Search PubMed⌕ Search

Biomedical subjects

M Holmes

Publications and source records attributed to M Holmes.

At least 19 recordsLinked to original sources
PubMed2006

Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages.

Chronic obstructive pulmonary disease (COPD) is associated with increased apoptosis and defective phagocytosis in the airway. As uncleared cells can undergo secondary necrosis and perpetuate inflammation, strategies to improve clearance would have therapeutic significance. There is evidence that the 15-member macrolide antibiotic azithromycin has anti-inflammatory properties. Its effects may be increased in the lung due to its ability to reach high concentrations in alveolar macrophages (AMs). The present study investigated the effects of low-dose (500 ng x mL(-1)) azithromycin on the phagocytosis of apoptotic bronchial epithelial cells and neutrophils by AMs. Flow cytometry was applied to measure phagocytosis and receptors involved in AM recognition of apoptotic cells. Cytokines were investigated using cytometric bead array. Baseline phagocytosis was reduced in COPD subjects compared with controls. Azithromycin significantly improved the phagocytosis of epithelial cells or neutrophils by AMs from COPD subjects by 68 and 38%, respectively, often up to levels comparable with controls. The increase in phagocytosis was partially inhibited by phosphatidylserine, implicating the phosphatidylserine pathway in the pro-phagocytic effects of azithromycin. Azithromycin had no effect on other recognition molecules (granulocyte-macrophage colony-stimulating factor, CD44, CD31, CD36, CD91, alphavbeta3 integrin). At higher doses, azithromycin decreased levels of pro-inflammatory cytokines. Thus, low-dose azithromycin therapy could provide an adjunct therapeutic option in chronic obstructive pulmonary disease.

Anti-Bacterial Agents↗
PubMed2006

Compartmentalization of intracellular proinflammatory cytokines in bronchial intraepithelial T cells of stable lung transplant patients.

Allograft rejection remains a major cause of morbidity and mortality following lung transplantation and is associated with an increased expression of T cell proinflammatory cytokines. We have shown that CD4(+) T cell proinflammatory cytokine production was significantly reduced in peripheral blood and bronchoalveolar lavage (BAL) of stable lung transplant patients, consistent with immunosuppression therapy. However, analysis of inflammatory cytokine profiles of intraepithelial T cells in bronchial brushing (BB) may be more relevant than peripheral blood or BAL T cells for assessing immune graft status. To investigate the immunomodulatory effects of currently used immunosuppressive regimens on bronchial intraepithelial T cell cytokine production, whole blood, BAL and BB from stable lung transplant patients and control volunteers were stimulated in vitro and cytokine production by CD8(+) and CD4(+) T cell subsets determined using multi-parameter flow cytometry. In bronchial intraepithelial T cell subsets in control subjects and transplant patients there was compartmentalization of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha production, a decrease in interleukin (IL)-2 production by CD4(+) T cells and CD4 : CD8 inversion compared with blood and BAL. Although there was a decrease in T cell proinflammatory cytokine production in blood of transplant patients, this was not found in BAL or bronchial intraepithelial CD8 T cell subsets, suggesting that the same level of immunosuppression may not occur in the lung of transplant recipients. Drugs that effectively reduce CD8 T cell proinflammatory cytokine production in the lung compartment may improve current protocols for reducing graft rejection in these patients.

Adult↗
PubMed2005

Case Study Part 1: How to calculate appropriate deterministic long-term toxicity to exposure ratios (TERs) for birds and mammals.

In the European Union, first-tier assessment of the long-term risk to birds and mammals from pesticides is based on calculation of a deterministic long-term toxicity/exposure ratio (TER(lt)). The ratio is developed from generic herbivores and insectivores and applied to all species. This paper describes two case studies that implement proposed improvements to the way long-term risk is assessed. These refined methods require calculation of a TER for each of five identified phases of reproduction (phase-specific TERs) and use of adjusted No Observed Effect Levels (NOELs) to incorporate variation in species sensitivity to pesticides. They also involve progressive refinement of the exposure estimate so that it applies to particular species, rather than generic indicators, and relates spraying date to onset of reproduction. The effect of using these new methods on the assessment of risk is described. Each refinement did not necessarily alter the calculated TER value in a way that was either predictable or consistent across both case studies. However, use of adjusted NOELs always reduced TERs, and relating spraying date to onset of reproduction increased most phase-specific TERs. The case studies suggested that the current first-tier TER(lt )assessment may underestimate risk in some circumstances and that phase-specific assessments can help identify appropriate risk-reduction measures. The way in which deterministic phase-specific assessments can currently be implemented to enhance first-tier assessment is outlined.

Animals↗
PubMed2005

Case Study Part 2: Probabilistic modelling of long-term effects of pesticides on individual breeding success in birds and mammals.

Long term exposure of skylarks to a fictitious insecticide and of wood mice to a fictitious fungicide were modelled probabilistically in a Monte Carlo simulation. Within the same simulation the consequences of exposure to pesticides on reproductive success were modelled using the toxicity-exposure-linking rules developed by R.S. Bennet et al. (2005) and the interspecies extrapolation factors suggested by R. Luttik et al. (2005). We built models to reflect a range of scenarios and as a result were able to show how exposure to pesticide might alter the number of individuals engaged in any given phase of the breeding cycle at any given time and predict the numbers of new adults at the season's end.

Animals↗
PubMed2005

Gemcitabine twice weekly as a radiosensitiser for the treatment of brain metastases in patients with carcinoma: a phase I study.

Conventional treatment for brain metastases (BM) is whole-brain radiotherapy (WBRT). Efficacy is poor. It might be increased by a potent radiosensitiser such as gemcitabine which is believed to cross the disrupted blood-brain barrier. Primary objective of this study was to determine the maximum tolerated dose (MTD) of twice weekly gemcitabine given concurrently with WBRT. Patients with BM from carcinoma were included. The dose of WBRT was 30 Gys (10 daily fractions). Gemcitabine was given 2-4 h prior to WBRT on days 1 and 8 for the first cohort of patients and then on days 1, 4, 8 and 11. Starting dose was 25 mg m(-2), escalated by 12.5 mg m(-2) increments. At least three patients were included per level. Dose limiting toxicity (DLT) was defined as grade 4 haematological or grade > or =3 nonhaematological toxicity. A total of 25 patients were included; 74% had a PS 1 (ECOG). In all, 23 had non-small-cell lung cancer, six colorectal, four breast, two renal cell and one oesophageal carcinoma. A total of 92% had concurrent extracranial disease. Six had single BM, 13 had two or three BM and six multiple. Up to 50 mg m(-2) (level 4) no DLT was observed. At 62.5 mg m(-2), one out of six patients developed DLT (thrombocytopenia-bleeding). The next dose level (75 mg m(-2)) was abandoned after grade 4 bone marrow toxicity (fatal neutropenic sepsis) was seen in one out of two patients. So that the dose of 50 mg m(-2) will be taken forward for further study.

Adult↗
PubMed2005

Intracellular cytokines in blood T cells in lung transplant patients--a more relevant indicator of immunosuppression than drug levels.

Allograft rejection remains a major cause of morbidity and mortality following lung transplantation and is associated with an increase in T-cell pro-inflammatory cytokine expression. Systemic levels of immunosuppressive drugs used to reduce pro-inflammatory cytokine expression are closely monitored to their 'therapeutic range'. However, it is currently unknown if levels of these drugs correlate with pro-inflammatory cytokine expression in peripheral blood T cells. To investigate the immunomodulatory effects of currently used immunosuppressive regimes on peripheral blood T-cell cytokine production, whole blood from stable lung transplant patients and control volunteers were stimulated in vitro and cytokine production by CD8+ and CD4+ T-cell subsets determined using multiparameter flow cytometry. T-cell IL-2 and TNFalpha production was significantly reduced from lung transplant patients compared to controls. CD4+ T-cell production of IFNgamma was also significantly reduced from lung transplant patients but production of IFNgamma by CD8+ T cells remained unchanged. There was an excellent correlation between the percentage of CD8+ T cells and the percentage of CD8+ T cells producing IFNgamma from transplant patients. T-cell IL-4 and CD8+ T-cell production of TGFbeta was significantly increased from lung transplant patients. We now provide evidence that current immunosuppression protocols have limited effect on peripheral blood IFNgamma production by CD8+ T-cells but do up-regulate T-cell anti-inflammatory cytokines. Drugs that effectively reduce IFNgamma production by CD8+ T cells may improve current protocols for reducing graft rejection in these patients. Intracellular cytokine analysis using flow cytometry may be a more appropriate indicator of immunosuppression than drug levels in these patients. This technique may prove useful in optimizing therapy for individual patients.

Adult↗
PubMed2005

Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation.

There is heterogeneity in the propensity of smokers to develop chronic obstructive pulmonary disease (COPD), and improved treatment strategies are hindered by limited understanding of COPD pathogenesis, especially as distinct from the effects of smoking per se. Although apoptosis is essential for tissue homeostasis, increased apoptosis may cause tissue damage and inflammation. This study addressed whether airway T-lymphocytes and airway epithelial cells (AEC) show an increased likelihood of undergoing apoptosis in COPD and if this was related to smoking. Apoptosis (7-amino-actinomycin D, Annexin, single-stranded DNA and caspase), Bcl-2, Bax and p53 were assessed in cells obtained from bronchial bushing and bronchoalveolar lavage from ex- and continuing smokers with COPD, and nonsmoking controls, using flow cytometry. A mean 87% increase in apoptosis of AEC and a 103% increase in T-lymphocyte apoptosis were found in COPD. There were no significant differences in apoptosis of AEC between current and ex-smokers with COPD. Apoptosis may contribute to chronic obstructive pulmonary disease pathogenesis, and continued excess apoptosis after smoking cessation may offer a new target for therapeutic interventions. Whether the persistence of increased apoptosis after smoking cessation results from changes in the pulmonary milleau after years of noxious insult, or whether some individuals have a natural predisposition toward increased apoptosis and possible development of chronic obstructive pulmonary disease remains to be determined.

Age Factors↗
PubMed2004

Role of soft bone, CSF and gray matter in EEG simulations.

Effects of soft skull bone, cerebrospinal fluid (CSF) and gray matter on scalp potentials were examined with highly heterogeneous finite element models of an adult male subject. These models were constructed from segmented T1 weighted magnetic resonance images. Models had voxel resolutions of 1x1x3.2 mm with a total of about 1.5 million voxels. The scalp potentials, due to a dipolar source in the motor cortex area, were computed with an adaptive finite element solver. It was found that the scalp potentials were significantly affected by the soft bone, CSF and gray matter tissue boundaries in the models.

Adult↗
PubMed2003

Increased production of TGF-beta and apoptosis of T lymphocytes isolated from peripheral blood in COPD.

Chronic obstructive pulmonary disease (COPD) is associated with inflammation of airway epithelium, including an increase in the number of intraepithelial T cells. Increased apoptosis of these T cells has been reported in the airways in COPD, and although this process is critical for clearing excess activated T cells, excessive rates of apoptosis may result in unbalanced cellular homeostasis, defective clearance of apoptotic material by monocytes/macrophages, secondary necrosis, and prolongation of the inflammatory response. Lymphocytes are known to traffic between the airway and the peripheral circulation, thus we hypothesized that in COPD, circulating T cells may show an increased propensity to undergo apoptosis. We analyzed phytohemagglutinin (PHA)-stimulated peripheral blood T cells from COPD patients and controls for apoptosis using flow cytometry and staining with annexin V and 7-aminoactinomycin D. As several pathways are involved in induction of apoptosis of T cells, including transforming growth factor (TGF)-beta/TGF receptor (TGFR), TNF-alpha/TNFR1, and Fas/Fas ligand, these mediators were also investigated in peripheral blood samples from these subject groups. Significantly increased apoptosis of PHA-stimulated T cells was observed in COPD (annexin positive 75.0 +/- 14.7% SD vs. control 50.2 +/- 21.8% SD, P = 0.006), along with upregulation of TNF-alpha/TNFR1, Fas, and TGFR. Monocyte production of TGF-beta was also increased. In conclusion we have demonstrated the novel finding of increased apoptosis of stimulated T cells in COPD and have also shown that the increased T-cell death may be associated with upregulation of apoptotic pathways, TGF-beta, TNF-alpha, and Fas in the peripheral blood in COPD.

Adult↗
PubMed2003

The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of machine perfusion (MP) compared to cold storage (CS), as a means of preserving kidneys prior to transplantation. Transplantation of kidneys from both heart-beating donors (HBDs) and non-heart-beating donors (NHBDs) is considered. Finally to review whether the use of MP can allow valid testing of kidney viability prior to transplantation. DATA SOURCES: Fifteen electronic bibliographic databases were searched. The reference lists of relevant articles and sponsor submissions were hand searched and various health service research-related resources were consulted via the Internet. REVIEW METHODS: A literature search was undertaken to identify relevant studies and a meta-analysis performed on the studies that had appropriate comparator groups and reported sufficient data. A structured review examined tests of viability of kidneys on MP. Economic modelling was used to determine the cost-effectiveness and cost-utility of MP. RESULTS: The meta-analysis suggested that the use of MP, as compared with CS, is associated with a relative risk of delayed graft function (DGF) of 0.804 (95% confidence limits 0.672 to 0.961). There was no evidence to suggest that this effect is different in kidneys taken from HBDs as opposed to NHBDs. Meta-analysis of 1-year graft survival data showed no significant effect, but the studies, even when aggregated, were severely underpowered with respect to the likely impact on graft survival. The size of effects demonstrated were in line with those predicted by an indirect model of graft survival based on the association of DGF with graft loss. The economic assessment indicated that it is unlikely that in the UK health setting complete cost recovery will be obtained from a reduction in the incidence of DGF. The probability that MP is cheaper and more effective than CS in the long term was estimated at around 80% for NHBD recipients and 50-60% for HBD recipients. Flow characteristics of the perfusate of kidneys undergoing MP may be an indicator of kidney viability, but data were inadequate to calculate the sensitivity and specificity of any test based on this. The concentration of alpha-glutathione-S-transferase (a marker of cell damage) in the perfusate may be the basis of a valid test. A threshold of 2800 micrograms/100 g gave a sensitivity of 93% and specificity of 33% (and hence a likelihood ratio of 1.41). CONCLUSIONS: The baseline analysis indicated that in the long-term MP would be expected to be cheaper and more effective than CS for both HBD and NHBD recipients. A definitive study of the clinical benefit of MP in order to establish its effect on DGF and longer term graft survival would be valuable, together with an economic evaluation of the benefits. While direct evidence relating to improvements in graft survival would be preferable, the small predicted improvement indicates that a very large sample size would be required. In addition to seeking direct evidence of the impact on DGF, research quantifying the impact of DGF on graft survival in this technology is required. Research is also needed to establish whether a valid test (or combination of tests) of kidney viability can be developed.

Cell Survival↗
PubMed2002

Nocardia asteroides isolated from three patients with cystic fibrosis.

Over a 7-year period, three patients with cystic fibrosis had multiple sputum specimens that were smear- and culture-positive for Nocardia asteroides. Two of the patients had received long-term, low-dose inhalational corticosteroid therapy. Although all three patients were treated with cotrimoxazole, resulting in eradication of the organism from the sputum, there was no change in their clinical state, radiological findings, or pulmonary function. The isolation of Nocardia asteroides from the respiratory tract of cystic fibrosis patients is an unusual finding. Its presence does not necessarily imply disease, and in these three cases, it most likely represented colonisation. The clinical significance of Nocardia spp. isolated from the respiratory tract of cystic fibrosis patients needs to be considered in the context of the individual clinical picture.

Adolescent↗
PubMed2002

Complete genome sequence and comparative analysis of the metabolically versatile Pseudomonas putida KT2440.

Pseudomonas putida is a metabolically versatile saprophytic soil bacterium that has been certified as a biosafety host for the cloning of foreign genes. The bacterium also has considerable potential for biotechnological applications. Sequence analysis of the 6.18 Mb genome of strain KT2440 reveals diverse transport and metabolic systems. Although there is a high level of genome conservation with the pathogenic Pseudomonad Pseudomonas aeruginosa (85% of the predicted coding regions are shared), key virulence factors including exotoxin A and type III secretion systems are absent. Analysis of the genome gives insight into the non-pathogenic nature of P. putida and points to potential new applications in agriculture, biocatalysis, bioremediation and bioplastic production.

Bacterial Proteins↗
PubMed2002

Thick vs thin loop transurethral resection of the prostate: a double-blind prospective trial of early morbidity.

OBJECTIVE: To compare blood loss, irrigation requirements and hospital stay between standard transurethral resection of the prostate (TURP) and resection incorporating vaporization, i.e. transurethral vaporization resection (TUVRP). PATIENTS AND METHODS: Seventy patients were prospectively randomized in a blinded fashion between TURP with a standard resection loop (thin loop) or resection with a roller cutting electrode (thick loop). The outcome was assessed as the change in haemoglobin at 30 min and 24 h after the resection finished. Secondary outcome measures were irrigation requirements, length of catheterization, hospital stay, changes in serum sodium, and complications. The nursing staff and surgical registrar managing the patients after surgery were unaware of the resection technique used. RESULTS: Data were available for 65 patients (36 thin loop and 29 thick loop resections). The mean decrease in haemoglobin after TURP was 14.8 g/L at 30 min and 11.8 g/L at 24 h; for TUVRP the corresponding values were 14.6 and 14.2 g/L (P = 0.69). In addition, there was no difference in irrigation requirements, changes in serum sodium, length of catheterization, hospital stay or bleeding complications. CONCLUSION: The use of a thick loop at higher cutting current settings during TUVRP offers no advantage over standard thin-loop TURP.

Aged↗
PubMed2001

Assessment of questionnaire validity for measuring total fat intake using plasma lipid levels as criteria.

The validation of dietary total fat measurements has been elusive because no specific biomarker exists. In metabolic studies with controlled diets, plasma fasting triglyceride levels are reduced with higher fat intake and can thus serve as an "alloyed gold" standard. Participants in this cross-sectional analysis were 269 men aged 47-83 years from the Health Professionals Follow-up Study who completed a semiquantitative food frequency questionnaire and provided fasting blood specimens in 1994. In a multiple regression analysis adjusted for age; smoking; alcohol consumption; physical activity; body mass index; and intakes of protein, dietary fiber, and total energy, total fat intake was inversely associated with fasting triglycerides (for a fat increase of 1% of energy, triglyceride levels were lower by 2.5% (95% confidence interval: -3.7 to -1.3%, p = 0.0002)). For reported fat intakes of 20% or less of energy, the geometric mean fasting triglyceride level was 179, and for more than 40% of energy, it was 102 mg/dl. In addition, as predicted by metabolic studies, the inverse association between dietary fat and fasting triglyceride level was much stronger among overweight men than among men with a BMI of less than 25. These data provide additional evidence that informative measurements of dietary fat can be obtained by carefully constructed food frequency questionnaires.

Adult↗
PubMed2001

Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study.

Our objective was to compare the efficacy, safety, and microbiology of once-daily intravenous (IV) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa (PA) pulmonary exacerbations in cystic fibrosis (CF). CF patients with PA-induced pulmonary exacerbations were allocated to receive either once-daily tobramycin (Mono) or conventional therapy with tobramycin/ceftazidime given 8-hourly (Conv). The two longitudinal groups received therapy in a double-blind, randomized manner over a period of 2 years. Tobramycin doses were adjusted to achieve a daily area under the time-concentration curve of 100 mg x hr/L in both groups. Results were assessed for both short-term changes (efficacy and safety after 10 days of IV antibiotics during acute exacerbations) and long-term changes (efficacy, safety, and sputum microbiology between study entry and exit). Pulmonary function tests (PFTs) on admission were similar in both groups. After 10 days of IV antibiotics, absolute mean improvements in percent of predicted PFTs were 12.8, 12.1, and 13.7 for forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), and forced expired flow between 25--75% of FVC (FEF(25--75%)) in the Conv group (n = 51 admissions) compared to 10.6, 9.9, and 10.6 in the Mono group (n = 47)(P<0.05 for all). Sixteen percent in the Conv group and 15% of patients in the Mono group did not respond to therapy by day 10. Long-term PFT patterns were similar for the Conv and Mono groups. The time between admissions did not differ. The Mono group showed a significant increase in tobramycin minimum inhibitory concentrations (MICs) against PA from study entry to study exit (P = 0.02, n = 27 strains); this failed to reach significance in the Conv group (P = 0.08, n = 25). There was no significant increase in the number of isolates, with MIC> or =8 mg/L in both groups. No short- or long-term changes in audiology or serum creatinine were found in either group. After 10 days of IV therapy, the urinary enzyme N-acetyl-beta-d-glucosaminidase/creatinine ratios increased in both groups (P0.05). This increase was greater in the Conv compared to the Mono group (P < 0.05). We conclude that this pilot study indicates once-daily tobramycin therapy to be as effective and safe as conventional 8-hourly tobramycin/ceftazidime therapy. Combination antibacterial therapy appears to offer no clinical advantage over once-daily tobramycin monotherapy. Tobramycin once-daily monotherapy is a potential alternative to conventional IV antibacterial therapy which deserves further investigation, including the impact on susceptibility of PA to tobramycin.

Adolescent↗
PubMed2001

Evaluation of particle size distribution of salmeterol administered via metered-dose inhaler with and without valved holding chambers.

BACKGROUND: Administration of inhaled medications to very young children is sometimes difficult. Administration of inhaled medications via metered dose inhalers (MDIs) to pediatric patients younger than 4 years of age requires use of a holding chamber/spacer with an attached facemask. OBJECTIVE: This in vitro study was conducted to determine the particle size distribution and overall dose of salmeterol delivered in conjunction with the use of various US-marketed valved holding chambers (VHCs) in comparison to the dose-delivered via MDI without VHCs. METHODS: Cascade impaction methodology with high-performance liquid chromatography was used to evaluate the fine particle mass (FPM) of salmeterol administered without and with the use of the following VHCs: Optichamber, medium and large Aerochambers, adult Aerochamber, and medium Aerochamber Plus. RESULTS: Particle size distributions for the Optichamber, various sizes of Aerochamber, and the Aerochamber Plus were very similar and the particle size distributions for all VHCs were similar to the distribution of the control. The FPM for particles ranging from 0.7 to <3.3 microm in diameter (in the range shown to provide the greatest lung dose to negotiate the small airways of infants) was similar across the various VHCs tested. Statistical comparison of the fine particle fraction for these stages shows a very similar profile when differences from the salmeterol MDI control were evaluated. CONCLUSIONS: In vitro results obtained under these test conditions demonstrate that all FPM values for the VHCs tested were within 15% of the control range, a difference that is unlikely to be clinically meaningful. These results indicate that the difference in FPM does not warrant a change in the recommended dosage of salmeterol administered when using the VHCs tested. Our results demonstrate that the use of an MDI and VHC provides a reasonable therapeutic approach for administration of salmeterol MDI to young children and other patients who have difficulties administering the MDI alone.

Administration, Inhalation↗