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Biomedical subjects

A R Allen

Publications and source records attributed to A R Allen.

At least 19 recordsLinked to original sources
PubMed2004

Lack of association between the -2518G/A polymorphism of the MCP-1 gene and ischaemic heart disease: a family-based investigation.

Using two recently described family-based tests of association, the possible role of the functional -2518G/A polymorphism in the promoter region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped for the MCP-1 -2518G/A polymorphism. Using the combined transmission disequilibrium test and the pedigree disequilibrium test, no association between the MCP-1 -2518G/A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MCP-1 -2518G/A polymorphism is not strongly associated with IHD.

Chemokine CCL2↗
PubMed2004

The intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism is not associated with ischaemic heart disease: an investigation using family-based tests of association.

The possible role of the K469E polymorphism in the intercellular adhesion molecule-1 (ICAM-1) gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family-based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped for the ICAM-1 K469E polymorphism. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the ICAM-1 K469E polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the ICAM-1 K469E polymorphism is not associated with IHD.

Adult↗
PubMed2003

Investigation of the C242T polymorphism of NAD(P)H oxidase p22 phox gene and ischaemic heart disease using family-based association methods.

Ischaemic heart disease is a complex phenotype arising from the interaction of genetic and environmental factors. Excessive production of reactive oxygen species leading to endothelial dysfunction is believed to be important in the pathogenesis of ischaemic heart disease. The NAD(P)H oxidase system generates superoxide anions in vascular cells; however, the role of the C242T polymorphism of the NAD(P)H oxidase p22 phox gene in ischaemic heart disease is unclear due to contradictory results from case-control studies. Consequently, we applied family-based association tests to investigate the role of this polymorphism in ischaemic heart disease in a well-defined Irish population. A total of 1023 individuals from 388 families (discordant sibships and parent/child trios) were recruited. Linkage disequilibrium between the polymorphism and ischaemic heart disease was tested using the combined transmission disequilibrium test (TDT)/sib-TDT (cTDT) and pedigree disequilibrium test (PDT). Both cTDT and PDT analyses found no statistically significant excess transmission of either allele to affected individuals (P =0.30 and P =0.28, respectively). Using robust family-based association tests specifically designed for the study of complex diseases, we found no evidence that the C242T polymorphism of the p22 phox gene has a significant role in the development of ischaemic heart disease in our population.

Adult↗
PubMed2002

Elongation correlates with nutrient deprivation in Pseudomonas aeruginosa-unsaturates biofilms.

Bacteria in nature frequently grow as biofilms, yet little is known regarding how biofilm bacteria morphologically adapt to low nutrient availability, which is common in unsaturated environments such as the terrestrial subsurface or on plant leaves. For unsaturated biofilms, in which the substratum may provide all nutrients, what are the relationships between nutrition and cell size and shape-the simplest metrics of cellular morphology? To address this question, we cultured Pseudomonas aeruginosa, a ubiquitous gram-negative bacterium that is environmentally and medically important, on membranes overlaying solid media, and then measured cellular dimensions using atomic force microscopy (AFM). Nutrition was controlled chemically by media composition and physically by stacking membranes to increase the path length for nutrient diffusion. Under conditions of carbon-nitrogen imbalance, low carbon bioavailability, or increased nutrient diffusional path length, cells elongated while maintaining constant width. A mathematical relationship suggests that, by elongating, biofilm bacteria strategically enlarge their nutrient collection surface without substantially changing the ratio of surface area to volume (SA/V). We conclude that P. aeruginosa growing as unsaturated biofilm with a planar nutrient source morphologically adapt to starvation by elongating. This adaptation, if generalizable, differs from a better-understood starvation response (i.e., cell size decreases; thus SA/V in-creases) for planktonic bacteria in well-mixed environments.

Adaptation, Biological↗
PubMed2000

VCAM-1 has a tissue-specific role in mediating interleukin-4-induced eosinophil accumulation in rat models: evidence for a dissociation between endothelial-cell VCAM-1 expression and a functional role in eosinophil migration.

Eosinophil accumulation has been associated with the pathogenesis of numerous allergic inflammatory disorders. Despite the great interest in this response, many aspects of eosinophil accumulation remain unknown. This is particularly true with respect to tissue-specific mechanisms that may regulate the accumulation of eosinophils in different organs. This study addressed this issue by investigating and comparing the roles of alpha(4)-integrins and vascular cell adhesion molecule 1 (VCAM-1) adhesion pathways in interleukin 4 (IL-4)-induced eosinophil accumulation in 2 different rat models of inflammation, namely pleural and cutaneous inflammation. Similar to our previous findings in studies in rat skin, locally administered IL-4 induced a time- and dose-dependent accumulation of eosinophils in rat pleural cavities, a response that was associated with generation of the chemokine eotaxin. The IL-4-induced eosinophil accumulation in skin and pleural cavities was totally inhibited by an antirat alpha(4)-integrins monoclonal antibody (mAb) (TA-2). In contrast, whereas an antirat VCAM-1 mAb (5F10) totally blocked the response in skin, IL-4-induced eosinophil accumulation in rat pleural cavities was not affected by VCAM-1 blockade. A radiolabeled mAb technique demonstrated that endothelial-cell VCAM-1 expression was induced in response to IL-4 in both skin and pleural membrane. The results indicate that although endothelial-cell VCAM-1 is present in skin and pleura, a functional role for it in IL-4-induced eosinophil accumulation was evident only in skin. These findings suggest the existence of tissue-specific adhesive mechanisms in regulating leukocyte migration in vivo and demonstrate a dissociation between VCAM-1 expression and eosinophil accumulation.

Animals↗
PubMed1999

Endothelial expression of VCAM-1 in experimental crescentic nephritis and effect of antibodies to very late antigen-4 or VCAM-1 on glomerular injury.

The migration of leukocytes into glomeruli in crescentic glomerulonephritis is fundamental to pathogenesis, and offers important therapeutic opportunities. We addressed the importance of VCAM-1, and its leukocyte ligand very late antigen-4 (VLA-4), in such leukocyte migration. In a rat model of nephrotoxic nephritis, glomerular expression of VCAM-1, studied by immunohistochemistry, was up-regulated by day 6 of nephritis. To quantify kidney endothelial VCAM-1 expression, a differential radiolabeled mAb technique was used, which demonstrated that protein expression was not up-regulated by day 2 of nephritis, but rose threefold between days 2 and 5, and remained elevated until at least day 28. An in vivo study was then performed, using blocking mAbs to either VCAM-1 or VLA-4, starting mAb treatment on the day prior to disease induction, and continuing until animals were sacrificed at day 7. mAbs to VLA-4 significantly attenuated renal injury (albuminuria, glomerular fibrinoid necrosis, and crescent formation), but mAbs to VCAM-1 had no significant effect. Surprisingly, the number of leukocytes within glomeruli was unaffected by anti-VLA-4 mAb therapy, despite the reduction in renal injury. Paradoxically, classical markers of macrophage activation were increased in the anti-VLA-4- and anti-VCAM-1-treated animals. This study demonstrates that kidney endothelial VCAM-1, in contrast to ICAM-1, is not up-regulated by day 2 of nephrotoxic nephritis, and plays little part in early leukocyte influx into glomeruli. However, VLA-4 is an important mediator of glomerular injury, operating after transendothelial leukocyte migration, and presumably binding to alternate ligands within the kidney.

Albuminuria↗
PubMed1996

Selective renal transplantation in primary hyperoxaluria type 1.

Primary hyperoxaluria type I (PHI) is a cause of end-stage renal disease in young people. It is caused by deficient activity of hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT), which results in hyperoxalemia and hyperoxaluria. The consequent urolithiasis and nephrocalcinosis result in renal impairment, with further reduction in oxalate excretion and eventual systemic oxalosis. Historically, renal transplantation has yielded very poor results in these patients because of recurrent oxalosis of the graft. Within the last 10 years, combined hepatorenal transplantation has been successfully applied, simultaneously correcting the metabolic lesion in the liver and replacing the damaged kidneys. It has, however, become apparent that medical therapy with vigorous hydration, inhibitors of stone formation and pyridoxine (AGT co-factor), may be successful at delaying, and occasionally in preventing, urolithiasis in some hyperoxaluric patients, particularly those whose hyperoxaluria is reduced by pyridoxine. This, together with intensive perioperative management and modern surgical methods of stone management such as lithotripsy, laser or ultrasound stone fragmentation, and percutaneous nephrolithotomy, means that renal transplantation alone may be feasible in selected patients. We describe a patient with PHI with clinical and biochemical evidence of significant residual AGT activity who underwent a successful live-related renal transplantation with excellent renal function and no stone recurrence 1 year posttransplantation. The appropriate transplantation strategies for these complex patients are discussed and include isolated renal transplantation for those patients who are without significant systemic oxalosis and have evidence of residual AGT activity.

Adult↗
PubMed1995

Regional differences in the effects of forced swimming on extracellular levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid.

The effects of forced swimming for 30 min on extracellular 5-hydroxytryptamine (5-HT) levels were examined in five brain regions in rats using in vivo microdialysis. A single dialysis probe was implanted under surgical anesthesia into either the striatum, ventral hippocampus, frontal cortex, amygdala, or lateral septum on the day before the study. Dialysate content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) was measured by HPLC. Forced swimming elevated extracellular levels of 5-HT in the striatum to a maximum of 90% above baseline. In contrast, forced swimming reduced 5-HT levels in the amygdala and lateral septum to 50 and 40% of baseline, respectively. In the hippocampus and frontal cortex, 5-HT levels were not altered significantly by forced swimming. In all five brain regions, forced swimming reduced 5-HIAA levels to 45-60% of baseline. These results suggest that forced swimming modulates 5-HT neurotransmission in a regionally specific manner. Aside from being a significant biological stressor, the forced swimming test is used as an animal behavioral model to detect antidepressant drugs, including drugs that alter 5-HT neurotransmission. It is possible that the alterations of extracellular levels of 5-HT produced by forced swimming in certain brain regions may be associated with the ability of antidepressant drugs to selectively alter behavioral performance during the forced swimming test.

Animals↗
PubMed1991

Effects of triadimefon on a multiple schedule of fixed-interval performance: comparison with methylphenidate, d-amphetamine and chlorpromazine.

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10-170 mg/kg, IP) and of methylphenidate (1-17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3-3.0 mg/kg, IP) and chlorpromazine (0.5-2.0 mg/kg, IP). Response rates were increased by d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Variable-ratio schedules of timeout from avoidance: effects of d-amphetamine and morphine.

Rats were trained on concurrent schedules in which pressing one lever postponed shock and pressing the other lever produced periods of signaled timeout from avoidance on variable-ratio schedules. These procedures generated high rates of timeout-reinforced responding and provided a baseline for studying the effects of drugs on behavior maintained by different types of negative reinforcement (shock postponement vs. timeout). Morphine (2.5 to 10.0 mg/kg) reduced behavior maintained by timeout at doses that increased or had no effect on avoidance responding. In contrast, d-amphetamine (0.125 to 2.0 mg/kg) produced large increases in timeout responding at doses that had minimal effect on avoidance in rats trained on variable-interval and variable-ratio schedules. Thus, the event-dependent effects of morphine, observed in previous studies in which timeout responding was maintained at low rates by interval schedules, were replicated with high timeout rates maintained by variable-ratio schedules. The effects of d-amphetamine could also be described as "event dependent" because timeout responding was stimulated more than avoidance regardless of the maintenance schedule or baseline rate.

Animals↗
PubMed1978

Auditory brain stem potentials in monkey (M. mulatta) and man.

Auditory brain stem potentials were mapped over the head of the rhesus monkey following monaural clicks. Latency and amplitude were dependent upon the recording site. No electrically indifferent point could be found on the head or neck. The results are interpreted as showing that waves I and V originate from single generators, whereas waves, II, III and IV originate from bilateral structures. Latency varied in a linear fashion with changes in intensity and click rate. In contrast there were variations in amplitude of the potentials independent of stimulus change. A comparison was made of auditory brain stem potentials in man, monkey, cat and rat to demonstrate the similarity of the responses across species.

Acoustic Stimulation↗
PubMedDate not supplied

Bitertanol, a triazole fungicide, increases operant responding but not motor activity.

Several recent reports indicate that triadimefon, a triazole fungicide, has effects on behavior that are similar to those of psychomotor stimulants. For example, triadimefon increases overall fixed-interval (FI) response rate, disrupts FI response patterning, increases motor activity, and produces stereotypies at high doses. The present study was designed to determine whether similar behavioral effects on FI performance and motor activity could be produced by another triazole fungicide, bitertanol. The effects of bitertanol (10-300 mg/kg, IP) were determined in rats on performance maintained under a multiple FI 1-min FI 5-min schedule of reinforcement. Intermediate doses of bitertanol increased response rates and disrupted response patterning in both FI components. A second experiment determined the effects of the same doses of bitertanol on motor activity. In contrast to its effects on operant responding, bitertanol did not increase motor activity at any of the doses tested. These findings indicate that the behavioral similarities between bitertanol and triadimefon are limited and that a dissociation exists between biteranol's effects on operant performance and motor activity.

Animals↗