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Biomedical subjects

A Devine

Publications and source records attributed to A Devine.

At least 19 recordsLinked to original sources
PubMed2006

The clinical utility of measured kyphosis as a predictor of the presence of vertebral deformities.

UNLABELLED: Meaured spinal kyphosis, as a predictor of prevalent and incident vertebral deformity, was examined in older women (>70 years) and found to not have sufficient sensitivity or specificity to justify its use as a predictor of present or future vertebral deformity risk. INTRODUCTION: Kyphosis may be attributable to vertebral deformity and was investigated as a clinical tool for predicting the presence and future risk of vertebral deformity. METHODS: Kyphosis was measured in 434 women aged 70 years or older and the kyphosis index (KI) calculated. Prevalent and incident vertebral deformities were assessed by morphometric X-ray absorptiometry (MXA). The predictive value of KI was examined. RESULTS: Severity of kyphosis was categorised by tertile of KI; 65% of anterior thoracic deformities occurred in the 33% of subjects in the highest (most kyphotic) tertile. Using this tertile as a predictor of anterior thoracic deformity, the probability for a positive test rose from 14% for the whole population to 28% and for a negative test the probability fell to 8%. For any spinal deformity the highest tertile of KI increased the probability of a positive test from 34% to 42% and reduced the probability for a negative test to 30%. The incidence of new deformities was 6% over 4 years; a high KI tertile did not increase the probability of any vertebral deformity. CONCLUSIONS: Severe kyphosis does not increase the probability of detection of a prevalent or incident spinal deformity sufficiently to make it a useful method of selecting patients for further evaluation of spinal deformity.

Absorptiometry, Photon↗
PubMed2006

No associations between OPG gene polymorphisms or serum levels and measures of osteoporosis in elderly Australian women.

Bone mass is the single most important risk factor for osteoporotic fractures in the elderly and is mainly influenced by genetic factors accounting for 40-75% of the inter-individual variation. Critical for the bone remodeling process is the balance between the newly discovered members of the tumor necrosis factor ligand and receptor superfamilies, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand, which mediate the effects of many upstream regulators of bone metabolism. In the present study, we evaluated the impact of sequence variations in the OPG gene on bone mass, bone-related biochemistry including serum OPG and fracture frequency in elderly Australian women. A total of 1101 women were genotyped for 3 different single nucleotide polymorphisms (SNP) within the OPG gene (G1181C, T950C and A163G). The effects of these SNPs and serum OPG on calcaneal quantitative ultrasound measurements, osteodensitometry of the hip and bone-related biochemistry were examined. We found no significant relationship between sequence variations in the OPG gene or serum OPG and bone mass, bone-related biochemistry or fracture frequency. Our findings confirm some recent publications investigating the same SNPs but diverge from others, indicating that generalization of the relationships found in this type of study must be done with caution and signify the importance of determining associations between polymorphisms and osteoporosis in different ethnic groups.

Absorptiometry, Photon↗
PubMed2005

Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women.

Osteoporosis is known to have a strong genetic basis. It has been proposed that polymorphisms within the KL (klotho) gene have a significant effect on aging, in particular, the osteoblast defect of aging. The association between polymorphisms within this gene and biochemical markers of bone formation and resorption, bone structure, and fracture rates was studied in 1,190 postmenopausal women with a mean age of 75 years. Genotyping of these polymorphic sites was carried out using Matrix-Assisted Laser Desorption Ionization--Time of Flight (MALDI-ToF) mass spectrometry. The G allele of SNP c.1775G>A was associated with a lower osteocalcin level than the A allele (P = 0.004) in a codominant model. SNPs C-387T and IVS1+8262c>t both showed nonsignificant associations with osteocalcin (P values of 0.063 and 0.068, respectively), but a haplotype analysis of 2 of 5 haplotypes of the three SNPs with a frequency greater than 4% revealed a significant association with osteocalcin (P = 0.036). None of the individual polymorphisms or haplotypes analyzed showed any associations with a marker of bone resorption the deoxypyridinoline creatinine ratio, bone structure, or fracture data. Therefore, the G polymorphism within the c.1775G>A SNP site and a haplotype including this are associated with a reduced osteoblast product osteocalcin. These data suggest that variation in the KL gene product affects osteoblast activity independent of osteoclast activity but that this defect does not result in an effect on bone structure in this population, perhaps because of "rescue" by other genetic or environmental factors in this population.

Absorptiometry, Photon↗
PubMed2005

Bone mass effects of a BMP4 gene polymorphism in postmenopausal women.

The pathogenesis of osteoporosis involves both genetic and environmental factors. On the basis of linkage data suggesting gene effects on bone density at chromosome 14q and data locating the BMP4 gene to 14q, we performed a positional candidate study to examine a possible association of BMP4 gene polymorphisms, hip bone density (n = 1012) and fracture rates (n = 1232) in postmenopausal women (mean age 75). On genotype analysis of the three selected single nucleotide polymorphisms (SNP), the 6007C > T polymorphism was associated with total and intertrochanteric hip BMD and BMD was lower in the 32% of subjects homozygous for the C allele. This polymorphism codes for a nonsynonymous amino acid change with the T allele coding for valine, while the C allele codes for alanine. The difference in BMD was 3.1% (TT vs. CC) and 2.3% (CT versus CC) for the total hip (P = 0.023), and 3.7% (TT vs. CC) and 2.8% (CT versus CC) for the intertrochanter site (P = 0.012). Haplotype analysis demonstrated 6 haplotypes of frequency greater than 2%. A major haplotype defined by G-C-T alleles in SNPs -5826G > A, 3564C > T and 6007C > T respectively, showed association with high bone mass. No SNP showed association with fracture rates. We conclude that a polymorphism found in the BMP4 gene, affecting amino acid sequence, is associated with hip bone density in postmenopausal women, presumably via regulation of anabolic effects on the skeleton.

Aged↗
PubMed2005

LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women.

Postmenopausal osteoporosis and bone mass are influenced by multiple factors including genetic variation. The importance of LDL receptor-related protein 5 (LRP5) for the regulation of bone mass has recently been established, where loss of function mutations is followed by severe osteoporosis and gain of function is related to increased bone mass. The aim of this study was to evaluate the role of polymorphisms in the LRP5 gene in regulating bone mass and influencing prospective fracture frequency in a well-described, large cohort of normal, ambulatory Australian women. A total of 1301 women were genotyped for seven different single nucleotide polymorphisms (SNPs) within the LRP5 gene of which five were potentially informative. The effects of these gene polymorphisms on calcaneal quantitative ultrasound measurements (QUS), osteodensitometry of the hip and bone-related biochemistry was examined. One SNP located in exon 15 was found to be associated with fracture rate and bone mineral density. Homozygosity for the less frequent allele of c.3357 A > G was associated with significant reduction in bone mass at most femoral sites. The subjects with the GG genotype, compared to the AA/AG genotypes showed a significant reduction in BUA and total hip, femoral neck and trochanter BMD (1.5% P = 0.032; 2.7% P = 0.047; 3.6% P = 0.008; 3.1% P = 0.050, respectively). In the 5-year follow-up period, 227 subjects experienced a total of 290 radiologically confirmed fractures. The incident fracture rate was significantly increased in subjects homozygous for the GG polymorphism (RR of fracture = 1.61, 95% CI [1.06-2.45], P = 0.027). After adjusting for total hip BMD, the fracture rate was still increased (RR = 1.67 [1.02-2.78], P = 0.045), indicating factors other than bone mass are of importance for bone strength. In conclusion, genetic variation in LRP5 seems to be of importance for regulation of bone mass and osteoporotic fractures.

Absorptiometry, Photon↗
PubMed2004

Association of an aromatase TTTA repeat polymorphism with circulating estrogen, bone structure, and biochemistry in older women.

Osteoporosis is a disease that is strongly genetically determined. Aromatase converts androgens to estradiol in postmenopausal women, therefore polymorphisms of the gene for this enzyme may be associated with bone mass and fracture. We investigated the association of the TTTA microsatellite polymorphism in intron 4 of the aromatase (CYP19) gene with bone mineral density (BMD) and fracture in 1,257 women aged 70 yr and greater. The data obtained were stratified based on the presence or absence of a [TTTA]n of 7 (A2), determined from a preliminary analysis of hip dual-energy X-ray absorptiometry BMD, which was present in 27% of the population. The presence of an A2 allele was associated with a higher free estradiol index (0.52 +/- 0.49, P = 0.049) compared with the absence of an A2 allele (0.47 +/- 0.45); higher BMD at all sites of the hip (3.4% total hip, 2.3% femoral neck, 3.6% intertrochanter, 4.1% trochanter) and the lumbar spine (12.7%); higher values for the calcaneal quantitative ultrasound parameters broadband ultrasound (1.3%), speed of sound (0.4%), and stiffness (3.7%); and higher peripheral quantitative computed tomography measures for total (3.4%), trabecular (3.3%), and cortical BMD (3.3%) and the derived stress strain index (SSI) parameters SSI polar (6.4%) and SSI x (6.8%) values. A lower deoxypryridinoline creatinine ratio was observed in subjects with an A2 allele (30.3 +/- 10.4 vs. 27.1 +/- 9.1, P = 0.03). The A2 allele was associated with a lower prevalence of vertebral fracture in subjects who were osteoporotic (odds ratio 0.27, confidence interval 0.09-0.79). Therefore, a common polymorphism of the aromatase gene, perhaps in linkage disequilibrium with a functionally significant CYP19 polymorphism, is associated with bone structure and bone turnover, either by local effects or by effects on circulating bioactive estrogen.

Aged↗
PubMed2004

Effects of endogenous estrogen on renal calcium and phosphate handling in elderly women.

High postmenopausal endogenous estrogen concentrations are an important determinant of preservation of bone mass and reduced fracture in elderly women. Calcium supplementation can also reduce bone loss in these patients, suggesting an interaction between estrogen deficiency and calcium balance. Potential mechanisms of estrogen on calcium transport include direct effects on the bone, the kidney, and the bowel. Previous studies have demonstrated effects of estrogen on renal phosphate handling. We have used a cross-sectional, population-based analysis of biochemical data obtained from ambulant elderly women to determine the association of endogenous estradiol with urine calcium and phosphorus excretion. The subjects were 293 postmenopausal women >70 yr old. Factors associated with renal calcium and phosphate excretion were measured, including the filtered calcium and phosphate load, parathyroid hormone (PTH), estradiol, and sex hormone-binding globulin (SHBG). The free estradiol concentration (FE) was calculated from a previously described formula. A high plasma estradiol concentration (r(2) = 0.023, P = 0.01) and a high FE (r(2) = 0.045, P = 0.001) were associated with reduced renal calcium excretion. The estradiol and FE effect on renal calcium excretion remained significant after adjusting for calcium filtered at the glomerulus and serum PTH. A high FE was associated with a reduced renal phosphate threshold in univariate analysis (r(2) = 0.023, P = 0.010). The effect remained significant after adjustment for serum PTH. The size of the effect of the FE was of the same order of magnitude as the effect of PTH on reducing renal calcium excretion and increasing renal phosphate excretion. These data support in vitro and animal data demonstrating an effect of estradiol on renal calcium and phosphate handling and indicate that, in elderly postmenopausal women, the effect is of a similar magnitude to the well-recognized effects of PTH on these physiologically regulated parameters.

Aged↗
PubMed2004

Prediction of incident osteoporotic fractures in elderly women using the free estradiol index.

A decline in postmenopausal estrogen concentration accelerates postmenopausal bone loss. We have examined the predictive power of endogenous estrogen production, DXA hip bone density (BMD), and heel quantitative ultrasound (QUS) on incident clinical fracture in a prospective 3-year population based, randomised controlled trial of calcium supplementation. Baseline blood testing on 1499 women mean (SD) age 75 (3) years for estradiol and sex hormone binding globulin measurements and ankle QUS measurements (Lunar Achilles) was undertaken. Bone density was measured using DXA (Hologic 4500A) at 1 year. Incident clinical fractures were confirmed by X-ray. At 3 years, 10% had sustained more than one incident fracture. The fracture group had significantly lower levels of free estradiol index (FEI) (0.40+/-0.44 versus 0.49+/-0.54 pmol/nmol), hip BMD (0.776+/-0.129 versus 0.815+/-0.124 g/cm(2)) and measures of QUS (BUA 98+/-8 versus 101+/-8 db/Hz, SOS 1504+/-22 versus 1514 +/-26 m/s; stiffness 67+/-11 versus 71+/-11 % mean young adult), respectively, than the non-fracture group. After adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture, incident fracture was predicted by free estradiol index (HR per SD: 1.43:95%CI: 1.08-1.91, P=0.013). After adjustment for BMD, SOS or stiffness, the free estradiol index no longer predicted fracture. When examined separately, the presence of a vertebral or an appendicular fracture was associated with an 18% lower free estradiol index compared with no fracture. The risk of vertebral fracture increased with decreased free estradiol index (HR per SD reduction: 1.63:95% CI: 0.91-2.92); the risk of appendicular fracture also increased with decreased free estradiol index (HR per SD reduction: 1.45:95% CI: 1.05-2.01) after adjustment for age, weight, use of topical estrogen, calcium supplementation and prevalent fracture. After further adjustment for hip BMD or QUS measures, the effect of free estradiol index was no longer significant for vertebral or appendicular fractures. Therefore, a low free estradiol index increases the probability of having an incident fracture as a result of decreased BMD. These data confirm the importance of postmenopausal estrogen concentration in the pathogenesis of osteoporosis in elderly women.

Administration, Topical↗
PubMed2003

Calcium-sensing receptor gene polymorphism A986S does not predict serum calcium level, bone mineral density, calcaneal ultrasound indices, or fracture rate in a large cohort of elderly women.

Postmenopausal osteoporosis is a complex and heterogeneous disease influenced by multiple factors and related to peak bone mass achieved in early adult life, followed by a subsequent continuous bone loss. Genetic variance and polymorphisms have been shown to be of clinical significance for osteoporotic fragility fractures. Previous studies have related variations in the calcium sensor receptor (CASR) gene to circulating Ca levels and bone mass in young women and adolescent girls. The aim of this study was to investigate the impact of the A986S polymorphism of the CASR gene on calcium homeostasis and bone metabolism in elderly women. We studied the distribution of the A986S polymorphism in a large cohort of 1252 ambulatory Australian women in relation to biochemical markers of bone metabolism, bone mass evaluated by quantitative ultrasound measurements (QUS) and DXA of the hip, prevalent and 36-month incident fracture data. No effect of the polymorphism was found on circulating calcium level, renal Ca excretion, or biochemical markers of bone turnover. Moreover, A986S was not associated with bone mass or prevalent or incident fractures. Power calculations revealed that a difference in circulating calcium levels of 0.05 mmol/l, a difference in DXA bone density of 24 mg, and a 1.6-fold difference in fracture rate could have been detected with a power of 80%. In conclusion, in a large cohort of elderly women the A986S polymorphism of the CASR gene was not found to be significant for calcium homeostasis or bone mass. It is questioned whether the polymorphism has any clinical significance for postmenopausal osteoporosis.

Aged↗
PubMed2003

The T869C TGF beta polymorphism is associated with fracture, bone mineral density, and calcaneal quantitative ultrasound in elderly women.

Osteoporosis is a disease that is strongly genetically determined and polymorphisms present in a range of candidate genes may be involved. A number of previous studies have shown an association between the T869C functional polymorphism of the gene for transforming growth factor beta (TGF beta) and bone mineral density (BMD) and fracture, but these studies have been limited to relatively small studies of selected subjects. In a population-based study of 1337 white women over age 70 we examined the TGF beta T869 polymorphism in relation to BMD, calcaneal quantitative ultrasound (QUS), and prevalent and incident fracture. The TGF beta C allele was observed in 50% of the subjects and was associated with reduced hip BMD at all sites (2.8% total hip, 2.4% femoral neck, 2.6% intertrochanter, and 3.4% trochanter) compared to the TGF beta TT genotype. The TGF beta C allele was also associated with a reduction in the QUS parameters BUA, SOS, and stiffness of 0.87%, 0.26%, and 2.4%, respectively, compared to the TGF beta TT genotype. After adjustment for body mass index in an analysis of variance model, the effect of the TGF beta C allele remained significant at the total hip, the femoral neck, and the trochanter, and for the QUS SOS and stiffness parameters. The TGF beta C allele was associated with an increase in osteoporosis [T score < or =-2.5 SD; odds ratio (OR) 2.07; 95% confidence interval (CI) 1.19-3.60] and prevalent fracture (1.37; 95% CI 1.06-1.75). After adjustment for BMD and QUS stiffness, the association of the TGF beta C allele with prevalent fracture was still present (OR 1.40; 95% CI 1.04-1.89), suggesting that the effect of the C allele on fracture was independent of a reduction in BMD and QUS stiffness. Subjects with normal BMD and a TGF beta C allele had an increased risk of incident fracture over 3 years compared to subjects with normal BMD and a TGF beta TT genotype (relative risk 3.95; 95% CI 1.52-10.29). This association was not found in osteopenic or in osteoporotic subjects, indicating a BMD-TGF beta C allele interaction in relation to the association of the TGF beta C allele with fracture risk. These findings are of potential clinical usefulness, as the TGF beta T869C genotype could be used, in conjunction with other genetic and clinical information, to determine an individual's risk of osteoporosis.

Aged↗
PubMed2002

Apolipoprotein E4 is associated with reduced calcaneal quantitative ultrasound measurements and bone mineral density in elderly women.

Some studies have reported an association between the apolipoprotein E4 (APOE4) allele and reduced bone density and increased propensity to fracture, but this remains controversial as other studies have not found an association between APOE4 and bone density or fracture. No information is available concerning the effect of the APOE4 allele on quantitative ultrasound (QUS) parameters. We therefore examined this issue in a population-based study of 1332 healthy elderly women, examining the effect of the APOE4 allele on QUS parameters at the calcaneus and comparing this to dual-energy X-ray absorptiometry (DEXA) bone mineral density (BMD) at the hip. In addition, we examined the effect of the APOE4 allele on fracture. Subjects who had at least one APOE4 allele (n = 308) had lower calcaneal QUS parameters and lower hip BMD at the total hip, trochanter, and intertrochanter, but not the femoral neck, compared to subjects without an APOE4 allele (n = 1024) after adjustment for age, body mass index (BMI), and smoking. The decrement in QUS parameters and BMD was approximately 2%. Those subjects having an APOE4 allele were also more likely to fall into a low bone density group, defined by a T score of <1 SD below the young normal range (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.08-2.22). We compared both prevalent and incident nontraumatic fractures over 2 years in the APOE4-present group compared with the APOE4-absent group. There were 354 subjects who entered the study with a history of one or more prevalent fractures, and 104 subjects sustained a nontraumatic fracture during the study. These fractures were not associated with the presence of the APOE4 allele, but a 2% decrement in BMD was unlikely to be associated with a statistically observable increase in fractures in this study. The APOE4 allele was not associated with a difference in any biochemical measures of bone formation or resorption, or in estrogen concentration, nor was it associated with a difference in BMI. Therefore, we conclude that the APOE4 allele is associated with a consistent decrease in both QUS parameters at the calcaneus and BMD at the clinically important hip site, and that this is not associated with differences in biochemical measures of bone formation or resorption.

Aged↗
PubMed2002

Antigen presentation by macrophages is enhanced by the uptake of necrotic, but not apoptotic, cells.

The aim of this study was to determine whether phagocytosis of necrotic or apoptotic cells affects antigen presentation by murine bone marrow-derived macrophages. After uptake of necrotic neutrophils, macrophages were able to stimulate significantly higher T cell proliferation in vitro against both the recall antigen albumin and the mitogen concanavalin A. No such effect was seen following phagocytosis of apoptotic neutrophils. Flow cytometry revealed that, within 4h of ingestion, macrophages that had taken up the necrotic cells expressed higher levels of CD40 than those that had phagocytosed apoptotic cells. Macrophage cultures pulsed with apoptotic, but not necrotic, neutrophils contained higher levels of transforming growth factor beta1, but lower concentrations of tumour necrosis factor alpha, compared to untreated controls. Our interpretation of these results is that macrophages that have taken up necrotic neutrophils co-stimulate T cells with greater efficiency due to rapid CD40 up-regulation, whereas those that have ingested apoptotic cells are not only ineffective in co-stimulation, but also secrete inhibitory cytokine.

Animals↗
PubMed2001

Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro.

R115777 [(B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone] is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. In vitro, using isolated human farnesyl protein transferase, R115777 competitively inhibited the farnesylation of lamin B and K-RasB peptide substrates, with IC50s of 0.86 nM and 7.9 nM, respectively. In a panel of 53 human tumor cell lines tested for growth inhibition, approximately 75% were found to be sensitive to R115777. The majority of sensitive cell lines had a wild-type ras gene. Tumor cell lines bearing H-ras or N-ras mutations were among the most sensitive of the cell lines tested, with responses observed at nanomolar concentrations of R115777. Tumor cell lines bearing mutant K-ras genes required higher concentrations for inhibition of cell growth, with 50% of the cell lines resistant to R115777 up to concentrations of 500 nM. Inhibition of H-Ras, N-Ras, and lamin B protein processing was observed at concentrations of R115777 that inhibited cell proliferation. However, inhibition of K-RasB protein-processing could not be detected. Oral administration b.i.d. of R115777 to nude mice bearing s.c. tumors at doses ranging from 6.25-100 mg/kg inhibited the growth of tumors bearing mutant H-ras, mutant K-ras, and wild-type ras genes. Histological evaluations revealed heterogeneity in tumor responses to R115777. In LoVo human colon tumors, treatment with R115777 produced a prominent antiangiogenic response. In CAPAN-2 human pancreatic tumors, an antiproilferative response predominated, whereas in C32 human melanoma, marked induction of apoptosis was observed. The heterogeneity of histological changes associated with antitumor effects suggested that R115777, and possibly farnesyl protein transferase inhibitors as a class, alter processes of transformation related to tumor-host interactions in addition to inhibiting tumor-cell proliferation.

3T3 Cells↗
PubMed2001

Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum.

Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P<0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41 micromol/g of protein respectively; mean difference -2.66 micromol/g; 95% confidence intervals -5.10 to -0.22 micromol/g; P<0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.

Adolescent↗
PubMed1999

Oxidative stress during acute respiratory exacerbations in cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis experience chronic systemic oxidative stress. This is coupled with chronic inflammation of the lung involving bronchial polymorphonuclear neutrophil accumulation and activation. We hypothesised that, during periods of acute respiratory exacerbation, free radical activity and consequent damage would be most marked and that intensive treatment of the infection would result in improvement towards values found during stable periods. METHODS: Plasma and red blood cells were collected from 12 healthy normal volunteers and from 12 patients with cystic fibrosis with an acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume in one second (FEV1) of more than 10%, and a decision to treat with intravenous antibiotics). Further samples were collected from patients following two weeks of treatment. Samples were analysed for inflammatory markers, markers of free radical damage, and aqueous and lipid phase scavengers. RESULTS: During respiratory exacerbations FEV1 and forced vital capacity (FVC) were lower than in controls (mean differences -2.82 (95% CI -2.12 to -3.52) and -3. 79 (-3.03 to -4.55) l, respectively) but improved following treatment (mean change 0.29 (95% CI 0.18 to 0.40) and 0.33 (0.23 to 0.43) l, respectively). Inflammatory markers during exacerbations were significantly higher in patients than in controls with the following mean (95% CI) differences: C reactive protein (CRP), 46 (17 to 75) g/l; neutrophil elastase alpha1-antiprotease complexes (NEAPC), 4.4 (1.77 to 7.07) mg/l; white cell count (WCC), 5.3 (4.7 to 5.9) x 10(9)/l. These markers decreased significantly following treatment with the following mean (95% CI) changes: CRP -26 (-10 to -42) g/l; NEAPC -3.1 (-1.3 to -4.9) mg/l; WCC -1.5 (-1.3 to -1.7) x 10(9)/l. Malondialdehyde (MDA) as a marker of free radical activity was significantly higher in patients during exacerbations than in controls with a mean (95% CI) difference of 193 (107 to 279) which improved with treatment (mean change -56 (95% CI -28 to -84) nmol/mmol cholesterol). Red blood cell polyunsaturated fatty acids were significantly lower in patients than in controls with a mean difference of -4.4(95% CI -2.6 to -6.2) moles percent, but did not improve significantly after treatment. Protein carbonyls during exacerbations were not different from controls but did increase with treatment compared with levels during the exacerbation (mean change 0.39 (95% CI 0.11 to 0.67) micromol/g protein). Aqueous and lipid phase scavengers in patients during exacerbations were significantly lower than in controls with the following mean (95% CI) differences: ascorbate, -19.0 (-2.7 to -35.3) micromol/l; sulphydryls, -122 (-77 to -167) micromol/l; retinol, -237 (-47 to -427) nmol/mmol cholesterol; beta-carotene, -52.8 (-11.8 to -93.8) nmol/mmol cholesterol; luteine, -50.4 (-10.4 to -90.4) nmol/mmol cholesterol; lycopene, -90.1 (-30.1 to -150.1) nmol/mmol cholesterol. Treatment resulted in improvement with the following mean (95% CI) changes: sulphydryls, 50 (32 to 68) micromol/l; retinol, 152 (47 to 257) nmol/mmol cholesterol; alpha- and beta-carotene, 0.6 (0.0 to 1.2) and 7.6 (0.0 to 15.2) nmol/mmol cholesterol, respectively; alpha-tocopherol, 839 (283 to 1405) nmol/mmol cholesterol; and lycopene, 8.2 (0.0 to 16.2) nmol/mmol cholesterol. CONCLUSIONS: Abnormalities of markers of inflammation, free radical activity, and radical scavengers were significantly more extreme during acute respiratory exacerbations and showed improvement with treatment. The need to provide protection from inflammation and free radical damage should therefore be dynamic and related to the inflammatory and oxidative processes.

Acute Disease↗
PubMed1999

Differential effects of necrotic or apoptotic cell uptake on antigen presentation by macrophages.

The induction of pathogenic immune responses may be dependent on the immune system receiving 'danger' signals resulting from tissue damage, rather than tolerogenic stimuli associated with normal cell turnover. The aim was to test this hypothesis by comparing the effects of the uptake of necrotic and apoptotic cells on the ability of antigen-presenting cells (APC) to stimulate immune responses in vitro. The experiments focused on presentation by the macrophage, which is the main cell type adapted for clearing cellular debris in vivo. Murine bone marrow-derived macrophages were pulsed with neutrophils that had been rendered apoptotic or necrotic, and tested for the ability to induce T cell responses. The macrophages that had taken up necrotic, but not apoptotic, cells were able to stimulate recall proliferation by ovalbumin-specific T cells. Furthermore, the response to the mitogen concanavalin A (Con A) was more than 6 times higher when macrophages had been pulsed with necrotic, in comparison with apoptotic, cells. In control experiments, macrophages that had not been exposed to dying neutrophils stimulated weak responses to ovalbumin and Con A. To determine why the uptake of apoptotic and necrotic cells exert opposing effects on the ability of macrophages to stimulate T cells, the expression of costimulatory molecules by treated macrophages, and their production of potentially immunomodulatory cytokines were measured. Flow cytometry revealed that macrophages that had taken up necrotic, but not apoptotic, neutrophils expressed increased levels of CD40 compared to untreated controls within 4 h. Macrophages pulsed with apoptotic cells secreted higher levels of transforming growth factor-beta1 than those ingesting necrotic cells or untreated controls. Our interpretation of these results is that macrophages that have taken up necrotic cell debris present antigens to T lymphocytes with greater efficiency due to transient CD40 upregulation, whereas those that have ingested apoptotic cells are ineffective APC since they secrete inhibitory cytokine.

Animals↗
PubMed1998

The management of metformin overdose.

Only two cases of deliberate self-poisoning with metformin have been described in the literature. We report the management of three cases, all of which presented with severe lactic acidosis. Two cases had a fatal outcome. The options for treatment and previous cases reported in the literature are reviewed. Recommendations for the management of metformin overdose include early recognition, intensive support of the cardiovascular system, the correction of metabolic acidosis and the maintenance of body temperature. The use of venovenous haemofiltration against a non-lactate containing fluid may improve outcome when sodium bicarbonate alone fails to reverse severe systemic acidosis.

Acidosis, Lactic↗