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Biomedical subjects

J Friel

Publications and source records attributed to J Friel.

At least 19 recordsLinked to original sources
PubMed2005

Monitoring of hematological, inflammatory and oxidative reactions to acute oral iron exposure in human volunteers: preliminary screening for selection of potentially-responsive biomarkers.

BACKGROUND: Iron is an essential micronutrient but also a major catalyst of oxidative and inflammatory reactions. OBJECTIVE: To evaluate the potential utility of selected biomarkers in blood or urine to indicate in vivo oxidative or inflammatory response to oral iron intake at pharmacological doses. METHODS: Three healthy volunteers provided morning, fasting samples of blood and urine on up to 13 study days--3 before, 7 during and 3 following a 7-consecutive-day period of receiving 120 mg of iron per day as ferrous sulfate in commercially available syrup. A series of 23 biomarkers were measured on each collection of biological fluids to monitor iron-responsive changes in biomarkers related to hematological or iron status, inflammation and in vivo oxidation. RESULTS: Among the inflammatory biomarkers measured, white blood cells, serum CRP and urinary neopterin showed no response to iron dosing. Only circulating interleukin-4 (IL-4) and TNF-alpha had abnormal responses with a time association to the oral iron intake. Among the oxidative biomarkers, expression of blood superoxide dismutase (SOD), hemoxygenase-1, catalase as well as circulating thiobarbituric acid reactive substances (TBARS), total oxidative capacity and carbonyl proteins were stable in response to iron exposure. Only urinary TBARS, 8-hydroxy-2-desoxyguanosine and isoprostanes evidenced consistent or suggestive responses to ingestion of the iron challenge. Serum hepcidin concentration increased dramatically in all three subjects after only the first 120 mg dose of iron, and remained elevated even 9 days after cessation of the iron intervention. CONCLUSIONS: Most of the candidate biomarkers show very limited promise as response-indicators to oral iron dosing at the 120 mg dosages or lower, but circulating IL-4, TNF-alpha as well as urinary TBARS, 8-hydroxy-2-desoxyguanosine and isoprostanes showed potential utility as reliable indicators of oxidative and inflammatory response to oral ferrous sulfate.

Administration, Oral↗
PubMed2003

Are syndromes in environmental medicine variants of somatoform disorders?

To date, relatively little is known about the etiology, pathophysiology, diagnosis, therapy, prevention and prognosis of environment-related syndromes like multiple chemical sensitivity (MCS), idiopathic environmental intolerance (IEI), sick building syndrome (SBS), chronic fatigue syndrome (CFS), candida syndrome (CS) and burnout syndrome (BS). Part of the reason is that these syndromes have not been clearly defined and classified in scientific categories distinct from each other, and that they show clinical similarities to classified somatoform disorders. Furthermore, there are at least three possible explanations for the existence of these syndromes: (1) The syndromes may result from the interaction of environmental factors, individual susceptibility and psychological factors (i.e., how they are perceived and seen by the patient); (2) they may reflect socially and culturally accepted methods of expressing distress; and/or (3) they may be iatrogenic. Despite all the uncertainties in evaluation of environmental syndromes, physicians have the duty to take the affected person's problems seriously. A comprehensive systematic classification which better accounts for these complex clinical manifestations is long overdue. Until these syndromes are well defined, the terms used for them should definitely not be applied to connote a specific disease process.

Environment↗
PubMed2003

A review and methodologic critique of the literature supporting 'chronic whiplash injury': part I - research articles.

The existence of a 'chronic whiplash injury' has been a source of debate in the medical literature for many years. Some authors have published articles suggesting that chronic whiplash syndrome is the result of chronic pathology (injury), and that this injury may occur at any collision speed; others have stated that any psychological factors are secondary rather than primary (etiologic) to the problem of chronic pain, or that secondary gain is a rare or uncommon phenomenon. These articles contradict scientific measures and efforts which show that for Quebec Task Force Grade 1 and 2 whiplash-associated disorders, the highly prevalent problem of chronic pain may be a culturally and psychosocially determined phenomenon, in which confounding psychosocial variables determine the behaviour and outcome following an otherwise benign acute injury. The authors of the current literature critique reviewed the biomedical and engineering literature relating to whiplash syndrome, searching for articles that supported the construct of 'chronic whiplash injuries'. Thirty seven articles containing fourteen distinct statements supporting the construct of 'chronic whiplash injuries' were found that fit the inclusion criteria. The methodology described in these articles was evaluated critically to determine if the authors' conclusions regarding 'chronic whiplash injuries' were scientifically sound. The authors of the current critique found that all of the articles contained significant methodologic errors relative to their respective authors' statements regarding chronic whiplash. The most frequent concerns reside with sampling, experimental design and interpretation of data.

Accidents, Traffic↗
PubMed2001

Low-level expression of functional foamy virus receptor on hematopoietic progenitor cells.

Foamy viruses have several qualities favorable for vector development: they are not known to cause disease; they can transduce stationary cells; and the foamy virus receptor is expressed on a wide variety of cells. Here, we analyzed the level of virus receptor expression on hematopoietic progenitor cells. Foamy virus binding was measured by a flow cytometric assay and was found to be considerably reduced in hematopoietic progenitors cell lines as well as in primary CD34(+) cells when compared to fibroblasts. Retroviral vectors based on murine leukemia virus (MLV) pseudotyped with a foamy virus envelope transduced hematopoietic cell lines with a more than 10-fold lower efficiency than fibroblasts. Moreover, less than 1% of primary CD34(+) hematopoietic progenitor cells were transduced with the foamy virus pseudotypes, while gene transfer efficiencies of 8-40% were achieved using pseudotypes with amphotropic envelope or the G protein of vesicular stomatitis virus. In conclusion, the expression of functional foamy virus receptors on hematopoietic progenitors cells was found to be insufficient to achieve high levels of gene transfer into CD34(+) hematopoietic progenitor cells with cell-free vector supernatants using current transduction protocols.

Animals↗
PubMed2001

Heat shock protein 27 inhibits apoptosis in human neutrophils.

BACKGROUND: Prolonged neutrophil(PMN) survival has been implicated in tissue injury following sepsis. A variety of bacterial products have been identified which inhibit PMN apoptosis including lipopolysaccharide(LPS). Extracellular heat shock proteins(Hsp) have recently been identified as potent regulatory signals for the innate immune system during the inflammatory response. We hypothesized that Hsp 27 can affect PMN phenotype with respect to apoptosis and cytokine profile. MATERIALS AND METHODS: PMN were isolated from the peripheral blood of healthy human volunteers by red blood cell sedimentation and gradient centrifugation. Cells were placed in media and cultured for 18 h with and without recombinant human Hsp 27 at various concentrations. In parallel experiments, PMN were stimulated with LPS, a known inhibitor of PMN apoptosis, for comparison. Apoptosis was quantified using annexin V and propidium iodide staining with flow cytometric analysis. Culture supernatants were assayed for secretion of TNF-alpha, IL-10, and IL-12. RESULTS: Hsp 27 significantly inhibits PMN apoptosis [control; 81.8 +/- 3.6%, vs Hsp 27, 60.4 +/- 4.1% p < 0.05]. The reduction is similar to that signaled by LPS, alone. Together their effect is not synergistic. The Hsp 27 response is dose-dependent. Hsp 27 does not induce secretion of TNF-alpha, IL-10, or IL-12, whereas LPS does signal IL-12 and TNF-alpha secretion. CONCLUSION: These data demonstrate that exogenous Hsp 27 may play a role in neutrophil-mediated tissue injury during trauma and sepsis via its ability to inhibit neutrophil apoptosis. However, Hsp 27 does not significantly alter neutrophil phenotype with respect to cytokine production profile.

Apoptosis↗
PubMed2001

Cognitive theory and illness behavior in disability syndromes.

There are many controversial disability syndromes, representing medicolegal and social dilemmas for a variety of medical disciplines. While illness behavior and sick role phenomena are often invoked to explain many of these syndromes, the extent to which such phenomena are under volitional control has not been thoroughly explored. The volitional control of illness behavior has important treatment implications, and may explain why cognitive therapy can be effective in these patients. Further understanding of the relevance of cognitive theory to illness behavior, the sick role, secondary gain, and disability may render even more effective cognitive therapy approaches. This review explores the consciousness states, the role of each state in information processing (in this case processing illness information), the automaticity and hence volitional state of each level of information processing, and the likelihood that illness behavior in disability syndromes is volitional. The cognitive model of these syndromes considers the interaction of automaticity, volition, and illness behavior and likely has numerous clinical, social, and legal applications.

Cognition↗
PubMed2001

Tertiary gain and disability syndromes.

Since the introduction of the concept of tertiary gain by Dansak in 1973, there has been little further publication or research on this topic. Yet, tertiary gain is often the subject of debate amongst physicians, therapists, insurers, the media, and even at times the general public. Much of the controversy of disability syndromes and the health and economic burden they present has focused on secondary gain and illness behaviour. The role of tertiary gain in illness behaviour is likely also relevant, and a model of tertiary gain is needed to begin further understanding the implications of this phenomenon for patients and those who treat them. This article introduces a phraseology for tertiary gain, and models the effects of tertiary gain on illness behaviour and the interactions of secondary and tertiary gain in the setting of disability syndromes.

Persons with Disabilities↗
PubMed2001

Inhibition of p38 mitogen activated protein kinase increases lipopolysaccharide induced inhibition of apoptosis in neutrophils by activating extracellular signal-regulated kinase.

BACKGROUND: Prolonged polymorphonuclear neutrophil (PMN) survival has been implicated in tissue injury after sepsis. Previously we reported that lipopolysaccharide (LPS) inhibits PMN apoptosis via the activation of the extracellular signal-regulated kinase (ERK). Conversely, the p38 mitogen activated protein kinase (MAPK) pathway is involved in the spontaneous apoptosis of PMNs. The interaction between these 2 pathways and their ability to regulate apoptosis during sepsis remain largely undefined. We hypothesize that there is interaction between the ERK and p38 pathways during sepsis. METHODS: PMNs were isolated from healthy volunteers by Ficoll gradient centrifugation and red blood cell sedimentation. Cells were then pretreated for 1 hour with the ERK inhibitor (PD98059, 10 micromol/L), p38 inhibitor (SB203580, 1 micromol/L), or vehicle. After treatment with LPS, apoptosis and MAPK activity were correlated. RESULTS: LPS stimulation significantly inhibits PMN apoptosis compared with unstimulated cells. Furthermore, inhibition of ERK significantly abrogates this effect, whereas inhibition of p38 augments LPS induced inhibition of apoptosis. Elk-1 phosphorylation (ERK target) is significantly increased by LPS alone and by inhibition of the p38 pathway during LPS stimulation. This correlates with ERK phosphorylation by Western blot. CONCLUSIONS: These data show that p38 inhibition enhances ERK activity during endotoxemia. Furthermore, these data suggest that cooperation between ERK and p38 MAPK pathways dictates the apoptotic potential of PMNs during inflammatory states.

Adult↗
PubMed2000

Transcriptional activation of the granulocyte-macrophage colony-stimulating factor receptor gene in cell mutants.

Retroviral insertional mutagenesis has proven to be a powerful in vivo approach for identifying genetic mutations involved in tumorigenesis or developmental abnormalities. Applying this approach to an in vitro system, where experimental design can be readily manipulated, would greatly increase its efficacy. In this study, we sought to determine whether retroviral insertional mutagenesis could be used to isolate cell mutants, in which the transcriptional activation of a receptor gene has occurred. Cells of the myeloid progenitor cell line FDC-P1(M), which do not express the alpha receptor subunit (GMRalpha) for granulocyte-macrophage colony-stimulating factor (GM-CSF), were infected and selected for growth in GM-CSF. Over 100 mutants were isolated at a frequency up to ninefold higher than that of uninfected controls. Expression of GMRalpha in these mutants was confirmed by blocking proliferation with GM-CSF antibodies, detection of high-affinity receptors, and Northern blot analysis. Significantly, in 7/18 mutants analyzed, gross DNA rearrangements had occurred in the GMRalpha locus. These rearrangements were demonstrated to be due to intergenic rearrangements, juxtaposing an active enhancer/promoter upstream of the GMRalpha gene. In one mutant it could be demonstrated that the wild-type allele was also expressed, providing evidence that secondary mutations had occurred. The implications of these results for retroviral insertional mutagenesis are discussed.

Animals↗
PubMed1999

Downregulation of c-kit (stem cell factor receptor) in transformed hematopoietic precursor cells by stroma cells.

We show a dramatic downregulation of the stem cell factor (SCF) receptor in different hematopoietic cell lines by murine stroma. Growth of the human erythroid/macrophage progenitor cell line TF-1 is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). However, TF-1 cells clone and proliferate equally well on stroma. Independent stroma-dependent TF-1 clones (TF-1S) were generated on MS-5 stroma. Growth of TF-1S and TF-1 cells on stroma still requires interaction between c-kit (SCF receptor) and its ligand SCF, because antibodies against c-kit inhibit growth to less than 2%. Surprisingly, c-kit receptor expression (RNA and protein) was downregulated by 2 to 3 orders of magnitude in TF-1S and TF-1 cells grown on stroma. This stroma-dependent regulation of the kit receptor in TF-1 was also observed on exposure to kit ligand-negative stroma, thus indicating the need for heterologous receptor ligand interaction. Removal of stroma induced upregulation by 2 to 4 orders of magnitude. Downregulation and upregulation of c-kit expression could also be shown for the megakaryocytic progenitor cell line M-07e and was comparable to that of TF-1, indicating that stroma-dependent regulation of c-kit is a general mechanism. Downregulation may be an economic way to compensate for the increased sensitivity of the c-kit/ligand interaction on stroma. The stroma-dependent c-kit regulation most likely occurs at the transcriptional level, because mechanisms, such as splicing, attenuation, differential promoter usage, or mRNA stability, could be excluded.

Animals↗
PubMed1999

Whiplash injury.

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Cultural Diversity↗
PubMed1998

Host cis-mediated extinction of a retrovirus permissive for expression in embryonal stem cells during differentiation.

The use of retroviral vectors for gene transfer into animals has been severely hampered by the lack of provirus transcription in the early embryo and embryonic stem (ES) cells. This primary block in provirus expression is maintained in differentiated cells by a cis-acting mechanism that is not well characterized. Retroviral vectors based on the murine embryonal stem cell virus (MESV), which overcome the transcriptional block in ES cells, were constructed to investigate this secondary mechanism. These vectors transferred G418 resistance to ES cells with the same efficiency as to fibroblasts, but overall transcript levels were greatly reduced. A mosaic but stable expression pattern was observed when single cells from G418-resistant clones were replated in G418 or assayed for expression of LacZ or interleukin-3. The expression levels in independent clones were variable and correlated inversely with methylation. However, a second, more pronounced, block to transcription was found upon differentiation induction. Differentiation of the infected ES cells to cells permissive for retroviral expression resulted in repression and complete extinction of provirus expression. Extinction was not accompanied by increased levels of methylation. Provirus expression is thus regulated by two independent cis-acting mechanisms: (i) partial repression in the undifferentiated state, accompanied by increased methylation but compatible with long-term, low expression of retroviral genes, and (ii) total repression and extinction during early stages of differentiation, apparently independent of changes in methylation. These results indicate a time window early during the transition from an undifferentiated to a differentiated stage in which provirus expression is silenced. The mechanisms are presently unknown, but elucidation of these events will have an important impact on vector development for targeting stem cells and for gene therapy.

Animals↗
PubMed1997

The role of soluble growth factors in inducing transient growth and clonal extinction of stroma cell dependent erythroblastic leukemia cells.

A coculture system of a murine erythroblastic leukemia cell line (ELM-D) with its supportive stromal cell line (MS-5) was established. Long-term growth of ELM-D cells is strictly stroma cell dependent. Interaction between stem cell factor (SCF) and its receptor, c-kit, was demonstrated to be important for stroma cell-dependent growth by anti c-kit neutralizing monoclonal antibody (mAb) inhibition experiments. Significantly, soluble growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) or SCF of MS-5 stromal cells (MS-5 CM) could replace the requirement of stroma cells for a considerable period. However, ELM-D cells maintained in these growth factors underwent clonal extinction after 3-6 weeks unless contact with stroma was re-established. Furthermore, IL-3 or GM-CSF acted in a dominant manner in inducing cell death in the presence of stroma cells. Cells showing clonal extinction undergo programmed cell death and do not differentiate. These altered growth properties of ELM-D cells exposed to soluble growth factors or to stroma cells appear to be analogous to those described for T or B cells primed by antigen presenting cells and then grown in growth factors.

Animals↗