysfunction after heart transplantation includes cellular rejection, vascular rejection, coronary allograft vasculopathy, cytomegalovirus infection, constrictive pericarditis, and unexplained mechanisms. Given the improvement in left ventricular function observed after empiric therapy with enhanced immunosuppression in patients with left ventricular dysfunction, immune-mediated phenomena may play an important pathogenic role.

Biopsy↗
PubMed1995

Differentiation of peptide molecular recognition by phospholipase C gamma-1 Src homology-2 domain and a mutant Tyr phosphatase PTP1bC215S.

Activated epidermal growth factor receptor (EGFR) undergoes autophosphorylation on several cytoplasmic tyrosine residues, which may then associate with the src homology-2 (SH2) domains of effector proteins such as phospholipase C gamma-1 (PLC gamma-1). Specific phosphotyrosine (pTyr)-modified EGFR fragment peptides can inhibit this intermolecular binding between activated EGFR and a tandem amino- and carboxy-terminal (N/C) SH2 protein construct derived from PLC gamma-1. In this study, we further explored the molecular recognition of phosphorylated EGFR988-998 (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly, I) by PLC gamma-1 N/C SH2 in terms of singular Ala substitutions for amino acid residues N- and C-terminal to the pTyr (P site) of phosphopeptide I. Comparison of the extent to which these phosphopeptides inhibited binding of PLC gamma-1 N/C SH2 to activated EGFR showed the critical importance of amino acid side chains at positions P+2 (Ile994), P+3 (Pro995), and P+4 (Gln996). Relative to phosphopeptide I, multiple Ala substitution throughout the N-terminal sequence, N-terminal sequence, N-terminal truncation, or dephosphorylation of pTyr each resulted in significantly decreased binding to PLC gamma-1 N/C SH2. These structure-activity results were analyzed by molecular modeling studies of the predicted binding of phosphopeptide I to each the N- and C-terminal SH2 domains of PLC gamma-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1995

Long-term risk stratification with dipyridamole imaging.

This study was undertaken to assess the reliability of clinical parameters and dipyridamole-thallium 201 images for predicting the occurrence of future cardiac events (nonfatal myocardial infarction or cardiac death). Dipyridamole myocardial perfusion imaging is routinely performed in patients who have possible or known coronary disease and a low exercise tolerance. A total of 753 patients underwent clinical assessment and semiquantitative dipyridamole-201TI imaging and were followed up as outpatients. Patients who underwent coronary revascularization during the follow-up period were excluded from the study because the decision to intervene would have been based at least in part on the test itself. There were 82 cardiac events and 54 noncardiac deaths, and 11 patients were lost to follow-up after a mean follow-up of 15 months. With use of a quantitative index reflecting the amount of jeopardized myocardium, patients could be stratified by dipyridamole imaging into subsets with coronary morbidity and mortality rates ranging from 1% to 89%, (p = 0.0001). When clinical and scintigraphic variables were subjected to backward stepwise logistic regression analysis, the significant predictors of cardiac events were the jeopardized myocardium index by scintigraphy (p < 0.0001), left ventricular hypertrophy on the electrocardiogram (p = 0.0009), and transient dipyridamole-induced left ventricular cavitary dilatation (p = 0.0073). Quantitative dipyridamole-201TI imaging appears to be a powerful predictor of future cardiac events in patients with coronary disease and a low exercise tolerance and is a potentially useful contributor to risk-profile assessment and to the treatment of these patients.

Aged↗
PubMed1994

Artificial intelligence versus logistic regression statistical modelling to predict cardiac complications after noncardiac surgery.

The traditional approach to developing models predictive of cardiac events has been to perform logistic regression (LR) analysis on a variety of potential predictors. An alternative to use an artificial intelligence system called a neural network (NN) which simulates biological intelligence. To evaluate the potential applicability of the latter method, we compared the ability of LR and NN techniques to predict cardiac events after noncardiac surgery. A total of 200 patients (training group) underwent cardiac risk assessment before major noncardiac surgery using 17 clinical parameters and 7 quantitative indices based on dipyridamole-thallium imaging. There were 21 post-operative myocardial infarctions and/or cardiac deaths. Data from the training group were used to develop two predictive models: one based on backward stepwise LR multivariate statistical analysis and the other one using a neural network. Both models were then validated on a second group of 160 consecutive patients also referred for preoperative risk stratification (validation group). The NN consisted of 14 input, 29 hidden, and 1 output neurons and used a back-propagation algorithm (learning rate 0.2, training tolerance 0.5, sigmoid transfer function). The sensitivity, specificity, positive and negative predictive accuracies for the prediction of postoperative events in the validation group of 160 patients were, respectively, 67% (6/9), 82% (124/151), 18% (6/33), and 98% (124/127) for LR, and 67% (6/9), 96% (145/151), 50% (6/12), and 98% (145/148) for the NN, with a difference in specificity which attained statistical significance (p < 0.01). Artificial intelligence may provide a useful alternative to conventional LR statistical analysis for the purpose of preoperative cardiac risk assessment.

Artificial Intelligence↗
PubMed1994

A gene defect that causes conduction system disease and dilated cardiomyopathy maps to chromosome 1p1-1q1.

Longitudinal evaluation of a seven generation kindred with an inherited conduction system defect and dilated cardiomyopathy demonstrated autosomal dominant transmission of a progressive disorder that both perturbs atrioventricular conduction and depresses cardiac contractility. To elucidate the molecular genetic basis for this disorder, a genome-wide linkage analysis was performed. Polymorphic loci near the centromere of chromosome 1 demonstrated linkage to the disease locus (maximum multipoint lod score = 13.2 in the interval between D1S305 and D1S176). Based on the disease phenotype and map location we speculate that gap junction protein connexin 40 is a candidate for mutations that result in conduction system disease and dilated cardiomyopathy.

Adult↗
PubMed1994

Normal qualitative and quantitative Tc-99m sestamibi myocardial SPECT: spectrum of intramyocardial distribution during exercise and at rest.

Exercise myocardial perfusion imaging with Tc-99m sestaMIBI is routinely used to detect underlying coronary stenoses. Ischemia is diagnosed in regions that display decreased tracer uptake during exercise as compared to rest. Tc-99m sestaMIBI SPECT images of 42 healthy volunteers were assessed both qualitatively (tomographic slices) and quantitatively (sectored polar map) for potential sources of misinterpretation. On the myocardial tomographic slices, the most common culprit artifacts were diaphragmatic attenuation and bowel interposition, which caused fixed or reversible "perfusion defects" in the inferior and posterior regions (in 19/35 abnormal segments), and artifacts related to the presence and shift of hot spots (observed in 11/28 men; in women, they were more difficult to demonstrate because of the overriding effect of breast attenuation). Hot spots shifts between exercise and rest usually resulted in pseudo-reversible defects in the anterolateral and lateral walls. The quantified polar map display of the myocardium showed a physiologic decrease in sestaMIBI activity in the basal anterolateral and basal posterolateral areas in men during exercise. There are many normal variants that may mimic coronary artery disease on tomographic sestaMIBI images. Before reporting an area of decreased activity as either a fixed or reversible perfusion defect, the interpreter should ensure that it does not represent an artifact or a normal variation in the intramyocardial distribution of sestaMIBI during exercise.

Adult↗