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Biomedical subjects

P Farmer

Publications and source records attributed to P Farmer.

At least 19 recordsLinked to original sources
PubMed2001

Biomarkers of genotoxicity of urban air pollution. Overview and descriptive data from a molecular epidemiology study on populations exposed to moderate-to-low levels of polycyclic aromatic hydrocarbons: the AULIS project.

Epidemiologic studies indicate that prolonged exposure to high pollution levels is associated with increased risk of cancer, especially lung cancer. However, under conditions of moderate or low air pollution, epidemiologic evidence does not permit reliable conclusions. Biomarker-based population studies may serve as complementary tools providing a better understanding of the relative contribution of ambient atmospheric pollution to the overall genotoxic burden suffered by city dwellers. However, past efforts to apply biomarkers to studies of low levels exposure to urban air pollution have given inconclusive results, partly because of the absence of adequate data on personal exposure, covering a time-window which is appropriate for the biomarkers being examined, as well as a battery of biomarkers reflecting different stages of the carcinogenic process. In the present paper, the potential of biomarker-based population studies to aid the assessment of the genotoxic and carcinogenic effects of urban air pollution is reviewed by reference to the achievements and limitations of earlier reported studies. The design and methodology adopted in a recently completed large-scale population study, carried out in the context of the European Union Environment and Climate Programme, known by the short name of AULIS project, is discussed and descriptive statistics of the main findings of the project are presented. These findings indicate that for cohorts suffering moderate-to-low exposures to airborne particulate-bound polycyclic aromatic hydrocarbons (PAHs), no simple correlation with biomarkers of genotoxicity existed and suggest that additional factors made a significant contribution to the overall genotoxic burden.

Adolescent↗
PubMed2001

Redox regulation in human melanocytes and melanoma.

The human melanocyte is continuously exposed to intrinsic and extrinsic sources of reactive biochemical species, but is finely tuned via the intrinsic anti-oxidant and radical properties of melanin to suppress the build-up of an altered redox phenotype. We propose that this control is lost during melanomagenesis and inappropriate redox-sensitive transcriptional factor activations occur which result in enhancement of an anti-apoptotic phenotype in the transformed cell. This conceptual framework offers testable steps to determine the role of redox alterations in the carcinogenic evolution, prevention and treatment of melanoma and other diseases of the melanocyte.

Animals↗
PubMed2001

Historical declines in tuberculosis: nature, nurture and the biosocial model.

The large declines in the incidence of tuberculosis over time in the industrially developed nations have usually been attributed to natural selection or to socio-economic improvements. Both explanations are beset with problems, as there is little firm evidence for the occurrence of natural selection of resistance to tuberculosis to any significant extent, and doubts have been expressed as to whether the incidence of a disease can be directly related to measures of socio-economic change without consideration of the impact of the many specific public health measures that have been taken. In addition, analyses of the changing prevalence of tuberculosis must consider the impact of changing environmental and ecological factors that affect, for example, the immunising effect of exposure to Mycobacterium bovis and saprophytic mycobacteria. It is also necessary to determine whether the causative organism is undergoing evolutionary change, as recent reports suggest.

Animals↗
PubMed2001

Papillary fibroelastoma of the heart: report of two cases and review of the literature.

Papillary fibroelastoma is the most common primary cardiac valvular tumor. Historically, papillary fibroelastoma was an incidental autopsy finding, deemed to have no clinical significance. More recently, reports of symptomatic cases of papillary fibroelastoma with complications such as myocardial infarction and stroke have led papillary fibroelastoma to be considered a potentially dangerous lesion. We report 2 cases of symptomatic papillary fibroelastoma, both of which presented with a stroke. Both patients underwent uneventful open-heart surgery. The literature is reviewed, with a compilation of 79 cases.

Echocardiography↗
PubMed2001

Case report: primary isolated angiomyolipoma of the spleen.

A primary isolated angiomyolipoma presenting as a splenic mass is described. This is the first reported case of primary splenic angiomyolipoma without angiomyolipoma in the kidney or evidence of tuberous sclerosis, and it coexists with an adenocarcinoid of the appendix.

Angiomyolipoma↗
PubMed2000

beta-adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IkappaB/NF-kappaB pathway.

In addition to their well-studied bronchodilatory and cardiotonic effects, beta-adrenergic agonists carry anti-inflammatory properties by inhibiting cytokine production by human mononuclear cells. In a model of human promonocytic THP-1 cells stimulated with lipopolysaccharide (LPS), we showed that beta-agonists inhibited tumor necrosis factor-alpha and interleukin-8 production predominantly via the beta(2)-adrenergic receptor through the generation of cAMP and activation of protein kinase A. This effect was reproduced by other cAMP-elevating agents such as prostaglandins and cAMP analogs. Activation and nuclear translocation of the transcription factor nuclear factor-kappaB induced by LPS were inhibited with treatment with beta-agonists, an effect that was prominent at late time points (>1 h). Although the initial IkappaB-alpha degradation induced by LPS was minimally affected by beta-agonists, the latter induced a marked rebound of the cytosolic IkappaB-alpha levels at later time points (>1 h), accompanied by an increased IkappaB-alpha cytoplasmic half-life. This potentially accounts for the observed nuclear factor-kappaB sequestration in the cytoplasmic compartment. We postulate that the anti-inflammatory effects of beta-agonists reside in their capacity to increase cytoplasmic concentrations of IkappaB-alpha, possibly by decreasing its degradation.

Adrenergic beta-Agonists↗
PubMed2000

Inhibition of osteoblast differentiation by tumor necrosis factor-alpha.

Tumor necrosis factor-alpha (TNF-alpha) has a key role in skeletal disease in which it promotes reduced bone formation by mature osteoblasts and increased osteoclastic resorption. Here we show that TNF inhibits differentiation of osteoblasts from precursor cells. TNF-alpha treatment of fetal calvaria precursor cells, which spontaneously differentiate to the osteoblast phenotype over 21 days, inhibited differentiation as shown by reduced formation of multilayered, mineralizing nodules and decreased secretion of the skeletal-specific matrix protein osteocalcin. The effect of TNF was dose dependent with an IC50 of 0.6 ng/ml, indicating a high sensitivity of these precursor cells. Addition of TNF-alpha from days 2-21, 2-14, 7-14, and 7-10 inhibited nodule formation but addition of TNF after day 14 had no effect. Partial inhibition of differentiation was observed with addition of TNF on only days 7-8, suggesting that TNF could act during a critical period of phenotype selection. Growth of cells on collagen-coated plates did not prevent TNF inhibition of differentiation, suggesting that inhibition of collagen deposition into matrix by proliferating cells could not, alone, explain the effect of TNF. Northern analysis revealed that TNF inhibited the expression of insulin-like growth factor I (IGF-I). TNF had no effect on expression of the osteogenic bone morphogenic proteins (BMPs-2, -4, and -6), or skeletal LIM protein (LMP-1), as determined by semiquantitative RT-PCR. Addition of IGF-I or BMP-6 to fetal calvaria precursor cell cultures enhanced differentiation but could not overcome TNF inhibition, suggesting that TNF acted downstream of these proteins in the differentiation pathway. The clonal osteoblastic cell line, MC3T3-E1-14, which acquires the osteoblast phenotype spontaneously in postconfluent culture, was also studied. TNF inhibited differentiation of MC3T3-E1-14 cells as shown by failure of mineralized matrix formation in the presence of calcium and phosphate. TNF was not cytotoxic to either cell type as shown by continued attachment and metabolism in culture, trypan blue exclusion, and Alamar Blue cytotoxicity assay. These results demonstrate that TNF-alpha is a potent inhibitor of osteoblast differentiation and suggest that TNF acts distal to IGF-I, BMPs, and LMP-1 in the progression toward the osteoblast phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Role of NFkappaB in the regulation of macrophage colony stimulating factor by tumor necrosis factor-alpha in ST2 bone stromal cells.

Expression of MCSF in bone is important to the regulation of osteoclastogenesis. We show here that tumor necrosis factor-alpha (TNFalpha) increases the production of both soluble (sMCSF) and membrane-bound (mMCSF) macrophage colony stimulating factor by ST2 bone stromal cells. Treatment of ST2 cells with TNFalpha caused sMCSF levels to increase by 394+/-5% from basal; mMCSF rose by 316+/-66% from 30+/-10 per 100,000 cells in the same time. These increases were consistent with increased expression of mRNAs encoding both isoforms. Increases in MCSF mRNA are also seen after stimulation with dexamethasone. To investigate the potential role of NFkappaB in this TNFalpha effect, we treated cells with sodium salicylate (NaS), an inhibitor of NFkappaB translocation. NaS decreased TNFalpha-stimulated NFkappaB activation by 50% as assessed by EMSA. Despite inhibition of NFkappaB signaling, NaS enhanced TNFalpha-stimulated MCSF secretion and did not prevent TNFalpha-stimulated increases in sMCSF mRNA, suggesting that NFkappaB was not involved in TNFalpha effect on the gene. TNFalpha failed to stimulate transcription of a 774 nucleotide MCSF promoter-luciferase reporter transfected into ST2 cells which contained the NFkappaB consensus sequence. Deletion of the seven nucleotides containing the NFkappaB homology response sequence from the MCSF promoter increased basal gene transcription by twofold. TNFalpha thus contributes to an osteoclastogenic environment through upregulation of bone expression of both MCSF isoforms. Our data suggests that NFkappaB is not the major signaling pathway through which this occurs.

Bone and Bones↗
PubMed1999

Intrinsic innervation of the oesophagus in fetal rats with oesophageal atresia.

Although the aetiology of oesophageal dysmotility after repair of oesophageal atresia and tracheo-oesophageal fistula (OA-TOF) remains controversial, oesophageal dysmotility also is present in isolated TOF or OA before surgery, suggesting a congenital cause. Our previous work with a model of OA-TOF in fetal rats demonstrated an abnormality in the course and branching pattern of the vagus nerve. However, little is known about the intramural nervous components of the atretic oesophagus. The intrinsic innervation of the atretic oesophagus was examined by immunohistological staining to see if there is an abnormality that might account for dysmotility. OA-TOF was induced in fetal rats by injecting adriamycin intraperitoneally into pregnant rats. Forty-eight controls, 40 OA-TOF, and 6 treated fetuses without OA-TOF were recovered. Whole-mount preparations of each oesophagus were stained with fluorescent antibodies against neuron-specific enolase (NSE), vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP). Compared with control fetuses, the density of the nerve plexus, ganglia, and number of cell bodies per ganglion immunostained by NSE, VIP, or SP was significantly reduced in OA-TOF fetuses. CGRP-immunoreactive nerve fibres in the oesophageal wall of both control and OA-TOF animals were found to be connected with extrinsic nerve bundles. No plexus-like nerve fibre network was observed. The results of the present study demonstrated significant abnormalities of the intramural nervous components of the oesophagus in OA-TOF fetal rats, involving both the excitatory (SP-labelled) and inhibitory (VIP-labelled) intramural nerves. These abnormalities may underlie the oesophageal dysmotility seen in OA-TOF patients.

Abnormalities, Drug-Induced↗
PubMed1999

Visceral anomalies in prenatally adriamycin-exposed rat fetuses: a model for the VATER association.

Adriamycin is teratogenic if given to pregnant rats. A wide range of anomalies involving the gastrointestinal, renal, and cardiovascular systems has been described, similar to the VATER association, yet it is not known if they are identical to the human pattern. The aim of this study was to document the visceral anomalies in rat fetuses exposed to adriamycin and to determine their similarities with the congenital defects in humans with the VATER association. The results revealed a spectrum of very similar anomalies. Furthermore, the characteristics of the tracheo-oesophageal anomalies had a lot of features in common with the human pattern. We conclude that the adriamycin-treated fetal rat is an excellent model for studying the VATER association.

Abnormalities, Drug-Induced↗
PubMed1999

Pathologies of power: rethinking health and human rights.

The field of health and human rights has grown quickly, but its boundaries have yet to be traced. Fifty-one years after the Universal Declaration of Human Rights, consensus regarding the most promising directions for the future is lacking; however, outcome-oriented assessments lead us to question approaches that rely solely on recourse to formal legal and civil rights. Similarly unpromising are approaches that rely overmuch on appeals to governments: careful study reveals that state power has been responsible for most human rights violations and that most violations are embedded in "structural violence"--social and economic inequities that determine who will be at risk for assaults and who will be shielded. This article advances an agenda for research and action grounded in the struggle for social and economic rights, an agenda suited to public health and medicine, whose central contributions to future progress in human rights will be linked to the equitable distribution of the fruits of scientific advancement. Such an approach is in keeping with the Universal Declaration but runs counter to several of the reigning ideologies of public health, including those favoring efficacy over equity.

Global Health↗