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Biomedical subjects

N Barnes

Publications and source records attributed to N Barnes.

At least 19 recordsLinked to original sources
PubMed2006

Survivin expression in in situ and invasive breast cancer relates to COX-2 expression and DCIS recurrence.

In lung cancer cyclooxygenase-2 (COX-2) expression has been reported to stabilise survivin, an inhibitor of apoptosis (IAP) which prevents cell death by blocking activated caspases. COX-2 expression limits the ubiquitination of survivin, protecting it from degradation. To determine if COX-2 expression in breast cancer showed an association with survivin expression, we assessed the levels of each protein in ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC); relating expression patterns to recurrence of DCIS after surgery. Patterns of COX-2 and survivin expression were determined by intensity-graded immunohistochemistry of the primary tumours. Patients with DCIS (n=161) which had either recurred (n=47) or shown no evidence of recurrence (n=114) 5 years following primary surgery were studied. These were compared to 58 cases of IBC. Survivin was expressed in the cytoplasm of 59% of DCIS and 17% of IBC. High levels of both cytoplasmic survivin and COX-2 expression significantly correlated to DCIS recurrence. COX-2 expression was present in 72% of DCIS, and levels of expression positively correlated with cytoplasmic survivin expression in DCIS and invasive disease. The majority of DCIS that recurred expressed both proteins (69%) vs 39% nonrecurrent. Recurrence was not seen in DCIS lacking both proteins at 5 years (P=0.001). Expression of the IAP survivin is increased in DCIS and correlates closely with COX-2 expression. Increased expression of IAP, (leading to reduced apoptosis) may explain the effect of COX-2 in increasing recurrence of DCIS after surgical treatment.

Biomarkers, Tumor↗
PubMed2005

New genotypes and factors associated with Cryptosporidium detection in mussels (Mytilus spp.) along the California coast.

A 3 year study was conducted to evaluate mussels as bioindicators of faecal contamination in coastal ecosystems of California. Haemolymph samples from 4680 mussels (Mytilus spp.) were tested for Cryptosporidium genotypes using PCR amplification and DNA sequence analysis. Our hypotheses were that mussels collected from sites near livestock runoff or human sewage outflow would be more likely to contain the faecal pathogen Cryptosporidium than mussels collected distant to these sites, and that the prevalence would be greatest during the wet season when runoff into the nearshore marine environment was highest. To test these hypotheses, 156 batches of sentinel mussels were collected quarterly at nearshore marine sites considered at higher risk for exposure to livestock runoff, higher risk for exposure to human sewage, or lower risk for exposure to both faecal sources. Cryptosporidium genotypes detected in Haemolymph samples from individual mussels included Cryptosporidium parvum, Cryptosporidium felis, Cryptosporidium andersoni, and two novel Cryptosporidium spp. Factors significantly associated with detection of Cryptosporidium spp. in mussel batches were exposure to freshwater outflow and mussel collection within a week following a precipitation event. Detection of Cryptosporidium spp. was not associated with higher or lower risk status for exposure to livestock faeces or human sewage sources. This study showed that mussels can be used to monitor water quality in California and suggests that humans and animals ingesting faecal-contaminated water and shellfish may be exposed to both host-specific and anthropozoonotic Cryptosporidium genotypes of public health significance.

Animals↗
PubMed2003

Anti-reflux surgery for the neonatal intensive care-dependent infant.

AIM: The benefit of anti-reflux surgery for gastro-oesophageal reflux (GOR) in early infancy is uncertain. The aim of this study was to assess the value of Nissen fundoplication in a group of infants with severe GOR. METHODS: 10 infants underwent Nissen fundoplication for gastro-oesophageal reflux following a failure of medical management. All had suffered life-threatening respiratory episodes as a consequence of gastro-oesophageal reflux, and were neonatal intensive care-dependent. Median (range) birth weight was 1.26 kg (0.48-3.8 kg), gestation 30 weeks (25-38 weeks); at surgery, weight was 3.25 kg (2.5-6.1 kg) at a corrected age of 11.5 weeks (term-22) weeks. For each infant, the success of enteral feeding and the level of support required pre- and post-operatively was compared, and where appropriate, the facilitation of palliative feeding was assessed. Median follow-up was 14 (3-36) months. RESULTS: No infant suffered intra-operative morbidity or mortality. One infant died within 1 month of surgery from a collapse unrelated to surgery. Eight of nine surviving infants were discharged from intensive care following extubation and the establishment of enteral feeding. One patient died of severe bronchopulmonary dysplasia 3 months post-surgery. One infant developed a gastrostomy site infection, and two required gastrostomy tube replacement within 6 months of surgery. All were thriving at follow-up. Two infants with a congenital myopathy died as a result of their muscle disease at 9 and 11 months post-operatively. CONCLUSIONS: Nissen fundoplication is a feasible, effective and safe operation in severe gastro-oesophageal reflux unresponsive to medical treatment in term and pre-term infants. It has an additional important role in facilitating safe palliative enteral feeding in infants with a diagnosis incompatible with survival into adulthood.

Female↗
PubMed2003

Intermittent enteral nutrition--a comparative study examining the effect on gastric pH and microbial colonization rates.

In a prospective randomized study we aimed to examine the effect on gastric pH and microbial colonization of enteral nutrition (EN) delivered both by intermittent and continual infusion. Forty-three mechanically ventilated patients were randomized to receive EN by one of three methods, intermittent or continual gastric or continual jejunal. We sampled gastric aspirate for pH and culture in all patients at 0600 hours and pH in gastric intermittent feeders at 2200 hours daily. Patients were studied for 12 days or until extubated. Data was obtained on 41 patients, of whom 73% had a diagnosis of trauma. Median APACHE II score was 17 and ventilation time 11 days. Twelve patients received gastric continuous, 15 gastric intermittent and 14 jejunal nutrition. No significant difference was observed between the three groups with regard to median 0600 pH (P = 0.16). This was lowest in the jejunal group (3.2) followed by the gastric intermittent group (4.0) and then gastric continuous group (5.0). With overnight cessation of EN in the gastric intermittent group, the median pH fell from 5.2 at 2200 to 4.0 at 0600 (P = 0.01) with no effect on gastric colonization. The probability of gastric colonization over time however was significantly lower in the jejunal group compared with the two gastric groups (Log rank test, P = 0.02). These results demonstrate that in a patient population consisting predominantly of trauma, overnight cessation of EN made no overall difference to 0600 gastric pH or colonization rates. The preservation of pH and lowered colonization in those given jejunal feeding may have implications in the pathogenesis of ventilator-associated infection and may warrant further study using larger patient numbers.

APACHE↗
PubMed2002

A review and assessment of tributyltin contamination in the North Sea, based on surveys of butyltin tissue burdens and imposex/intersex in four species of neogastropods.

It is evident from measures of butyltin tissue burdens and imposex or intersex in neogastropods that tributyltin (TBT) contamination of coastal waters and open parts of the North Sea is now low. It has been declining for at least the past decade. This is probably due to two measures. First, regulations prohibiting the use of TBT-based paints on small boats and fish farms have reduced inputs of TBT from these sources so that they are now negligible (except possibly where the regulations are flaunted). Second, there is evidence from sites, where commercial vessels are the sole source of TBT, that the adoption of TBT SPC paints has been effective in reducing environmental levels of these contaminants. However, poor dockyard practices, allowing TBT-contaminated wastes, including paint flakes, to accumulate in sediments have left a legacy of hot-spots of contamination in some ports. The impact is localised so that TBT contamination is low in coastal areas immediately adjacent to ports.

Animals↗
PubMed2002

Assessing the burden of respiratory disease in the UK.

This review explores the health and social burden of some of the main respiratory diseases (asthma, chronic obstructive pulmonary disease, cryptogenic fibrosing alveolitis, cystic fibrosis, lung cancer, mesothelioma, obstructive sleep apnoea and tuberculosis) in order to increase awareness of these diseases and highlight areas where improvements in care are required. The overall impact of respiratory diseases in the U.K. in terms of prevalence, mortality, morbidity and economic costs, with particular reference to secondary care has been considered and comparisons made with the rest of Europe where data are available. Respiratory diseases are responsible for a significant proportion of serious morbidity and premature death among the population of the U.K. and they will continue to present a growing challenge; special support is needed to tackle this burden.

Adolescent↗
PubMed2002

Effects of fluticasone propionate on inflammatory cells in COPD: an ultrastructural examination of endobronchial biopsy tissue.

BACKGROUND: Inhaled corticosteroids (ICS) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease (COPD) is unknown. METHODS: A study of endobronchial biopsy samples was conducted as part of a double blind, placebo controlled, randomised trial of parallel design. Patients had mild to moderately severe COPD (FEV(1) 25-80% of predicted) and were given 3 months treatment with ICS, fluticasone propionate (FP; 500 micro g twice daily, n=14) or placebo (n=10). Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells. RESULTS: Compared with their baseline values, FP resulted in a significant decrease (on average 65%) in the numbers of mucosal mast cells (median 7.8 (range 1-33) v 2.8 (1-14), p<0.05). The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared: 8.8 (1-24) v 2.8 (1-14) (p<0.05). Unexpectedly, there were significantly more neutrophils in the FP than in the placebo group: 4.0 (0-23) v 1.7 (0-8), respectively (p<0.05). There were no alterations to other cell types including mononuclear cells. Symptoms markedly improved in the patients treated with FP for 3 months. CONCLUSION: Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa: the reduction in mast cell numbers may account for the improvement in symptoms over this time.

Aged↗
PubMed2001

Exacerbations of Bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants.

Eosinophilia has been reported during exacerbations of bronchitis, but the mechanisms of tissue recruitment of eosinophils are unclear. We quantified eosinophils and the concurrent expression of cytokines and chemokines probably responsible for the tissue eosinophilia in bronchial biopsies obtained from three groups of nonatopic subjects: (1) healthy nonsmokers (n = 7; FEV1 % predicted = 108 +/- 4 [mean +/- SEM]); (2) nonasthmatic smokers with chronic bronchitis (CB) in a stable phase of their disease (n = 11; FEV1 % predicted: 75 +/- 5); and (3) nonasthmatic subjects with CB who sought medical advice for an exacerbation of their condition (n = 9; FEV(1) % predicted: 61 +/- 8). We applied anti-EG2 antibody and immunostaining to detect and count eosinophils. We performed in situ hybridization to visualize and enumerate cells expressing the genes for interleukin (IL)-4 and IL-5 and the eosinophil chemokines eotaxin, monocyte chemoattractant protein (MCP)-4, or regulated on activation, normal T-cell expressed and secreted (RANTES). We confirmed an increase in EG2-positive eosinophils in patients with CB in exacerbation. We found messenger RNA (mRNA) positivity for IL-4 and IL-5 in CB, but the between-group differences were not statistically significant. However, the numbers of lymphomononuclear cells expressing eotaxin mRNA were significantly greater in the smokers with CB than in the healthy nonsmokers without CB (p < 0.01). Following an exacerbation, RANTES expression was upregulated and this chemokine was strongly expressed in both the surface epithelium and in subepithelial lymphomononuclear cells: only RANTES showed a significant positive correlation with the increasing number of EG2-positive cells (r = 0.51; p < 0.03). In conclusion, an allergic profile of inflammation can also occur in CB: the marked upregulation of RANTES in the epithelium and subepithelium most likely accounts for the increased eosinophilia associated with an exacerbation of bronchitis.

Adult↗
PubMed2001

Analysis of montelukast in mild persistent asthmatic patients with near-normal lung function.

Few studies have specifically evaluated controller therapy in patients with mild persistent asthma. We used a subgroup analysis to investigate the effects of montelukast, a potent cysteinyl leukotriene receptor antagonist, on adult patients on the milder end of the asthma severity spectrum. We have identified seven double-blind, randomized, placebo-controlled studies of adult patients with mild-to-moderate chronic asthma in which montelukast was investigated. Subsets of patients with baseline forced expiratory volume in 1 sec (FEV1) > 80% and > 75% predicted or further restricted by less than daily rescue beta-agonist use were included as four cohorts (A, B, C, D), and efficacy measures, including change in FEV1 rescue-free days, beta-agonist use, nocturnal awakenings and blood eosinophil counts were evaluated. Cohorts A to D comprised 21%, 8%, 11%, and 4%, respectively, of patients from these studies. Mean pretreatment FEV1 ranged from 81% to 84% predicted and daily beta-agonist use from 2.4 to 4.5 puffs day(-1) in the four cohorts. Pooled results demonstrated a treatment effect for montelukast over placebo in all cohorts, for all endpoints. There was a significant improvement in FEV1 in montelukast-treated patients (7-8% over baseline) compared with placebo (1-4% over baseline, between-group difference P < or = 0.02) for all cohorts. Similarly, the percentage of rescue-free days increased substantially more with montelukast (22-30%) than with placebo (8-13%). This subgroup analysis indicates that montelukast produced improvements in parameters of asthma control in patients with milder persistent asthma that should be confirmed in additional prospective trials.

Acetates↗
PubMed2001

A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis.

BACKGROUND: Turner syndrome accounts for 15-20% of childhood usage of growth hormone (GH) in the UK but final height benefit remains uncertain. The most effective strategy for oestrogen replacement is also unclear. METHODS: Fifty eight girls who, at start of treatment, were of mean age 9.1 years and projected final height 142.2 cm were randomised to receive in year 1, either low dose ethinyloestradiol 50-75 ng/kg/day, GH 28 IU/m(2) surface area/week as a daily injection, or a combination of ethinyloestradiol and GH. After the first year, the ethinyloestradiol treated girls received combination treatment. After two years, girls aged over 12 years were given escalating ethinyloestradiol to promote pubertal development. RESULTS: Near final height was available for 49 girls at age 16.5 years, 146.8 cm, representing a gain of 4.6 cm, range -7.9 to +11.7 cm. Twelve of the 49 girls gaining 7.5 cm or more were less than 13 years at the start and had received GH for at least four years. Height gain was correlated with greater initial height deficit. Fifteen girls (31%) reached 150 cm or more compared to a predicted 10%. Early supplementation with ethinyloestradiol provided no final height advantage. CONCLUSIONS: Final height gain was modest at 4.6 cm. Younger, shorter girls gained greatest height advantage from GH. Low dosage ethinyloestradiol before planned induction of puberty was not beneficial.

Adolescent↗
PubMed2000

Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses.

MUC1 is highly expressed in adenocarcinomas and is a possible target for immunotherapy. In mice, oxidized mannan linked to MUC1 (M-FP), given in vivo, induces potent MHC-restricted CTL and tumor protection. Because of the resistance of cancer patients to immunization, ex vivo immunization of macrophage/dendritic cells was examined using oxidized mannan MUC1 to target the mannose receptor and the MHC Class I antigen presentation pathway. Here, we show that murine mannose receptor (MR) bearing macrophages derived from peritoneal exudate cells (PEC) and cultured ex vivo with M-FP can, after adoptive transfer, efficiently present MUC1 to T cells, leading to the generation of high frequency of CTL and protection from tumor challenge. Mice immunized once with syngeneic PEC pulsed with M-FP elicit a similar CTLp frequency to that obtained with three in vivo immunizations. Targeting the MR is crucial to obtain high frequency CTL, and without oxidation the CTLp frequency was low. GM-CSF is important, as GM-CSF o/o mice gave reduced responses, a deficiency corrected by in vivo GM-CSF. In addition, the treatment of macrophages ex vivo with GM-CSF gave enhanced responses and treating mice with GM-CSF prior to M-FP immunizations also enhanced cellular responses. M-FP targets the MR and ensures rapid passage of peptides to Class I molecules, and can also directly stimulate in vitro IL-12 production by macrophages. While many studies are now focussing on dendritic cells, in this study the cells involved were adherent F4/80+ 33D1- macrophages. The findings could be of benefit for the immunization of patients with cancer.

Animals↗
PubMed2000

The IgG Fc contains distinct Fc receptor (FcR) binding sites: the leukocyte receptors Fc gamma RI and Fc gamma RIIa bind to a region in the Fc distinct from that recognized by neonatal FcR and protein A.

The CH2-CH3 interface of the IgG Fc domain contains the binding sites for a number of Fc receptors including Staphylococcal protein A and the neonatal Fc receptor (FcRn). It has recently been proposed that the CH2-CH3 interface also contains the principal binding site for an isoform of the low affinity IgG Fc receptor II (Fc gamma RIIb). The Fc gamma RI and Fc gamma RII binding sites have previously been mapped to the lower hinge and the adjacent surface of the CH2 domain although contributions of the CH2-CH3 interface to binding have been suggested. This study addresses the question whether the CH2-CH3 interface plays a role in the interaction of IgG with Fc gamma RI and Fc gamma RIIa. We demonstrate that recombinant soluble murine Fc gamma RI and human Fc gamma RIIa did not compete with protein A and FcRn for binding to IgG, and that the CH2-CH3 interface therefore appears not to be involved in Fc gamma RI and Fc gamma RIIa binding. The importance of the lower hinge was confirmed by introducing mutations in the proposed binding site (LL234,235AA) which abrogated binding of recombinant soluble Fc gamma RIIa to human IgG1. We conclude that the lower hinge and the adjacent region of the CH2 domain of IgG Fc is critical for the interaction between Fc gamma RIIa and human IgG, whereas contributions of the CH2-CH3 interface appear to be insignificant.

Amino Acid Motifs↗
PubMed2000

Immunoglobulin G3 antibodies specific for the 19-kilodalton carboxyl-terminal fragment of Plasmodium yoelii merozoite surface protein 1 transfer protection to mice deficient in Fc-gammaRI receptors.

Merozoite surface protein 1 (MSP-1(19)) is a leading malaria vaccine candidate. Specific antibodies contribute to immunity; binding to macrophages is believed to represent the main action of malaria antibodies. We show that an MSP-1(19)-specific immunoglobulin G3 (IgG3) monoclonal antibody can passively transfer protection to mice deficient in the alpha chain of Fc-gammaRI whose macrophages cannot bind IgG3.

Animals↗