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Biomedical subjects

D Harris

Publications and source records attributed to D Harris.

At least 109 records · Page 6Linked to original sources
PubMed1997

Audit of ascertainment of deaths to children born in Cumbria, UK, 1950-89 through the NHS central register.

STUDY OBJECTIVE: To evaluate the completeness of notification of deaths by the National Health Service Central Register (NHSCR) for England and Wales. DESIGN: Deaths for a birth cohort were ascertained through scanning the relevant volumes of NHSCR. Attempts were made to confirm these deaths and additional deaths were ascertained through searching local records. Logistic regression was used to investigate how the probability of a death being missed by NHSCR varied with the year of birth, age at death, sex, and social class. SETTING: Deaths up to the end of 1989 in the CA postal area among 264,046 children born between 1950 and 1989 to mothers living in Cumbria. RESULTS: NHSCR originally ascertained 4139 deaths; local searches confirmed 3338 (81%) of these and found an additional 342. Most deaths missed by the NHSCR were neonatal deaths in the 1950s and 1960s. In the 1950s, 31% of children who died in the neonatal period either were not entered on NHSCR or, if they were entered, there was no record of their death. For children born from 1970 onwards, ascertainment of deaths through NHSCR was over 99% complete. CONCLUSIONS: The NHSCR was started in 1948 for the administration of records of National Health Service patients. It seems that many babies who died soon after birth were not therefore recorded. In parallel with the increasing use of NHSCR for epidemiological purposes, there has been a substantial and continuing improvement in its clerical procedures since the mid 1960's.

Cause of Death↗
PubMed1997

Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary of alphaT3-1 cell line: differential roles of calcium and protein kinase C.

The mechanism of mitogen-activated protein kinase (MAPK, ERK) stimulation by the GnRH analog [D-Trp6]GnRH (GnRH-a) was investigated in the gonadotroph-derived alphaT3-1 cell line. GnRH-a as well as the protein kinase C (PKC) activator 12-O-tetradecanoyl phorbol-13-acetate (TPA) stimulated a sustained response of MAPK activity, whereas epidermal growth factor (EGF) stimulated a transient response. MAPK kinase (MEK) is also activated by GnRH-a, but in a transient manner. GnRH-a and TPA apparently activated mainly the MAPK isoform ERK1, as revealed by Mono-Q fast protein liquid chromatography followed by Western blotting as well as by gel kinase assay. GnRH-a and TPA stimulated the tyrosine phosphorylation of several proteins, and this effect as well as the stimulation of MAPK activity were inhibited by the PKC inhibitor GF 109203X. Similarly, down-regulation of TPA-sensitive PKC subspecies nearly abolished the effect of GnRH-a and TPA on MAPK activity. Furthermore, the protein tyrosine kinase (PTK) inhibitor genistein inhibited protein tyrosine phosphorylation and reduced GnRH-a-stimulated MAPK activity by 50%, suggesting the participation of genistein-sensitive and insensitive pathways in GnRH-a action. Although Ca2+ ionophores have only a marginal stimulatory effect, the removal of Ca2+ markedly reduced MAPK activation by GnRH-a and TPA, but had no effect on GnRH-a and TPA stimulation of protein tyrosine phosphorylation. Interestingly, the removal of Ca2+ also partly inhibited the activation of MAPK by EGF and vanadate/H2O2. Thus, a calcium-dependent component(s) downstream of PKC and PTK might also participate in MAPK activation. Elevation of cAMP by forskolin exerted partial inhibition on EGF, but not on TPA or GnRH-a action, suggesting that MEK activators other than Raf-1 might be involved in GnRH action. We conclude that Ca2+, PTK, and PKC participate in the activation of MAPK by GnRH-a, with Ca2+ being necessary downstream to PKC and PTK.

Animals↗
PubMed1997

Human gene therapy for melanoma: CT-guided interstitial injection.

OBJECTIVE: Our intent is to describe the role of CT in the intratumoral injection of Allovectin-7 (Vical, San Diego, CA), an allogeneic class I major histocompatibility complex antigen, HLA-B7, formulated with cationic lipid, in the treatment of metastatic malignant melanoma. MATERIALS AND METHODS: Ten patients with metastatic malignant melanoma were treated with gene therapy in which we used CT-guided intratumoral injection of plasmid DNA containing the HLA-B7 gene. This therapy was part of a phase I gene therapy trial in patients with metastatic melanoma. CT guidance was chosen as an accurate way to direct gene delivery in patients with deep, impalpable lesions. Tumor locations included pulmonary, mediastinal, hepatic, adrenal, and paracaval sites. Patients in the CT protocol underwent baseline CT studies. Examinations were repeated 2, 4, and 8 weeks after gene therapy and thereafter at 3-month intervals. Both injected and noninjected tumors were measured. CT-guided injections of 10, 50, or 250 micrograms of plasmid DNA were performed with 22-gauge spinal needles. Injection volumes were between 1.0 and 4.0 ml, depending on tumor size. CT-guided core biopsy specimens were obtained (with 18- or 20-gauge needles) from the selected tumor before therapy and 2, 4, and 8 weeks after therapy to assess HLA-B7 plasmid DNA and gene expression. Peripheral blood was analyzed for cytotoxic T lymphocytes directed against HLA-B7. RESULTS: CT-guided intratumoral injections were successful in delivering genetic material to all patients with impalpable tumors. Significant responses (as defined by a decrease of 25% or more in the product of the length and width of the injected tumor) were observed in six of the 10 patients. One of these six patients who had a solitary lesion remains free of disease 19 months after gene therapy. HLA-B7 protein expression was detected in 89% of biopsy specimens, and plasmid DNA and messenger RNA were detected in 56% and 22% of biopsy specimens, respectively. CONCLUSION: CT provides a safe, accurate, and efficacious way to monitor and assess tumor progression and response, and it provides guidance for biopsies and intratumoral injections during gene therapy. Significant responses in injected tumors of six of the 10 patients in our study suggest that further clinical trials of this gene therapy are warranted.

Adult↗
PubMed1997

Stöckert roller pump generated pulsatile flow: cerebral metabolic changes in adult cardiopulmonary bypass.

There is evidence that during cardiopulmonary bypass (CPB), pulsatile pump flow improves cerebral metabolism. This was a study to explore the effect of pulsatile versus nonpulsatile perfusion on cerebral lactate, pyruvate, glucose and beta-hydroxybutyrate using a Stöckert roller pump. We found no significant differences between the arterial-venous (A-V) differences of lactate, glucose and beta-hydroxybutyrate (p > 0.05). When the upward trend of A-V pyruvate was accounted for, there was again no difference (p = 0.2). Arterial lactate:pyruvate ratios were not significantly different between pulsatile and nonpulsatile pump flow (p > 0.05). Venous lactate:pyruvate ratios were significantly higher during pulsatile bypass, but when the downward trend was accounted for, the differences between pulsatile and nonpulsatile values were no longer significant (p = 0.4). Therefore, the metabolic changes were not significant. There was no significant difference in systemic vascular resistance (SVR) during pulsatile and nonpulsatile flow (p = 0.4). Pulsatile flow delivered by the Stöckert roller pump appears to have no metabolic or SVR advantages in adults undergoing CPB.

3-Hydroxybutyric Acid↗
PubMed1997

Pilots' knowledge of the relationship between alcohol consumption and levels of blood alcohol concentration.

The U.K. Civil Aviation Authority is currently proposing that a maximum BAC (Blood Alcohol Concentration) limit of just 0.02% should be imposed on United Kingdom pilots. In this survey of 477 pilots, it was found that a large proportion could not determine when their BAC was likely to fall below this level after drinking alcohol and could, therefore, potentially inadvertently infringe the proposed regulation. Another large proportion of pilots felt that they were safe to fly before their BAC had dropped below 0.02%, which may be indicative of a willingness to infringe the regulations. Estimates of when it was safe to fly also became more inaccurate as the amount drunk increased and varied with the type of alcoholic beverage consumed. It was also found that the conclusions drawn were heavily dependent upon the formula used to estimate BAC. This methodological problem identified has considerable implications for the study of alcohol consumption when flying.

Adult↗
PubMed1997

Advanced surgical procedures: bone augmentation.

Over the last ten years there has been a significant increase in the range and type of edentulous defects that can be treated using osseointegrated implants. Encouraged by the long-term success of implant reconstructions in the edentulous mandible and maxilla, and the availability of novel implant attachments, clinicians will now undertake more elaborate treatment involving the partially edentate and those with localized or generalized tissue deficiencies. This clinical trend places increasing demands on the predictability, complexity and accuracy of the surgical procedure necessary to allow a successful prosthetic reconstruction. This is especially so when potential implant sites lie in areas of high aesthetic or functional requirements.

Alveolar Bone Loss↗
PubMed1996

Gray matter deficits in young onset schizophrenia are independent of age of onset.

This study examined whether the degree of brain dysmorphology observable in adulthood was related to onset age of schizophrenic symptoms. Brain magnetic resonance imaging (MRI) scans were acquired in 57 men with schizophrenia, whose age at MRI was 19-53 years, and whose symptom onset ranged from age 7 to 29 years; all were inpatients in a state hospital. Volumes of intracranial space, cortical gray matter (GM) and white matter (WM), and cerebrospinal fluid (CSF) in lateral and third ventricles and cortical sulci were derived from MRI scans and corrected by regression analysis for variations attributable to age and head size, quantified in a control sample of healthy community volunteers. The schizophrenic patients had larger volumes of cortical and ventricular CSF and smaller volumes of cortical GM but not WM than age-matched controls, whether or not volumes were adjusted for head size and age norms. Age of onset did not correlate with any of the five age-adjusted brain measures. Neither current age, length of illness, nor symptom severity correlated with age-normalized volumes of cortical GM, sulcal CSF, or ventricular CSF. These observations are consistent with the theory that brain structure deficits 1) first develop prior to symptom onset (perhaps during the prenatal and/or early childhood process of GM development); 2) probably establish a vulnerability to subsequent dysfunctionality; but 3) are nonprogressive.

Adult↗
PubMed1996

Leukemia-inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways.

Leukemia-inhibitory factor (LIF) is an inflammatory cytokine with pleiotropic activities. LIF was originally described as a differentiation factor of a murine leukemia cell line and was subsequently found to possess a broad spectrum of biological functions. Although LIF has been extensively studied in the hematopoietic system, little is known about its effects in solid tumors. We investigated the role of LIF in breast, kidney and prostate cancers. Using a clonogenic assay, we found that LIF significantly stimulated proliferation of 2 estrogen receptor-positive breast cancer cell lines (MCF-7 and T47-D) in a dose-dependent fashion at concentrations ranging from 10 to 200 ng/ml. This effect was observed both in the presence of FCS and under serum- and estrogen-free culture conditions, suggesting that the effect of LIF is direct and does not depend on estrogen or any other cytokine. Neither line produced LIF protein, as assessed by ELISA. In contrast, the estrogen receptor-negative breast cancer line MDA MB-231 produced LIF but did not respond to either LIF or its neutralizing antibodies. Similarly, increasing concentrations of LIF did not affect the growth of primary kidney (A-498), metastatic kidney (ACHN) and prostate (DU 145) cancer cell lines. These lines produce LIF, however, and antibodies to LIF significantly suppressed their proliferation, suggesting that they were maximally stimulated by the endogenously produced cytokine. Taken together, our data suggest that LIF acts as either a paracrine or an autocrine growth factor for breast, kidney and prostate cancers.

Breast Neoplasms↗
PubMed1996

A neuropsychological study of early onset schizophrenia.

Characterizing a pattern of cognitive dysfunction in early onset schizophrenic patients may illuminate neurodevelopmental contributions to the illness. A cohort of chronically institutionalized schizophrenic patients with a variable range of age of onset (range 7-29 years) was administered a comprehensive battery of neuropsychological tests that included the Luria-Nebraska Neuropsychological Test Battery. After statistical control of age, parental socioeconomic class (SES) effects, and thorazine equivalents, age of illness onset was positively correlated with performance on measures of motor ability, perceptual motor and pure motor speed, receptive and expressive speech, and overall cognition function, and inversely related to severity of negative symptoms; that is, earlier age of onset was associated with worse cognitive performance and an increase in negative symptoms. This study demonstrates that an early age of onset in schizophrenic illness is associated with impairment on tasks which involve motor and language abilities, functions linked to the frontal, temporal, and subcortical regions of the brain. This association is not due to the effects of medication, negative symptoms, or duration of illness.

Adult↗
PubMed1996

Sensitivity, reproducibility, and accuracy in short tandem repeat genotyping using capillary array electrophoresis.

The Human Genome Initiative has increased significantly the rate at which disease-causing genes are being mapped and sequenced. New cost-effective methods to locate the genes and to characterize disease-causing mutations require robust, reproducible, and accurate protocols for measuring DNA fragment lengths. Capillary array electrophoresis (CAE) offers rapid, high-resolution separations, high throughput, and sensitive detection. To assess the utility of CAE for the accumulation of genetic information, we tested both sizing accuracy and reproducibility using 48-capillary prototype systems. Two multiplex PCR allelic ladder standards and several CA-repeat markers were analyzed in > 100 runs. Reproducibility in typing > 8000 genotypes reveals a standard deviation of less than 0.2 bp on these systems under optimized conditions. However, sequence-dependent migration anomalies were observed at most simple sequence loci even when analyzed under denaturing conditions, resulting in a systematic bias in estimated fragment sizes. We show here that, by normalizing results to known typing controls, one can obtain locus-averaged accuracies of < 0.06 bp and normalized results within 1 bp of actual. We detect as little as a 1:30,000 dilution of a DNA quantitation standard stained with highly sensitive intercalating dyes, indicating an 80-zeptomole sensitivity limit. However, to obtain reproducible electrokinetic injection, approximately 200 attomoles of fluorescein-labeled DNA is required. These sensitivity limits, sizing precision, and accuracy, together with the 1-hr run times for 48-96 samples, indicate that CAE is a viable method for high-throughput genetic analysis of simple sequence repeat polymorphisms.

Capillary Action↗
PubMed1996

A 'domains of practice' approach to the standards of psychiatric and mental health nursing.

Standards have considerable influence on the practice of a discipline. As the written and explicit expectations of nurses held by their professional group, nursing practice standards serve as a basis for performance evaluation and as a clarification of the areas of nurses' accountability. Delineated here are the issues that the Canadian Federation of Mental Health Nurses faced as they attempted to identify and describe the nursing behaviours essential to this specialty area. A rationale for the 'domains of practice' approach is provided. The problems inherent in creating such a national document are addressed. Seven practice domains are described; the standards for two domains, the 'Helping' and the 'Effective Management of Rapidly Changing Situations', are outlined in detail.

Canada↗
PubMed1996

Effect of systemic administration of isotretinoin on blood lipids and fatty acids in acne patients.

BACKGROUND: In many studies, an increase in total cholesterol and triglycerides with isotretinoin therapy have been shown and investigators have commented on potential cardiovascular risk. A low intake of linoleic acid, the main essential fatty acid in man, may act as an independent risk factor for coronary heart disease. In vitro etretin alters both the incorporation of extracellular fatty acids into cell membranes and the fatty acid composition of the cell membrane itself. It is, therefore, important to establish whether isotetinoin has any effect on the metabolism of polyunsaturated fatty acids. METHODS: The effect of treatment with isotretinoin for 4 months on the metabolism of polyunsaturated fatty acids in patients with acne was assessed. Quantitative total cholesterol and triglycerides as well as plasma phospholipid, triglycerides, and cholesteryl ester fatty acids were measured in 12 patients and red cell phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol fatty acids were measured in 13 patients before and after isotretinoin therapy. RESULTS: There was a significant increase in the concentrations of cholesterol (P < 0.02) and triglycerides (P < 0.04) during treatment. There was no significant difference is plasma phospholipids, triglycerides, and cholesterol esters, or in the red cell phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol during isotretinoin therapy. CONCLUSIONS: This study failed to demonstrate any effect of isotretinon on the metabolism of polyunsaturated fatty acids. There was a significant increase in total cholesterol and triglyceride levels following isotretinoin therapy supporting the findings of many previous studies.

Acne Vulgaris↗
PubMed1996

Limited role for nitric oxide in mediating cerebrovascular control of newborn piglets.

AIMS: To investigate the effects of the nitric oxide (NO) synthase inhibitor L-nitro-arginine methyl ester (L-NAME) on cerebral blood flow, and its response to alterations in arterial carbon dioxide tension (CBF-CO2 reactivity). METHODS: Cerebral blood flow was measured six times at varying arterial carbon dioxide tension (PaCO2) using the intravenous 133Xenon clearance technique in eight mechanically ventilated piglets of less than 24 hours postnatal age. After the third measurement L-NAME was administered as a bolus (20 mg/kg) and subsequently infused (10 mg/kg/hour). RESULTS: PaCO2 ranged between 2.7-8.9 kPa. Cerebral blood flow decreased by 14.0% (95% confidence interval 1.9-27.4) after L-NAME. CBF-CO2 reactivity was 18.4% per kPa (95% CI 14.1-22.2) before L-NAME and 15.2%/kPa (95% CI 11.1-19.3) afterwards; the difference between the CBF-CO2 reactivities was 3.2%/kPa (95% CI -0.4-6.8): these were not significantly different. CONCLUSIONS: Inhibition of nitric oxide synthesis reduces cerebral blood flow no more than a 0.5-1.0 kPa fall in PaCO2. Nitric oxide is not an important mediator of CBF-CO2 reactivity.

Animals↗
PubMed1996

Molecular and biologic characterization of a newly established Philadelphia-positive acute lymphoblastic leukemia cell line (Z-33) with an autocrine response to GM-CSF.

We have recently established a new Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL) cell line, designated Z-33. This line has L2 morphology, ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1-positive ALL patient from whom the line was derived. In addition, a rearranged immunoglobulin heavy-chain gene (JH) band was found in Z-33 cells by Southern blot analysis, confirming B cell clonality. Cytogenetic analysis of the cell line revealed t(9;22)(q34;q11.2). Polymerase chain reaction (PCR)-amplified cDNA from Z-33 cells demonstrated an e1-az BCR-ABL junction, and the p190BCR-ABL protein was detected in them by the immune complex kinase assay. Z-33 cells produce interleukin (IL)-1 beta, IL-6, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta, Neither IL-1 beta, G-CSF, TNF-alpha, nor their corresponding antibodies affected the cell line's growth. In contrast, anti-GM-CSF neutralizing antibodies suppressed Z-33 colony formation, and GM-CSF stimulated it in a dose-dependent fashion. In addition, receptor studies with biotinylated GM-CSF demonstrated specific binding to Z-33 cells, indicating that the cells express GM-CSF receptors. Taken together, our data suggest that the Ph1-positive Z-33 ALL cells produce GM-CSF, express GM-CSF receptors, and show an autocrine proliferative response to this cytokine.

Antibodies↗
PubMed1995

Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation.

Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine protease that specifically cleaves precursor IL-1 beta to its biologically active form. Recent studies have also implicated ICE in the induction of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do this, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to penetrate cells and bind covalently to the active site of ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mumol/L of BAMCK downregulated production of mature IL-1 beta but had no effect on tumor necrosis factor-alpha. To test the effects of the inhibitor on AML cells, we first used the OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mumol/L) and downregulated mature IL-1 beta production, as assessed by Western immunoblotting. Similar results were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a dose-dependent fashion at concentrations ranging from 0.4 to 5 mumol/L but not proliferation of normal marrow progenitors; the suppressive effect was reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mumol/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitors may have a role in future therapies for AML.

Adult↗