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Biomedical subjects

J Irwin

Publications and source records attributed to J Irwin.

At least 19 recordsLinked to original sources
PubMed1998

Crystal structure of the anti-fungal target N-myristoyl transferase.

N-myristoyl transferase (NMT) catalyzes the transfer of the fatty acid myristate from myristoyl-CoA to the N-terminal glycine of substrate proteins, and is found only in eukaryotic cells. The enzyme in this study is the 451 amino acid protein produced by Candida albicans, a yeast responsible for the majority of systemic infections in immuno-compromised humans. NMT activity is essential for vegetative growth, and the structure was determined in order to assist in the discovery of a selective inhibitor of NMT which could be developed as an anti-fungal drug. NMT has no sequence homology with other protein sequences and has a novel alpha/beta fold which shows internal two-fold symmetry, which may be a result of gene duplication. On one face of the protein there is a long, curved, relatively uncharged groove, at the center of which is a deep pocket. The pocket floor is negatively charged due to the vicinity of the C-terminal carboxylate and a nearby conserved glutamic acid residue, which separates the pocket from a cavity. These observations, considered alongside the positions of residues whose mutation affects substrate binding and activity, suggest that the groove and pocket are the sites of substrate binding and the floor of the pocket is the catalytic center.

Acyl Coenzyme A↗
PubMed1997

Relevance of human papillomavirus screening in management of cervical intraepithelial neoplasia.

OBJECTIVE: To evaluate the utility of human papillomavirus detection in identifying women with abnormal Papanicolaou smears who can be safely followed up with cytologic study only, we conducted a study to determine the sensitivity, specificity, and negative and positive predictive values of a Food and Drug Administration-approved human papillomavirus test kit for detection of cervical intraepithelial neoplasia in colposcopically directed biopsy specimens. STUDY DESIGN: We enrolled women with abnormal Papanicolaou smears referred to a colposcopy clinic serving indigent patients. All 1128 women had a referral Papanicolaou smear, a clinic Papanicolaou smear, and a sample for human papillomavirus deoxyribonucleic acid test; 1075 underwent colposcopically directed biopsies and endocervical curettage. We used the HPV Profile kit for human papillomavirus testing. RESULTS: Of 486 women with low-grade squamous intraepithelial lesions on Papanicolaou smear, 35.4% had high-risk human papillomavirus deoxyribonucleic acid detected, and of 592 with high-grade lesions, 44.4% had high-risk human papillomavirus detected. Among 527 women with biopsy specimens showing cervical intraepithelial neoplasia and in 267 with cervical intraepithelial neoplasia grades 2 or 3, 38.7% and 56.2% had high-risk human papillomavirus deoxyribonucleic acid detected. However, the sensitivity of human papillomavirus deoxyribonucleic acid detection to identify biopsy-confirmed cervical intraepithelial neoplasia grades 2 or 3 was 55.7%, and the positive predictive value of the test was only 34.9%. CONCLUSION: Human papillomavirus appears to be causally associated with cervical cancer but human papillomavirus screening does not appear to be of value to identify women with abnormal Papanicolaou smears who can be safely followed up with cytologic study alone.

Adolescent↗
PubMed1997

Occupational noise-induced hearing loss.

Occupational noise-induced hearing loss is, at least in theory, preventable. One way to assess the problem and whether preventative measures are effective is to assess employees' hearing. In order to minimize cost and time off work this can be carried out effectively in the workplace as long as certain conditions are met.

Audiometry↗
PubMed1995

Dietary control and tissue specific expression of branched-chain alpha-ketoacid dehydrogenase kinase.

The branched-chain alpha-ketoacid dehydrogenase complex, catalyst for the rate-limiting step of branched-chain amino acid catabolism, is controlled by a highly specific protein kinase (branched-chain alpha-ketoacid dehydrogenase kinase) that associates tightly with the complex. The activity state (proportion of the enzyme in its active, dephosphorylated state) of the complex varies dramatically in different rat tissues. The activity state of the complex in the liver is greater than that in any other tissue, and liver contains the lowest amount of kinase protein and kinase mRNA. However, protein malnutrition, a condition under which the complex is largely phosphorylated and inactive, resulted in a three- to fourfold increase in hepatic kinase activity with an accompanying increase in amounts of kinase protein and mRNA. Refeeding a 50% protein diet restored the normal activity state and the original levels of kinase protein and mRNA. The amount of kinase protein associated with the complex rather than changes in specific activity of the kinase appears responsible for observed differences in activity states of the complex in several rat tissues tested. Accordingly, the levels of kinase protein and mRNA measured are highest in tissues with greatest kinase activity (heart > kidney > liver), correlating reasonably well inversely with activity state of the branched-chain alpha-ketoacid dehydrogenase complex in the respective tissues. These observations suggest that the amount of kinase protein expressed in various tissues and in response to dietary protein deficiency is an important factor determining the activity state of the complex.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1995

The HIV information project for transfusion recipients a decade after transfusion.

OBJECTIVE: To gather information on which to base decisions about a general notification program for pediatric patients a decade after their receiving transfusions. DESIGN: The physicians of a cohort of 1793 patients who underwent cardiac surgery were sent letters asking them to contact and counsel patients identified from cardiovascular surgery and blood bank databases about their risk for human immunodeficiency virus (HIV) infection. Questionnaires were used to collect data about physicians' HIV practices; telephone interviews were conducted to collect information about patients' and parents' knowledge and attitudes about HIV and transfusions. Because of unexpected media interest, questionnaires and interviews were modified to include questions about the source of information. The HIV-testing status of patients reported by physicians was anonymously cross-referenced with specimens received by the Laboratory Services Branch, Ontario Ministry of Health, Toronto. SETTING: A large Canadian pediatric tertiary care hospital in Toronto. PARTICIPANTS: Seven hundred ninety-three patients undergoing cardiopulmonary bypass between 1980 and 1985. RESULTS: The HIV Information Project successfully reached most (approximately 75%) of this cohort and, with the help of the media, many other at-risk transfusion recipients. The information was new for many; almost all informed wanted to undergo testing. The seroprevalence of this group that received multiple transfusions was, at minimum, 8.5 patients in 1000. Six previously unsuspected HIV-seropositive cases were diagnosed. CONCLUSIONS: Although we had assumed that most patients receiving transfusions would be aware of their risk for HIV infection, our results indicate that, even a decade after the transfusion, many recipients were not aware of the risk and wanted to undergo testing. Testing identified asymptomatic infected patients.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The relationship between stool hardness and stool composition in breast- and formula-fed infants.

"Constipation" and "hard stools" are associated with formula feeding of both term and preterm infants and, in the latter, can lead to life-threatening complications. This study tested the hypothesis that stool hardness is related to excretion of fatty acid (FA) soaps in term infants, and in the extreme to milk bolus obstruction in premature infants. Stools (n = 44) were collected from 20 formula-fed and 10 breast-fed infants aged 6 weeks and were classified using visual charts for stool hardness on a 5-point scale (1, watery; 5, hard). Stools were analysed for nitrogen, minerals, and lipid, the latter divided between the soap and nonsoap fractions. We explored the relationship between stool hardness or solids content and stool constituents, relative to both wet and dry weight. Calcium and FA soaps were the dominant factors significantly related to stool solids and hardness score across the breast- and formula-fed groups. An 8% increase in stool dry weight FA soap content corresponded to a 1-point change in stool hardness score. Stools from formula-fed infants had a higher solids content and were classified as significantly harder than those from breast-fed infants (hardness scores, 4.0 +/- 0.5 versus 2.6 +/- 0.7, mean +/- SD) and on both a wet- and dry-weight basis contained severalfold higher levels of minerals and lipid and considerably less carbohydrate. Differences in lipids between formula- and breast-fed infants' stools were due almost entirely to FAs (mainly C16:0 and C18:0) excreted as soaps (27.7 +/- 7.5% compared to 3.1 +/- 4.1% of dry weight), suggesting the groups differed markedly in their handling of saturated FAs. An inspissated stool sample from a premature infant requiring surgical disempaction of an obstructed small intestine was found to be enriched in FA and calcium relative to the preterm formula. FA soaps, predominantly saturated, accounted for one third of the stool dry weight. These data support the hypothesis that calcium FA soaps are positively related to stool hardness; we speculate that this may, at least in part, explain the greater stool hardness in formula- versus breast-fed infants and milk bolus obstruction in preterm infants. This conclusion is consistent with the physical properties of calcium FA soaps.

Breast Feeding↗
PubMed1994

Purification and partial characterization of 3-hydroxyisobutyryl-coenzyme A hydrolase of rat liver.

An unusual feature of valine catabolism is a reaction in which an intermediate of its catabolic pathway, (S)-3-hydroxyisobutyryl-CoA, is hydrolyzed to give the free acid and CoA-SH. The enzyme responsible for this reaction, 3-hydroxyisobutyryl-CoA hydrolase (EC 3.1.2.4), was purified 7200-fold from rat liver in this study. The purified enzyme consists of a single polypeptide with an M(r) of 36,000 in the native and denatured forms. The hydrolase is highly specific for (S)-3-hydroxyisobutyryl-CoA and 3-hydroxypropionyl-CoA (Km, 6 and 25 microM, respectively) with optimal activity around pH 8. The turnover rate of the enzyme for (S)-3-hydroxyisobutyryl-CoA is 270 s-1, which is high relative to other enzymes of the valine pathway. Likewise, activity of the enzyme expressed on a wet weight basis is also very high in the major tissues of the rat. These findings suggest that rapid destruction of (S)-3-hydroxyisobutyryl-CoA produced during valine catabolism is physiologically important. We propose that the need for a mechanism to protect cells against the toxic effects of methacrylyl-CoA, which is maintained in equilibrium with (S)-3-hydroxyisobutyryl-CoA by crotonase, explains why valine catabolism involves this enzyme and why its tissue activity is so high.

Acyl Coenzyme A↗
PubMed1993

One aid or two?--more visits please!

A prospective trial of hearing aid provision was undertaken to define factors which might be used to allow hearing aids to be fitted optimally. Patients referred for the provision of a hearing aid were studied prospectively at each of five visits when they were questioned by means of a proforma. Fifty-six patients completed the trial and gave adequate responses for analysis. No audiometric or symptomatic criteria were found to be of use in predicting the final choice of hearing aid combination. It may be that initial sequential monaural aiding leads to a higher uptake of binaural aids in the long term. Patients valued multiple visits to the clinic and sequential trials of monaural aiding, the majority felt that binaural aids should be tried.

Adult↗
PubMed1991

Stressor-induced alterations of natural killer cell activity and central catecholamines in mice.

Natural killer (NK) cell cytotoxicity was determined at various intervals (0.5, 24 or 48 h) following exposure to uncontrollable footshock in 3 strains of mice. Stressor application provoked reductions of NK activity, but the time course of the NK changes varied across strains. Whereas NK cytotoxicity was markedly reduced in C57BL/6J mice 0.5-48 h following stressor exposure, this effect was delayed in C3H/HeJ mice, being evident 24-48 h following stressor application. In BALB/cByJ mice, NK activity was significantly reduced 24 h after footshock, but in contrast to the other strains returned to control levels within 48 h of stressor exposure. Central NE and DA concentrations and activity were influenced by the stressor treatment in a strain-dependent fashion. However, the relationship between the central amine variations and the alterations of NK cytotoxicity associated with the stressor was limited.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Behavioral characterization of intracranial self-stimulation from mesolimbic, mesocortical, nigrostriatal, hypothalamic and extra-hypothalamic sites in the non-inbred CD-1 mouse strain.

A behavioral analysis of intracranial self-stimulation (ICSS) was provided for mesolimbic/mesocortical, nigrostriatal, hypothalamic and extrahypothalamic sites in the CD-1 mouse. Robust responding and rapid acquisition of mesocortical ICSS appeared dorsally along notably fluorescent sites in rostral and caudal planes. ICSS was diminished demonstrably in medial and ventral positions in posterior planes. Mesolimbic ICSS from the medial and ventral nucleus accumbens (Nas), was accompanied by significant elevations in locomotor activity, corresponding to regions of dopamine (DA) and cholecystokinin co-localization. Stimulation-induced seizures appeared from both the Nas as well as the mesocortex. ICSS from the ventral tegmental field (VTA) was evident along its medial, lateral and dorsal borders with longer pulse durations more likely to elicit responding. Seizure activity was absent from the VTA. Striatal ICSS was conspicuously poor in dorsal and medial locations; regions presumably devoid of tegmental innervation. ICSS emerged from both the ventrocaudal and anteromedial striatum; regions linked to innervation by the dorsolateral and ventromedial VTA. The red nucleus, a previously neglected self-stimulation site supported marked responding for ICSS. Regions supporting rubral ICSS were correlated with thalamic innervation sites; notably the ventrolateral thalamic nucleus and the parafascicular nucleus, regions found to support ICSS. The substantia nigra supported high rates of responding for ICSS when electrode placement was restricted to the dorsomedial portion of the pars compacta. Electrode deviations lateral and dorsal to the substantia nigra pars medialis induced a progressive decline in responding. Hypothalamic sites were found to support significant responding for ICSS, although such performance was frequently associated with seizure induction. Taken together these data (1) provide the first behavioral analysis of ICSS in mice responding from previously unexamined DA sites in the mesolimbic (e.g. VTA, Nas) and nigrostriatal systems (e.g. caudate, red nucleus) (2) suggest an anatomical reconsideration of the assumptions underlying the elicitation of ICSS from the frontal cortex (3) suggest that the neural circuitry underlying thalamic, caudate, rubral and frontal cortical ICSS are interrelated and (4) suggest that the Nas and the frontal cortex, like the hypothalamus, in the mouse appear to be particularly sensitive to stimulation-induced seizures.

Animals↗
PubMed1989

The effect of antidepressants on immune function in mice.

Depression or its treatment with antidepressant agents may have an impact on the normal function of the immune system. To address this issue in an animal model, we studied the effect of maprotiline and desipramine treatment of mice on several immunological activities associated with host resistance to cancer and infections. Our results indicate that chronic maprotiline treatment depressed natural killer (NK) cell function, measured in vivo as clearance of tumor cells from the lung or in vitro as cytolytic activity. Cell-mediated immunity, measured as delayed hypersensitivity in vivo and T and B lymphocyte proliferative responses in vitro, was largely unaffected. Although antidepressant toxicity at high concentrations inhibited T, B, and NK cell activity, it is unlikely that this is the basis for the in vivo effects.

Animals↗