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Biomedical subjects

M Johnson

Publications and source records attributed to M Johnson.

At least 73 records · Page 4Linked to original sources
PubMed2001

Early molecular changes in irradiated aortic endothelium.

Irradiated aortic endothelial cells (EC) exhibit distinct morphological, functional, and physiological responses to ionizing radiation (IR). However, the molecular basis for these responses has not been fully characterized. Cultured bovine and rat aortic endothelial cells were exposed to single fraction doses (0-30 Gy) of gamma radiation. IR caused dose-dependent DNA strand breaks which were repaired to near baseline levels within 30 min. A dose-dependent inhibition of cell growth was noted for IR greater than 1 Gy. At doses greater than 2.5 Gy, morphologic changes consistent with apoptosis and loss of cell viability were present beginning 12-16 h after radiation, with subsequent detachment of EC from the cell monolayer. By Western blot analysis, expression of p53, gadd45, p21, and bax protein increased in a time-and dose-dependent manner; p53 expression was maximal at 3 h after IR, and gadd45, bax and p21 levels peaked at 6 h. By Reverse Transcriptase Polymerase Chain Reaction (RT-PCR), levels of p53 mRNA were not significantly increased after IR, whereas gadd45 exhibited time- and dose-dependent increase in mRNA synthesis after IR. Activation of intracellular caspases, manifest by proteolytic poly (ADP-ribose) polymerase (PARP) and lamin B cleavage, was maximal at 15 h after IR, concident with other indices of EC apoptosis, including oligonucleosomal DNA degradation, TUNEL immunostaining, and morphologic changes. The tripeptide protease inhibitor z-Val-Ala-Asp (zVAD) prevented PARP and lamin cleavage, DNA fragmentation, morphological changes, and cell detachment in irradiated EC. The combined data suggested that gamma radiation induces a dose- and time-dependent sequence of early events in cultured EC with modulate growth arrest, apoptosis, and possibly premature senescence in surviving cells.

Amino Acid Chloromethyl Ketones↗
PubMed2001

Vascular endothelial growth factor-mediated autocrine stimulation of prostate tumor cells coincides with progression to a malignant phenotype.

Vascular endothelial growth factor (VEGF), which is often produced at high levels by tumor cells, is a well-known mediator of tumor angiogenesis. VEGF receptor tyrosine kinases, KDR/Flk-1 and Flt-1, have been thought to be expressed exclusively by endothelial cells. In this study, we have used a prostate tumor progression series comprised of a differentiated rat prostate epithelial cell line, NbE-1, and its highly motile clonal derivative, FB2. Injection of NbE-1 cells into the inferior vena cava of syngeneic rats indicated that these cells are nontumorigenic. Using the same model, FB2 cells generated rapidly growing and well-vascularized tumors in the lungs. NbE-1 expressed marginal levels of VEGF, whereas high levels of VEGF protein were detected in FB2-conditioned medium and in FB2 tumors in vivo. Analysis of (125)I-VEGF(165) binding to NbE-1 and FB2 cells indicated that only motile FB2 cells expressed the VEGF receptor Flt-1. Consistent with this finding, physiological concentrations of VEGF induced chemotactic migration in FB2 but not in NbE-1 cells. This is the first documentation of a functional Flt-1 receptor in prostate tumor cells. Our results suggest two roles for VEGF in tumor progression: a paracrine role as an angiogenic factor and a previously undescribed role as an autocrine mediator of tumor cell motility.

Animals↗
PubMed2001

Matriptase and HAI-1 are expressed by normal and malignant epithelial cells in vitro and in vivo.

Matriptase and its cognate, Kunitz-type serine protease inhibitor, HAI-1, comprise a newly characterized extracellular matrix-degrading protease system that may function as an epithelial membrane activator for other proteases and latent growth factors. Both enzyme and inhibitor have been detected in breast cancer cells, immortalized mammary epithelial cells, and human milk, but not in cultured fibroblasts nor in fibrosarcoma cells. To test the hypothesis that this system is expressed by normal breast epithelium, invasive breast cancers, and other cancers of an epithelial origin (carcinomas) but not in cancers of a mesenchymal origin, we have expanded our expression analysis of matriptase and HAI-1 in vitro and in vivo. Matriptase and HAI-1 were detected at the protein and mRNA levels both in hormone-dependent and hormone-independent cultured breast cancer cells, and this expression correlated with the expression of the epithelial markers E-cadherin or ZO-1. However, none of the breast cancer cell lines tested that express the mesenchymal marker vimentin express matriptase or HAI-1, consistent with an epithelial-selective expression of this system. Expression of matriptase, as determined by Western blot analysis, was observed in primary human breast, gynecological, and colon carcinomas, but not in stromal-derived ovarian tumors and human sarcomas of various origins and histological grades. The epithelial-selective expression of matriptase and HAI-1 was further confirmed in human breast cancers by immunohistochemistry and in situ hybridization, where the expression of the protease and the inhibitor were found in the carcinoma cells and in surrounding normal breast epithelia. The expression of the matriptase/HAI-1 system by malignant epithelial cells in vivo suggests a possible role for this protease in multiple aspects of the pathophysiology of epithelial malignancy, including invasion and metastasis.

Biomarkers↗
PubMed2001

Visual hallucinations are associated with lower alpha bungarotoxin binding in dementia with Lewy bodies.

Patients with dementia with Lewy bodies (DLB) commonly experience psychotic symptoms, most notably visual hallucinations. Previously, it has been shown that visual hallucinations in DLB are associated with reduced cortical choline acetyltransferase activity, a marker of cholinergic innervation, but not with predominantly postsynaptic muscarinic M1 receptor binding. In the present investigation, nicotinic acetylcholine receptor (nAChR) levels in the temporal cortex (Brodmann's areas [BA] 20 and 36) were measured in a group of 24 prospectively assessed DLB patients; comparisons were made between groups with or without visual and auditory hallucinations and delusional misidentification. Visual hallucinations and delusional misidentification were associated with lower [(125)I]alpha bungarotoxin binding in areas 36 and 20 (P<.05), but not with changes in [(3)H]epibatidine binding. There were no significant associations with auditory hallucinations. [(3)H]epibatidine, but not [(125)I]alpha bungarotoxin, binding for all DLB cases was reduced compared to controls (P<.001). Loss of cortical alpha 7 nicotinic receptors may contribute to hallucinations and delusional misidentification in DLB, with implications for treatment and understanding the mechanisms of psychotic symptoms in dementia.

Aged↗
PubMed2001

Nicotine attenuates DOI-induced head-twitch response in mice: implications for Tourette syndrome.

Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that twitches of the head in mice or twitches of head and shoulders in rats following administration of the selective 5HT(2A/C) agonist DOI (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. In this study, the effects of acute and chronic administration of nicotine on DOI-induced head twitch response (HTR) in male albino ICR mice were evaluated. Both acute and chronic nicotine (daily injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in 65% increase in [125I]alpha-bungarotoxin binding in cerebellum and 41% increase in striatal [3H]cytisine binding. However, the acute inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS.

Animals↗
PubMed2001

Cancer pain management skills among medical students: the development of a Cancer Pain Objective Structured Clinical Examination.

Recent surveys suggest that most physicians have inadequate knowledge to assess and manage cancer pain; however, the important domain of clinical performance has not yet been clearly evaluated. The Objective Structured Clinical Examination (OSCE) has become a widely- used and accepted method to evaluate the clinical abilities of medical students. The purpose of this study was to develop and test a Cancer Pain OSCE for medical students evaluating their clinical competence in the area of cancer pain management. A four-component Cancer Pain OSCE was developed and presented to 34 third-year medical students during a sixteen-week combined medicine/surgery clerkship. The content of the objective criteria for each component of the OSCE was developed by a multidisciplinary group of pain experts. The OSCE was designed to assess the students' cancer pain management skills of pain history-taking, focused physical examination, analgesic management of cancer pain, and communication of opioid analgesia myths. Actual cancer survivors were used in the five-minute individual stations. The students were asked to complete a cancer pain history, physical examination, manage cancer pain using analgesics, and communicate with a family member regarding opioid myths. Clinical performance was evaluated using pre-defined checklists. Results showed the student's average performance for the history component was the highest of all four components of the examination. Out of 34 points possible on this clinical skills item, students on average (SD) scored 24.5 (5.2), or 72%. For the short-answer analgesic management component of the Cancer Pain OSCE, the overall score was 32%. Most students managed cancer pain with opioids, however, very few prescribed regular opioid use, and the use of adjuvant analgesics was uncommon. Student performance on the focused cancer pain physical examination was, in general, poor. On average students scored 61% on the musculoskeletal system, but only 31% on both the neurological and lymphathic examination. The overall percent score for the cancer pain OSCE was 48%. We conclude that the Cancer Pain OSCE is a useful performance-based tool to test individual skills in the essential components of cancer pain assessment and management. Of the four components of the Cancer Pain OSCE, medical students performed best on the cancer pain history and performed poorly on the cancer pain physical examination. Information gained from this study will provide a foundation on which future small-group medical student structured teaching will be based.

Analgesics↗
PubMed2001

Laminar distribution of nicotinic receptor subtypes in cortical regions in schizophrenia.

The laminar cortical distribution of the [125I]alpha-bungarotoxin, [3H]cytisine and [3H]epibatidine nicotinic acetylcholine receptor ligands was investigated by quantitative autoradiography in autopsy tissue from the cingulate, orbitofrontal and temporal cortices of control and schizophrenia subjects matched for age and smoking history. Different laminar binding patterns were observed for the various nicotinic ligands both in schizophrenic and control brains. [125I]alpha-Bungarotoxin binding was distributed homogeneously across all cortical layers in all three brain regions, with highest binding densities in the cingulate cortex. [3H]Cytisine and [3H]epibatidine binding varied across the cortical ribbon, with high binding in layers I, III, V and VI, within the three cortical regions. A significantly reduced [125I] alpha-bungarotoxin binding (-54%) was observed in the cingulate cortex of schizophrenia subjects, in comparison with normal individuals who smoked tobacco. In the same brain region also a significantly higher [3H]cytisine binding (48-77%) was observed in nearly all layers, except for layer I of the schizophrenia subjects, when compared to normal individuals with a history of tobacco use. No significant changes in [3H]epibatidine binding was observed within the individual cortical layers between control subjects and patients with schizophrenia, but when calculated as a whole region (i.e. measurements performed across the whole cortical ribbon), the temporal cortex showed a significant increase in [3H]epibatidine binding in schizophrenia subjects compared to control subjects. The results suggest opposite changes of the alpha4beta2 and alpha7 nicotinic receptor subtypes in the cingulate cortex of patients with schizophrenia which might reflect involvement of two different nicotinic receptor mechanisms in schizophrenia brain.

Acetylcholine↗
PubMed2001

The role of radionuclides in primary musculoskeletal tumors beyond the 'bone scan'.

Radionuclides represent a means of functional imaging, which is able to reflect the metabolic state of tissues. Recently developed radiotracers and older radiotracers with newer applications, imaged through single photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide significant information in the diagnosis, grading, therapy response or recurrence of primary musculoskeletal tumors. The unique ability of these radiotracers to demonstrate non-invasively the efflux pump rate, which is a common reason of therapy failure, as well as the metabolic and proliferative rates of the tumors should be a powerful tool in the orthopaedic oncology in the evaluation of musculoskeletal tumors.

Bone Neoplasms↗
PubMed2001

Memory interference during language processing.

The authors studied the operation of working memory in language comprehension by examining the reading of complex sentences. Reading time and comprehension accuracy in self-paced reading by college students were studied as a function of type of embedded clause (object-extracted vs. subject-extracted) and the types of noun phrases (NPs) in the stimulus sentences, including relative clauses and clefts. The poorer language comprehension performance typically observed for object-extracted compared with subject-extracted forms was found to depend strongly on the mixture of types of NPs (descriptions, indexical pronouns, and names) in a sentence. Having two NPs of the same type led to a larger performance difference than having two NPs of a different type. The findings support a conception of working memory in which similarity-based interference plays an important role in sentence complexity effects.

Adult↗
PubMed2001

Arguments for 'British Pluralism' in qualitative health research.

AIMS OF THE STUDY: This paper examines the argument that certain qualitative research methods can be used in 'pure' forms. Whilst rigid adherence to particular published procedures might be possible, we argue that in many cases this is neither necessary nor more likely to increase the validity of the research outcome. METHODOLOGICAL PURITY: In examining the works of well-known claimants to particular research approaches such as grounded theory and phenomenology we show that purity of method is uncommon. In particular it is possible to demonstrate that all published qualitative methods are subject to their own underlying relativist philosophy. The implication of this is that all are social constructions and that their execution will necessarily be negotiated in time and context. CONCLUSION: We conclude that analysis of varied examples of qualitative research shows methods to be more flexible than is often admitted. What we describe as 'British Pluralism' is an attempt to accept this reality whilst maintaining rigour through integrity, clear accounts, reflexivity and constructive critique of one's own work and that of others.

Bias↗
PubMed2001

Living and coping with excessive infantile crying.

AIM: The aim of the study was to elicit from parents how they lived and coped with a baby who cries excessively. It sought to identify factors which made coping more difficult, as well as interventions perceived by parents to be effective in improving the situation. BACKGROUND: The excessive crying of a baby can be one of the most trying aspects of parenthood. Although there have been many studies into the cause and treatment of the problem, these have produced little convincing evidence and even less agreement among investigators. In the light of this an alternative approach is to provide effective support to enhance coping until the crying abates. DESIGN: This study was based in pragmatic ethnography and followed an adapted grounded theory approach. A total of 25 adults from 14 families participated, recounting their experiences with 20 babies who either were currently crying excessively or had done so previously while less than 1 year old. Data was collected by a factual questionnaire and tape-recorded focused interviews conducted in the family home augmented by periods of participant observation. OUTCOMES: Almost every aspect of family life was disrupted, resulting in strained relationships, feelings of guilt, and concerns about losing control. Repeated attempts had to be made to establish a diagnosis and to find a cure. Such attempts failed, leading to a repeated cycle of hope and disappointment. The greatest potential to effect a positive impact lay in the supportive role of health visitors. They needed to visit frequently; stay for a prolonged period; demonstrate engagement with the family and its difficulties; and impart specific messages with conviction and sincerity. CONCLUSION: A specific, vital role was found for the health visitor in supporting parents through this problem, and aspects of the role were identified in which further study is indicated.

Activities of Daily Living↗
PubMed2001

Role of the nucleoid-associated protein Fis in the regulation of virulence properties of enteropathogenic Escherichia coli.

Virulence gene expression in enteropathogenic Escherichia coli (EPEC) is governed by a combination of environmental factors and virulence regulators. These factors control the expression of the bundle-forming pili (BFP), intimin, the type III secretion apparatus and the secreted proteins EspA, EspB, EspD and Tir. Expression of the bfp genes occurs for a short period in early exponential phase during growth in tissue culture medium. The nucleoid-associated regulator protein, Fis, is also expressed transiently during this period. To determine whether Fis was responsible for the growth phase-dependent expression of bfp, fis was deleted from the EPEC strain E2348/69S. Paradoxically, the Delta fis mutant retained the ability to colonize HEp-2 cells in a characteristic localized adherence pattern, and Fis was found negatively to regulate the expression of BFP. However, the Delta fis mutant failed to induce the accretion of filamentous actin, which is associated with attaching and effacing lesions. Using a combination of Western blotting and a novel multiplex primer extension assay (MPEA), we showed that, although the expression of intimin and Tir was not affected, transcription of the LEE4 operon encoding espADB and the virulence activator, Ler, were found to be Fis dependent.

Adhesins, Bacterial↗
PubMed2001

Developing evidence-based clinicians.

Evidence-based care has heralded an advancement for health with extensive rhetoric and incentives encouraging clinicians to become active participants in practice change. This paper explores two mechanisms-research utilization and systematic reviews--as processes to develop empowerment in clinicians, and develop an ethos of basing practice on research. The intent of these approaches is to create an environment that enables clinicians to seek solutions to practice problems, inform practice decisions and develop practice policy using evidence from research. The goal is to develop evidence-based clinicians who remain active and interested in their practice and who are committed to promoting the application of research to practice. The strengths and weaknesses of these methods are explored within two case studies where they are applied to the management of hypothermia and the efficacy of postoperative observations. Key points of application for each of the methods are outlined in the conclusions.

Australia↗
PubMed2001

Assessing the cost-effectiveness of HAART for adults with HIV in England.

OBJECTIVE: To assess the cost-effectiveness of highly active antiretroviral therapy (HAART) compared with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV infected individuals. DESIGN: Different data sources on the clinical effects and costs of treatments were combined using a Markov model. SETTING: English HIV treatment centres. Perspective UK public finance. INTERVENTIONS: HAART - dual NRTI therapy plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor - vs. dual NRTI therapy. PARTICIPANTS: Hypothetical cohorts of 1000 individuals infected with HIV. Outcome measures Projected life expectancy, cost-effectiveness in UK pound per life-year saved and per quality-adjusted life-years (QALYs) saved. RESULTS: Assuming a 2-year additional treatment effect of therapy with HAART produced incremental cost-effectiveness ratios of pound14 602 per life-year saved and pound17 698 per QALY saved. CONCLUSIONS: The results were sensitive to a number of assumptions including the cost of HAART and the discount rate, but they suggest that the use of HAART in England is at least moderately cost-effective compared with treatment with two NRTIs alone.

Adult↗
PubMed2001

A randomized, double-blind, placebo-controlled study of itraconazole capsules for the prevention of deep fungal infections in immunodeficient patients with HIV infection.

OBJECTIVES: To determine whether systemic or deep fungal infections can be prevented, a double-blind, placebo-controlled, phase III trial of itraconazole prophylaxis was undertaken in HIV-infected patients. METHODS: HIV-1 infected patients with CD4 counts < 300 cells/microL were treated with itraconazole (200 mg per day) or matching placebo and followed for 2 years. Development of deep fungal infections, episodes of mucocutaneous candidiasis, change in CD4 count, survival and safety data were collected at each study visit. RESULTS: Three hundred and seventy-four patients received study medication, 187 were given itraconazole and 187 matching placebo. Time to development of deep fungal infection did not differ between groups, in an intention to treat analysis. Low CD4 cell count and prior use of Pneumocystis carinii pneumonia (PCP) prophylaxis were significantly associated with a more rapid development of deep fungal infection (P = 0.044 and 0.017, respectively). Itraconazole treatment significantly reduced the incidence of oral candidosis (25% vs. 48% P < 0.001) and time to development of oral candidosis (508 vs. 413 days, P < 0.001) but not the number of deep fungal infections (11 vs. 13). Survival did not differ significantly between groups (nine vs. 14 deaths). CD4 counts decreased significantly over time in both study arms. Adverse events did not differ between groups; 20% vs. 23% stopped study medication due to an adverse experience. CONCLUSIONS: Although itraconazole prophylaxis significantly reduced the number and time to development of oral candidosis, too few episodes of deep fungal infection were noted to determine whether itraconazole prophylaxis was effective for this condition. Chronic itraconazole treatment is well tolerated in HIV-infected patients with marked immunodeficiency.

AIDS-Related Opportunistic Infections↗
PubMed2001

Beta2-adrenoceptors: mechanisms of action of beta2-agonists.

The human beta2-adrenoceptor is a member of the 7 transmembrane family of receptors. It is encoded by a gene on chromosome 5 and is widely distributed in the respiratory tract. Following beta2-adrenoceptor activation, intracellular signalling is mainly produced by inducing cyclic AMP. This produces airway relaxation through phosphorylation of muscle regulatory proteins and modification of cellular Ca2+concentrations. Beta2-agonists have been characterised into those which directly activate the receptor (salbutamol/terbutaline), those which are taken up into a membrane depot (formoterol) and those which interact with a receptor-specific, auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in asthmatic patients. Beta-adrenoceptor desensitisation is associated with beta2-agonist activation and differs depending on the cell type. It is reflected in the different profiles of clinical tolerance to chronic beta2-agonist therapy. A number of polymorphisms of the beta2-receptor have been described which appear to alter the behaviour of the receptor, including the degree of downregulation and response to beta2-agonists.

Adrenergic beta-Agonists↗