Search PubMed⌕ Search

Biomedical subjects

John J O'Connor

Publications and source records attributed to John J O'Connor.

At least 19 recordsLinked to original sources
PubMed2006

Interleukin-18 mediated inhibition of LTP in the rat dentate gyrus is attenuated in the presence of mGluR antagonists.

Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory impairments. We have previously demonstrated the inhibition of long-term potentiation (LTP), a recognised model for memory, in the dentate gyrus region of the rat hippocampus, by interleukin-18. We have also previously shown that the inhibitory effect of TNF-alpha on LTP can be attenuated by inhibitors of metabotropic glutamate receptors (mGluRs). We therefore went on to investigate the effects of the mGluR antagonists MPEP and MTPG on the effect of IL-18 on LTP in the rat dentate gyrus in vitro. Recordings of field excitatory post-synaptic potentials (EPSPs) were made from the medial perforant path of rat hippocampal slices. IL-18 (100 ng/ml) applied for 20 min before-HFS had no significant effect on baseline EPSPs but significantly impaired LTP (IL-18 LTP 116+/-9%, versus control LTP 163+/-6% 1h post-tetanus, P<0.001, n=5). Perfusion of the mGluR5 specific antagonist MPEP (5 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but significantly attenuated the inhibitory effect of IL-18 on LTP at 30 min but not 1h (177+/-2% and 138+/-8%, respectively, compared to controls; n=5). Perfusion of the group II mGluR antagonist MTPG (50 microM) for 40 min prior to application of IL-18 had no significant effect on baseline EPSPs but was found to significantly reverse the inhibitory effect of IL-18 on LTP at 1h (164+/-6% compared to IL-18 alone, n=5). This study provides novel evidence of the involvement of mGluRs in the IL-18 mediated inhibition of LTP.

Alanine↗
PubMed2006

Codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene is associated with increased cardiovascular risk in the dyslipidemic diabetic participants of the Veterans Affairs HDL intervention trial (VA-HIT).

The threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene, when compared to the wild type, is associated with dyslipidemia. Since dyslipidemia is common in diabetes and is associated with increased cardiovascular risk, we tested the hypothesis that Thr-54 is associated with increased cardiovascular risk in patients with diabetes. The secondary prevention veterans affairs HDL intervention trial (VA-HIT) was carried out in patients with dyslipidemia. The DNA of trial participants (n=776) was screened for the Thr-54 polymorphism and cardiovascular endpoints were monitored. The polymorphism was detected in 370 (47.7%). For first occurrence of the primary endpoint [myocardial infarction (MI) or coronary heart disease (CHD) death] the hazard ratio (HR) and confidence intervals (Cox proportional hazards model) was 2.5 (1.2, 5.3) p=.02 in diabetic carriers of Thr-54 versus carriers without diabetes or fasting glucose >7 mmol/L. For the expanded endpoint (stroke, MI or CHD death), the corresponding HR was 3.0 (1.4, 5.4) p=.0003 and for the stroke alone the corresponding HR was 3.5 (1.4-8.9) p=.01. The higher cumulative incidence of the expanded endpoint in diabetic participants carrying the FABP2 polymorphism versus non-diabetic carriers was consistently present throughout the 5 years of the study (p=.0002). We conclude that based on the VA-HIT data, the Thr-54 polymorphism of the FABP2 gene is associated with a 2-3.5-fold increase in cardiovascular risk in dyslipidemic men with diabetes compared to their non-diabetic counterparts.

Aged↗
PubMed2005

The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: the Veterans Affairs HDL Intervention Trial (VA-HIT).

BACKGROUND: The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that gemfibrozil, which activates peroxisome proliferator-activator receptor alpha (PPARalpha), significantly reduced the risk of cardiovascular (CV) events in men with low HDL cholesterol (< 40 mg/dl) and established coronary heart disease. Treatment was particularly beneficial in those with insulin resistance (IR) or diabetes mellitus (DM). We hypothesized that the association between a functional polymorphism at the PPARA locus (L162V) and the risk of a CV event, as well as response to fibrate therapy, might be greatest in those with either IR or DM (DM/IR) in VA-HIT. METHODS AND RESULTS: A total of 827 men (placebo, n = 413; gemfibrozil, n = 414) from the VA-HIT were genotyped. This population included a high proportion of subjects with DM/IR. In VA-HIT, the PPARA V162 allele was associated with reduced levels of HDL cholesterol and the presence of DM/IR at baseline. It was also associated with reduced risk of CV events in those with DM/IR but not in those with neither (DM/IR *PPARA genotype, P = 0.005). Among subjects with DM/IR, treatment with gemfibrozil reduced CV events in non-carriers from 29.9 to 17.8% and carriers of the V162 allele from 14.7 to 4.8%. In contrast, carriers of the V162 allele with no DM/IR who were treated with gemfibrozil experienced significantly more CV events than did those who received placebo (20.6% versus 13.6%; P = 0.01). CONCLUSIONS: The effect of the L162V polymorphism at the PPARA locus on CV risk depends on the presence of DM/IR. Among subjects treated with gemfibrozil, the V162 allele was associated not only with reduced CV risk in subjects with DM/IR, but also with significantly increased CV risk in the absence of these traits, identifying this genetic variant as a potential marker for predicting which subjects may have a favorable response to fibrate therapy.

Alleles↗
PubMed2005

Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system.

Increasing attention is being paid to the role of inflammatory and immune molecules in the modulation of central nervous system (CNS) function. Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine, the receptors for which are expressed on neurones and glial cells throughout the CNS. Through the action of its two receptors, it has a broad range of actions on neurones which may be either neuroprotective or neurotoxic. It plays a facilitatory role in glutamate excitotoxicity, both directly and indirectly by inhibiting glial glutamate transporters on astrocytes. Additionally, TNF-alpha has direct effects on glutamate transmission, for example increasing expression of AMPA receptors on synapses. TNF-alpha also plays a role in synaptic plasticity, inhibiting long-term potentiation (LTP), a process dependent on p38 mitogen activated kinase (p38 MAP) kinase. In the following review we look at these and other effects of TNF-alpha in the CNS.

Animals↗
PubMed2004

A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in vitro.

Recent studies have implicated Ras signalling in synaptic plasticity. In this study we have investigated a role for the low molecular weight G proteins Ras, Rap, Ra1 and Rac in long-term potentiation and depression using Clostridium Sordelli Lethal Toxin-82 (LT-82), which inactivates Ras, Rap, Ra1 and Rac, and manumycin A, a Ras inhibitor. Perfusion of hippocampal slices with LT-82 (200 ng/ml) attenuated LTP (83+/-10%, n=5, P<0.01, compared with controls of 160+/-11% at 60 min post HFS, n=5). LT-82 had no effect on LTD (63+/-1% at 100 ng/ml, n=5 and 66+/-1% at 200 ng/ml, n=4, compared to controls of 56+/-6%, n=6). Manumycin A (2 microM) had no effect on LTP (162+/-2%, n=5, compared to controls of 167+/-13%, n=5), but significantly attenuated LTD (88+/-6%, n=5, P<0.01, compared to controls of 63+/-9%, n=7). LT-82 (200 ng/ml) significantly increased the amplitude of the isolated NMDA-EPSP at 60 min post-drug application (240+/-40%, n=5, P<0.01, compared with controls of 100+/-4%, n=5). However, manumycin A, had no significant effect on NMDAR-EPSP amplitude (92+/-2%, n=5, compared with controls). These results demonstrate an important role for Ras in LTD and a role for Rap, Ra1 and Rac in LTP.

Animals↗
PubMed2004

Mobility of the human ankle and the design of total ankle replacement.

Our prior research has shown that currently available total ankle implants fail to restore physiologic ankle mobility. Most of the modern mobile-bearing designs that feature a flat tibial component and a talar component with anatomic curvature in the sagittal plane function nonphysiologically with the natural ligament apparatus. To establish a more natural relationship between the implanted components and the retained ankle ligaments, we have developed a new design. According to our prior research, we suggest that physiologic ankle mobility is reproduced best with a design featuring a spherical convex tibial component, a talar component with radius of curvature in the sagittal plane longer than that of the natural talus, and a fully conforming meniscal component. Our preliminary observations in trial implantation and in a few patients suggest that while reproducing physiologic ankle mobility, the new design is capable of maintaining complete congruence at the two articulating surfaces of the meniscal bearing over the entire motion arc, with the prospect of minimizing wear of this component.

Ankle Joint↗
PubMed2003

The inhibition of long-term potentiation in the rat dentate gyrus by pro-inflammatory cytokines is attenuated in the presence of nicotine.

Nicotine has previously been shown to affect both long-term potentiation (LTP) and long-term depression and to reverse age-related impairments of LTP in the hippocampus. Levels of proinflammatory cytokines are known to be elevated with age and to inhibit LTP. In the present study we have investigated the effects of three pro-inflammatory cytokines on nicotine-enhanced LTP in the rat hippocampus in vitro. In the presence of nicotine the inhibitory effect of interleukin-1 beta, interleukin-18 and tumour necrosis factor-alpha on LTP was eliminated. Furthermore, significant depotentiation of established LTP could not be obtained in slices treated with nicotine. These experiments demonstrate that nicotine can reverse the inhibitory effects of pro-inflammatory cytokines on LTP.

Animals↗
PubMed2003

A comparison of the gaits of Chinese and Caucasian women with particular reference to their heelstrike transients.

OBJECTIVE: To examine the hypothesis that the differences reported in incidence of osteoarthrosis in Chinese and Caucasians could be associated with differences in habitual gait. DESIGN: The effects of race and age on walking speed and heelstrike transient were examined.Background. The relatively low incidence of gonarthrosis in Chinese populations compared to Caucasians remains unexplained. Repetitive impulsive loading exhibited at heel strike in the walking process has been linked to the development of gonarthrosis, while the gait characteristics of people at different risk levels for gonarthrosis have not been compared quantitatively. METHODS: The gait of 117 healthy women, 76 Chinese and 41 Caucasians, was studied with an optometric system and two force plates in an 8-m walkway. Natural walking speed, stride length, cadence and maximum loading rate at heelstrike were collected. RESULTS: The Caucasian women over age 45 walked significantly faster with significantly higher maximal loading rate than age-matched Chinese women (P<0.005). Age effects on most gait parameters measured were found significant in the Chinese group (P<0.01) but not in the Caucasian group. CONCLUSIONS: Chinese women slow down their walking speed and reduce the cadence of their gait earlier in their life span and, thus, lower their heelstrike transients. Significant racial differences in gait might explain the lower prevalence of gonarthrosis reported in Chinese women. RELEVANCE: Significantly larger heelstrike transients and significantly faster walking speed were seen in the population at higher risk for gonarthrosis. Walking slowly with lower heelstrike transients might be an effective preventive measure against gonarthrosis.

Adult↗
PubMed2003

Femoral muscle attachment locations in children and adults, and their prediction from clinical measurement.

Accurate representation of children's musculo-skeletal anatomy is becoming increasingly important to biomechanical techniques such as gait analysis. This study used magnetic resonance imaging to examine the locations of the femoral insertions of the psoas, vastus medialis and gastrocnemius muscles in five adults and 17 children (including 7 children with cerebral palsy). The relationship of muscle attachment locations with age and bone geometry was then determined. Scaling techniques and external measurements of parameters such as femoral anteversion/antetorsion were shown to have potential for prediction of the locations of femoral muscle attachment points. It was shown that femoral anteversion can be modelled geometrically as occurring proximal to the lesser trochanter.

Adult↗
PubMed2003

Role of passive structures in the mobility and stability of the human subtalar joint: a literature review.

The subtalar joint plays a fundamental role in the transmission of loads between the leg and the foot. Although anatomical structures of this joint have been described extensively, much ambiguity about their location, shape, and function still persists. There is also disagreement regarding mobility, for example, whether the joint can be considered a hinge, screw-like, or a multiaxial joint. The most relevant studies from the literature are reported and the main experimental observations discussed. Recent studies have described the subtalar joint as a structure with no degrees of unresisted freedom, i.e., motion from the single neutral position is attained only by deformation of the ligaments and of the articular surfaces.

Biomechanical Phenomena↗
PubMed2003

Should patients with coronary disease and high homocysteine take folic acid?

All patients with known coronary artery disease should take prescription strength (1 mg/d) folic acid, vitamin B12 (400 microg/d), and vitamin B6 (10 mg/d), which have few if any known adverse effects. In this study, therapy to reduce homocysteine levels with prescription strength folic acid (1 mg) and vitamins B12 and B6 for 6 months following coronary angioplasty reduced the risk of need for revascularization of target lesions and of overall adverse cardiac events at least 6 months following cessation of therapy. Based on this study, it is unknown whether the benefit is related to baseline homocysteine levels or whether there is further benefit to continuing treatment beyond 6 months. Over-the-counter folic acid supplements (800 microg or less) were not studied and may not be as beneficial.

Comment↗
PubMed2002

Methods of detection of the transcription factor NF-kappa B in rat hippocampal slices.

The hippocampus is one of the most studied sites for understanding the cellular and molecular mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD), mechanisms believed to underlie the formation and storage of memories. The early-phases of LTP and LTD have been most intensively studied and have been shown to involve the activation of several kinases and phosphatases, respectively. The factors involved in the later stages have largely yet to be elucidated. We have focused our attention on the transcription factor NF-kappaB as a possible factor involved in such late-phase processes, and have developed both immunocytochemistry and electrophoretic mobility shift assay (EMSA) to measure the activated forms of this factor. This is important as many of the studies in this area are performed in vitro and to our knowledge quantitative assessment has not previously being deemed feasible in slice work. The pro-inflammatory cytokines TNF-alpha and IL-1beta both led to pronounced nuclear activation of NF-kappaB in the dentate granule cells as demonstrated by immunostaining and EMSA, respectively. Electrophysiological measurements taken from slices treated with TNF-alpha showed that it inhibited LTP (field excitatory post-synaptic potentials (fEPSP) 116+/-10%, n = 9, 60 min post-tetanus compared to control fEPSP 185+/-9%, n = 6; P < 0.001). The neurotransmitter L-glutamate also led to activation of NF-kappaB and electrophysiology recordings showed a small but sustained increase in synaptic transmission (fEPSP 106+/-12%, 30 min post-drug). These methods provide valuable tools to forward our understanding of the role of NF-kappaB in plasticity as well as in many neurological disorders being mimicked by in vitro studies.

Animals↗
PubMed2002

Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.

OBJECTIVE: We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. METHODS AND RESULTS: We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08). CONCLUSIONS: Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.

Alleles↗
PubMed2002

A model for lever-arm length calculation of the flexor and extensor muscles at the ankle.

A sagittal-plane mathematical model of joint mobility, including the mechanical effect of the extensor retinacula, was used to predict the lever arm lengths of the main flexor and extensor muscles of the human ankle over the range of movement. In plantarflexion, the centre of rotation lies posteriorly and distally, maximising the lever arm of the tibialis anterior. The action of the gastrocnemius and soleus is maximised in dorsiflexion. Traditional calculation of ankle joint moment based on a fixed centre of rotation is acceptable only in exercises such as level walking with a limited range of motion about the neutral position. The present model with a moving centre is particularly advised in exercises which take the joint nearer to the extremes of sagittal motion.

Ankle Joint↗