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Biomedical subjects

N Macdonald

Publications and source records attributed to N Macdonald.

At least 19 recordsLinked to original sources
PubMed2006

Proteomic analysis of suction blister fluid isolated from human skin.

The regulation of cutaneous immune responses in health and disease is mediated locally by proteins such as cytokines and chemokines. We used a novel approach involving proteomic profiling of fluid drawn from suction blisters to compare and contrast protein expression in normal skin with that in nonlesional skin from a patient with plaque psoriasis. We also examined the impact of exogenous interleukin-1beta, a proinflammatory cytokine, on protein expression in these tissues. Described here are the results of proteomic profiling of 670 proteins from blister fluid, and the identification by differential expression of nine proteins between one volunteer with psoriasis and one normal volunteer. Although the apparent disease association of these nine proteins will require validation using additional volunteers, the identification of candidate protein biomarkers through proteomic analyses of blister fluid represents a promising approach for monitoring the disease activity and efficacy of therapeutic intervention in human skin diseases.

Biomarkers↗
PubMed2004

Recent trends in diagnoses of HIV and other sexually transmitted infections in England and Wales among men who have sex with men.

OBJECTIVES: To examine trends in rates of diagnoses of HIV and other sexually transmitted infections (STIs) in men who have sex with men (MSM) in England and Wales between 1997 and 2002. METHODS: Estimates of the MSM population living in England and Wales, London and the rest of England and Wales were applied to surveillance data, providing rates of diagnoses of HIV and STIs and age group specific rates for HIV and uncomplicated gonorrhoea. RESULTS: Between 1997 and 2002, rates of diagnoses of HIV and acute STIs in MSM increased substantially. Rates in London were higher than elsewhere. Rises in acute STIs were similar throughout England and Wales, except for uncomplicated gonorrhoea and infectious syphilis, with greater increases outside London. Rates of gonorrhoea diagnoses doubled between 1999 and 2001 (661/100,000, 1271/100,000, p<0.001) in England and Wales followed by a slight decline to 1210/100,000 (p=0.03) in 2002-primarily the result of a decline in diagnoses among men aged 25-34 (1340/100,000, 1128/100,000, p<0.001) and 35-44 (924/100,000, 863/100,000, p=0.03) in London. HIV was the third most common STI diagnosed in MSM in England and Wales and the second in London, with the highest rate (1286/100,000) found among men aged 35-44 in London in 2002. CONCLUSIONS: Rates of diagnosis of HIV and other STIs have increased substantially among MSM in England and Wales. Increases show heterogeneity by infection, geography, and age over time. Rates in London were twice those seen elsewhere, with greatest changes over time. The observed changes reflect concomitant increases in high risk behaviour documented in behavioural surveillance survey programmes.

Adolescent↗
PubMed2002

PPAR alpha and the regulation of cell division and apoptosis.

Peroxisome proliferators (PPs) such as the hypolipidaemic drug, nafenopin and the phthalate plasticiser 2-diethylhexylphthalate induce rodent hepatocyte cell proliferation and suppress apoptosis leading to tumours. PPs act via the nuclear hormone receptor peroxisome proliferator activated receptor alpha (PPAR alpha) which directly regulates genes implicated in the response to PPs such as the peroxisomal gene acyl CoA oxidase. As expected for xenobiotics that perturb proliferation, PPs alter expression of cell cycle regulatory proteins. However, the ability to alter expression of cyclins and cyclin-dependent kinases is shared by physiological hepatic mitogens such as epidermal growth factor and is thus unlikely to be specific to the PP-induced aberrant growth associated with hepatocarcinogenesis. Recent evidence suggests that the response of hepatocytes to PPs is not only dependent upon PPAR alpha but also on the trophic environment provided by nonparenchymal cells and by cytokines such as tumour necrosis factor alpha. Additionally, the ability of PPs to suppress apoptosis and induce proliferation depends upon survival signalling mediated by p38 mitogen activated protein kinase. The cross talk between PPAR alpha-mediated transcription, survival signalling and cell cycle will be discussed with particular emphasis on relevance to toxicology.

Antigens, CD↗
PubMed2002

Numbers of adults with diagnosed HIV infection 1996-2005--adjusted totals and extrapolations for England, Wales and Northern Ireland.

Using data from the annual surveys of individuals receiving HIV related treatment or other care from 1996 to 2000, trends in prevalent numbers of diagnosed HIV infections have been extrapolated to the years 2001-05. Results show that the adjusted prevalent number for 1996 was 14,205 and that this has increased by 62% by the end of 2000, and will have increased by 139% by the end of 2005. The drivers for this increase have been the sustained rise in diagnoses in infections heterosexually acquired in sub-Saharan Africa and the continuing numbers of new diagnoses in men who have sex with men.

Adult↗
PubMed2001

Quantitative proteomic analysis of mouse liver response to the peroxisome proliferator diethylhexylphthalate (DEHP).

Peroxisome proliferators (PPs) are a diverse group of chemicals that cause hepatic proliferation, suppression of apoptosis, peroxisome proliferation and liver tumours in rodents. The biochemical response to PPs involves changes in the expression of peroxisomal beta-oxidation enzymes and fatty acid transport proteins such as acyl-CoA oxidase and liver fatty acid binding protein. The response to PPs is mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha) and the livers of PPARalpha-null transgenic mice do not develop tumours in response to PPs. In order to identify the molecular pathways underlying the adverse effects of PPs in rodent liver, we carried out two-dimensional differential gel electrophoresis to provide quantitative proteomic analyses of diethylhexylphthalate (DEHP)-treated wild-type or PPARalpha-null mouse livers. Since tumourigenesis is both PP- and PPARalpha-dependent, analyses were focused on these changes. Fifty-nine proteins were identified where altered expression was both PPARalpha- and PP-dependent. In addition, six proteins regulated by the deletion of PPARalpha were identified, possibly indicating an adaptive change in response to the loss of this receptor. The proteins that we identified as being regulated by PPARalpha are known to be involved in lipid metabolism pathways, but also in amino acid and carbohydrate metabolism, mitochondrial bioenergetics and in stress responses including several genes not previously reported to be regulated by PPARalpha. These data provide novel insights into the pathways utilised by PPs and may assist in the identification of early markers rodent nongenotoxic hepatocarcinogenesis.

Animals↗
PubMed2001

The role of palliative care in the home in medical education: report from a national consensus Conference.

A working group on teaching palliative care in the home was convened at The National Consensus Conference on Medical Education for Care Near the End of Life. Our consensus statement includes: (1) a justification for education in the home; (2) general guidelines about teaching palliative care at this site; (3) identification of major barriers to training in the home, and some suggestions for overcoming these barriers; and (4) specific suggestions about how and what to teach. We find that the home is an excellent site for training in comprehensive palliative medicine. Housecalls afford an unusually rich and compelling opportunity to learn about the patient's and family's experience of severe illness and the impact of culture and environment on health care, and can have a broad humanizing effect on trainees. We propose that all medical students be familiar with this form of care. Trainees should learn the potential benefits and difficulties of managing terminal illness in the community, appreciate the role of health care teams in assuring safe, secure, high-quality care, and acquire the special knowledge, skills, and attitudes required for providing state-of-the-art palliative care for patients and families facing a terminal illness in the home, including for those dying at home. Instituting education in the home setting will require faculty development, support for more home visiting by physicians, and supervision of trainees in the home by other members of the health care team. Academic medical centers and hospice/home health agencies should collaborate to develop effective training programs.

Clinical Clerkship↗
PubMed2001

An outbreak of hepatitis A among young men associated with having sex in public venues.

An increase in hepatitis A virus (HAV) infection was noted among young men in the former Thames regions during 1997. A retrospective case-control study, using a standardised questionnaire at interview, was conducted in the area most affected (London and East Sussex) to investigate the hypothesis that this increase was mainly among homosexual men and to establish the risk factors associated with transmission. Forty-eight cases and 161 controls completed questionnaires. Forty-one cases (85%) described their sexuality as homosexual (p < 0.0001). Cases were more likely than controls to have eaten shellfish (Odds Ratio (OR) 2.4; 95% Confidence Interval (CI) 1.16, 5.04) during the two months before onset of illness. Cases had more sexual partners (p = 0.015), and more casual sexual partners (p = 0.007) than controls. Cases were more likely to have had sex in a gay sauna (OR 3.5; 95% CI 1.53, 8.30), or in a gay club, pub or disco (OR 2.9; 95 CI 1.29, 6.63) than controls. After adjusting for confounding factors, cases were more likely to have eaten shellfish (adjusted [adj] OR 3.0; 95% CI 1.33, 6.59) and to have had sex in a gay sauna (adj OR 3.9; 95% CI 1.42, 10.59). Public health messages need to inform homosexual men about recognised risk factors such as eating shellfish and travel abroad to endemic areas, as well as sexual risks. Homosexual men can benefit from hepatitis A vaccine. We would suggest that in an outbreak situation men who have multiple anonymous partners and have sex in public venues should be targeted as a priority for health education and immunisation.

Adolescent↗
PubMed2000

PPARalpha-dependent alteration of GRP94 expression in mouse hepatocytes.

The adverse effects of the peroxisome proliferators (PPs), a class of rodent nongenotoxic hepatocarcinogens, include suppression of apoptosis, induction of hepatocyte proliferation, and liver enlargement which eventually leads to tumours. The response to PPs is mediated by the peroxisome proliferator activated receptor alpha (PPARalpha). We carried out proteomic analyses of PP-treated hepatocytes from wild-type and PPARalpha-null mice to identify the molecular pathways underlying the adverse effects of PPs. We have identified eighteen protein spots exhibiting differential expression in PP-treated wild-type mouse hepatocytes. Several proteins involved in lipid metabolism pathways, but also ATP synthase beta subunit, which are regulated by PPs were identified. In addition, both 2D silver-stained gels and Western blotting analysis indicated that the anti-apoptotic glucose-regulated protein 94 (GRP94) is consistently overexpressed upon stimulation with PPs, providing us with novel insights into the anti-apoptotic mechanism activated by PPs.

Animals↗
PubMed2000

Suppression of mouse hepatocyte apoptosis by peroxisome proliferators: role of PPARalpha and TNFalpha.

Peroxisome proliferators (PPs) are a diverse group of nongenotoxic chemicals that in rodents cause hepatic peroxisome proliferation, liver enlargement, increased replicative DNA synthesis and suppression of apoptosis. The effects of PPs in vivo can be reproduced in vitro where PPs can induce mouse hepatocyte DNA synthesis and suppress both spontaneous apoptosis and that induced by transforming growth factor beta (TGFbeta). In vitro, high concentrations (>500 U/ml) of exogenous tumour necrosis factor (TNFalpha) [M. Rolfe, N.H. James, R.A. Roberts, TNF suppresses apoptosis and induces S-phase in rodent hepatocytes: a mediator of the hepatocarcinogenicity of peroxisome proliferators?, Carcinogenesis 18 (1997) 2277-2280] are also able to stimulate hepatocyte DNA synthesis and suppress apoptosis, implicating TNFalpha in mediating or permitting the liver growth response to PPs. Here, using cultured mouse hepatocytes isolated from PPARalpha null mice, we have examined the role of the peroxisome proliferator activated receptor alpha (PPARalpha) in mediating the suppression of apoptosis caused by PPs. In addition we have investigated further the role of TNFalpha in mediating the rodent response to PPs. The PP nafenopin (50 microM) was unable to stimulate DNA synthesis measured by bromodeoxyuridine incorporation in these PPARalpha null mouse hepatocytes (96% of control), unlike epidermal growth factor, a growth factor used as a positive control. In assays of apoptosis using H33258 staining of chromatin condensation, nafenopin was unable to suppress either spontaneous or TGFbeta1-induced apoptosis. In contrast, high concentrations of TNFalpha (>500 U/ml) were able to both stimulate DNA synthesis (204% of control) and suppress apoptosis in PPARalpha null hepatocytes (40% and 38% of control for spontaneous and TGFbeta1-induced apoptosis respectively). However, TNFalpha could not stimulate beta-oxidation of palmitoyl CoA in either PPARalpha null mouse or B6C3F1 (PPARalpha wild type) mouse hepatocytes. These data confirm the dependence of the response to PPs on PPARalpha by demonstrating that PPARalpha mediates the suppression of hepatocyte apoptosis in response to PPs. In addition, the data provide evidence that high concentrations of TNFalpha can modulate DNA synthesis and apoptosis in the absence of PPs and PPARalpha. Thus, in vivo, physiological levels of TNFalpha may be permissive for a PPARalpha-dependent growth response to PPs.

Animals↗
PubMed2000

Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha.

Peroxisome proliferators (PPs) are nongenotoxic rodent hepatocarcinogens that cause liver enlargement and hepatocarcinogenesis associated with peroxisome proliferation, induction of hepatocyte DNA synthesis and suppression of apoptosis. Acyl CoA oxidase (ACO) is a key enzyme of peroxisomal beta-oxidation and its transcriptional activation by PPs is often used as marker for the rodent response. PPs activate the peroxisome proliferator activated receptor-alpha, PPARalpha. Recent data suggest a role for tumour necrosis factor alpha (TNFalpha). This cytokine appears to be permissive for a PPARalpha-dependent growth response to PPs. Humans and guinea pigs appear to be nonresponsive to the adverse effects of PPs noted in rodents. These species differences can be attributed to reduced quantity of full length functional PPARalpha in human liver and evidence supports the presence of a truncated form of PPARalpha, hPPARalpha8/14 in human liver. In addition, species differences could be attributed to qualitative differences in the PPARalpha-mediated response because the promoter for human ACO differs in sequence and activity from the rat equivalent. These data contribute to our understanding of how chemicals may cause tumours in rodents and how this response may differ in humans.

Animals↗
PubMed2000

Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression.

Diethylhexylphthalate (DEHP) is a phthalate plasticizer that belongs to the peroxisome proliferator (PP) class of rodent nongenotoxic hepatocarcinogens. Previously, we have shown that MEHP (a principal metabolite of DEHP and the proximal PP) induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes in vitro. Here, we present further studies of species differences in response to DEHP. In rats, 4 days of exposure to DEHP (950 mg/kg per day by gavage) induced peroxisomal beta-oxidation, DNA synthesis and suppressed apoptosis. In contrast, there was no response of guinea pig liver to DEHP. In rat hepatocytes in vitro, MEHP (250, 500 and 750 microM) induced peroxisomal beta-oxidation, DNA synthesis and suppressed apoptosis. In contrast to the pleiotropic response noted in rat hepatocytes, there was no response of human hepatocytes to 250, 500 or 750 microM MEHP. PPs activate the peroxisome proliferator activated receptor alpha (PPARalpha) that binds to DNA at peroxisome proliferator response elements (PPREs) within the promoters of PP-responsive genes such as rat acyl CoA oxidase (ACO). However, the human ACO gene promoter differs at three bases within the PPRE from the rat ACO promoter and appears refractory to PPs. To address species differences in response to DEHP at the molecular level, we used promoter-reporter gene assays to compare the ability of MEHP to induce gene expression from the rat or the human ACO promoter. MEHP gave a concentration-dependent increase in reporter gene expression from the rat ACO gene promoter with either mouse or human PPARalpha. In contrast, the human ACO promoter was unable to drive MEHP-induced gene transcription irrespective of the species origin of PPARalpha. These data provide further weight of evidence at the cellular and molecular levels for a lack of risk to human health from the phthalate DEHP.

3T3 Cells↗
PubMed2000

Proteomic analysis of differential protein expression in primary hepatocytes induced by EGF, tumour necrosis factor alpha or the peroxisome proliferator nafenopin.

Peroxisome proliferators are nongenotoxic rodent-liver carcinogens that have been shown to cause both an induction of hepatocyte proliferation and a suppression of apoptosis. Both epidermal growth factor (EGF) and the peroxisome proliferator nafenopin induce DNA replication in primary rat hepatocyte cultures, but apparently through different signalling pathways. However, both EGF and nafenopin require tumour necrosis factor alpha (TNFalpha) signalling to induce DNA replication. By examining proteins isolated from rat primary hepatocyte cultures using two-dimensional gel electrophoresis and mass spectrometry, we found that proteins showing an altered expression pattern in response to nafenopin differed from those showing altered expression in response to EGF. However, many proteins showing altered expression upon stimulation with TNFalpha were common to both the EGF and nafenopin responses. These proteome profiling experiments contribute to a better understanding of the molecular mechanisms involved in the response to peroxisome proliferators. We found 32 proteins with altered expression upon stimulation with nafenopin, including muscarinic acetylcholine receptor 3, intermediate filament vimentin and the beta subunit of the ATP synthase. These nonperoxisomal protein targets offer insights into the mechanisms of peroxisome proliferator-induced carcinogenesis in rodents and provide opportunities to identify toxicological markers to facilitate early identification of nongenotoxic carcinogens.

Actins↗
PubMed2000

PPAR alpha-mediated responses in the rodent liver: a holistic biochemical view.

Carcinogenesis through the direct action of genotoxic, DNA damaging chemicals is an established and well-studied paradigm. As yet there are no short term tests available for non-genotoxic rodent carcinogens that do not damage DNA but cause liver tumours in long term rodent bioassays. A key aim is to develop short term in vitro screens for the detection of nongenotoxic carcinogens, and this requires knowledge of the mode or mechanism of action of this class of chemicals. The largest and most chemically diverse family of non-genotoxic hepatocarcinogens is the peroxisome proliferators (PPs) such as hypolipidaemic fibrate drugs, plasticizers used in clingwrap/medical tubing and certain pesticides and solvents. PPs mediate their biological responses via activation of the transcription factor PPAR alpha (peroxisome proliferator activated receptor alpha), a member of the nuclear hormone receptor superfamily. PPAR alpha activation is responsible for the pleiotropic effects of PPs in rodent liver such as the induction of enzymes of the b-oxidation pathway, hepatocyte DNA synthesis, liver enlargement and tumourigenesis. Although much is known, we are far from defining the key cell cycle regulating targets of PPs, due perhaps to past limitations of technology. The technology of proteomics allows quantitative measurement of the expression levels of potentially thousands of individual genes at the protein level on exposure to toxic insult. This is predicted to revolutionise the way many biological systems are investigated. Here we review the current knowledge of proteins involved in the response to peroxisome proliferators and describe the impact of proteomics in this field.

Animals↗