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Biomedical subjects

H J Murray

Publications and source records attributed to H J Murray.

8 recordsLinked to original sources
PubMed2003

A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro.

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of activity-dependent synaptic plasticity that are thought to be involved in learning and memory. Evidence has shown that cyclooxygenase-2 (COX-2), an enzyme that converts arachidonic acid to prostaglandins, is expressed in postsynaptic dendritic spines and is regulated by synaptic activity. COX-2 inhibition has been shown to directly attenuate LTP in the dentate gyrus of the hippocampus. Also recently the p38 MAP kinase cascade, a pathway utilised by cells for COX-2 expression, has been implicated in LTD induction in the CA1 region of the hippocampus. Here we demonstrate for the first time a direct role for COX-2 and p38 MAP kinase in LTD and confirm the inhibitory role of COX-2 in LTP in the rat dentate gyrus. Perfusion of the COX-2 inhibitor NS-398 (1 micro M) 60 min before tetanic stimulation resulted in an attenuation of LTD (84+/-5%, n=5 compared to controls of 57+/-7%, n=6, P<0.05). Prolonged exposure (2 h) to NS-398 (1 micro M) resulted in a significant reduction in LTP (71+/-8%, n=5, P<0.01 compared to controls of 170+/-11%, n=5 at 60 min post HFS). The p38 MAPK inhibitor, SB220025 (250 nM) significantly attenuated LTD (88+/-5%, n=7; P<0.01 compared to vehicle controls at 60 min, 56+/-5%, n=6) but had no significant effect on LTP. Both NS-398 and SB220025 had no significant effect on the isolated NMDA-mediated EPSP. These data demonstrate a role for COX-2 and p38 MAPK in LTD in the dentate gyrus in vitro that is independent of NMDA receptor activation.

Animals↗
PubMed2003

A role for c-Jun N-terminal kinase in the inhibition of long-term potentiation by interleukin-1beta and long-term depression in the rat dentate gyrus in vitro.

Recent evidence has emphasised the importance of mitogen-activated protein kinase activation in the modulation of hippocampal synaptic plasticity. Whilst extracellular-regulated kinase activation is now regarded as a critical step in the induction of long-term potentiation (LTP), activation of p38 and c-Jun N-terminal kinase (JNK) is associated with its inhibition. Here, the effects of the novel JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-1 (SP600125) were investigated on the inhibition of LTP by cytokines interleukin-1beta, interleukin-18 and tumour necrosis factor-alpha in the dentate gyrus. Perfusion of SP600125 alone prior to tetanic stimulation of the medial perforant path did not significantly affect baseline synaptic transmission, post-tetanic potentiation or the magnitude of induced LTP. When SP600125 was perfused onto slices prior to application of cytokines, this resulted in a complete reversal of the cytokine-mediated inhibition of LTP. Moreover, the magnitude of LTP attained in these slices was significantly greater than that obtained in vehicle control slices. Next, we investigated the effects of the JNK inhibitor on the impairment of pharmacologically isolated N-methyl-D-aspartate receptor-mediated potentials (NMDA-EPSPs) by interleukin-18. Whilst not affecting baseline amplitude when perfused alone, prior perfusion of SP600125 alleviated the depressive effect of interleukin-18 on NMDA-EPSPs. Finally, we examined the possibility of JNK involvement in the induction of long-term depression (LTD) in the dentate gyrus. Perfusion of SP600125 prior to low-frequency stimulation of the perforant path resulted in a significant attenuation of induced LTD, which suggests that JNK activation is a critical mediator of LTD in the dentate gyrus. These results directly implicate, for the first time, differential activation of JNK in the modulation of distinct forms of hippocampal synaptic plasticity. Whereas acute over-activation of JNK by pathophysiological concentrations of cytokines is detrimental to LTP, physiologic activation of JNK appears necessary for the induction of LTD.

Analysis of Variance↗
PubMed1996

The association between callus formation, high pressures and neuropathy in diabetic foot ulceration.

The presence of an ulcer beneath callus on the diabetic foot has been a well-documented and common clinical finding. We have conducted a prospective study to examine whether callus can be used to predict plantar intrinsic neuropathic diabetic foot ulcer formation. Sixty-three diabetic patients (43 male, 25 Type 1), median age 62 years (IQ range 52, 67), median diabetes duration 17 years (IQ range 8,25) participated in the study. All had neuropathy and peak plantar foot pressures (measured using a dynamic optical pedobarograph) > or = 10 kg cm-2. Calluses and previous ulcers were documented and classified. All ulcers occurring prior to and during the study were recorded, re-examination was 15.4 (range 10-22) months from baseline. Seven ulcers (6 patients) occurred during the study. Pressures were higher in the ulcer than non-ulcer sub-group (p = 0.04) with a relative risk of developing an ulcer of 4.7 for an area of elevated plantar pressure. This compares with a relative risk of 11.0 for an ulcer developing under an area of callus, and a relative risk of 56.8 for an ulcer developing on a site of previous ulceration. This study confirms that a history of previous ulceration is the highest risk factor for ulceration and demonstrates, for the first time, that the presence of plantar callus is highly predictive of subsequent ulceration. Careful history taking and examination of the foot to detect the presence of callus require no special training or equipment and callus should be recognized as a 'high risk' factor for foot ulceration.

Callosities↗
PubMed1995

The pathophysiology of diabetic foot ulceration.

Multiple mechanisms contribute to the etiopathogenesis of diabetic foot ulceration. Of these, neuropathy is probably the most important as a contributing factor, but it is the combination of neuropathy with other factors that leads to ulceration. Trauma in the neuropathic foot may be extrinsic, for example, in poorly fitting footwear, or intrinsic, for example, high foot pressures. These and other mechanisms are discussed in this article.

Autonomic Nervous System↗
PubMed1993

Painful neuropathy and foot ulceration in diabetic patients.

OBJECTIVE: To examine the prevalence of painful symptoms in neuropathic patients with or without foot ulceration. It has been suggested that there are two clinical presentations of sensory diabetic neuropathy with little overlap: painful (acute or chronic) and painless with recurrent foot ulceration. RESEARCH DESIGN AND METHODS: We examined three groups of diabetic patients matched for age and duration of diabetes--24 without neuropathy on clinical grounds (mean age 56.1 yr [range 38-76 yr], diabetes duration 12.6 yr [0.4-40 yr]), 30 with neuropathy (mean age 55.3 yr [range 21-73 yr], diabetes duration 17.3 yr [range 0.2-61 yr]), and 40 with neuropathic foot ulceration (mean age 58.1 yr [range 41-72 yr], diabetes duration 18.5 yr [range 1-46 yr])--and compared them with 20 healthy subjects (mean age 50 yr [range 37-69 yr]). For evaluation of neuropathy, the neuropathy symptom score, neuropathy disability score, and vibration perception threshold were measured. RESULTS: No difference existed between the neuropathic and foot ulcer groups in the neuropathy symptom score (4.2 +/- 3.9 [mean +/- SD] vs. 2.5 +/- 2.1, NS) and neuropathy disability score (15.1 +/- 5.7 vs. 16.8 +/- 6.1, NS), but the vibration perception threshold was lower in the neuropathic group (30.1 +/- 13.4 vs. 40.5 +/- 13.8 V, P < 0.001). Painful symptoms (neuropathy symptom score > 3), either in the past or during the time the study was conducted, had been experienced by none of the control subjects, 7 (29%) of the nonneuropathic group, 18 (60%) of the neuropathic group, and 17 (43%) of the foot ulcer group (NS for the last two groups), and were present at the time of examination in 13 (43%) of the neuropathic group and in 13 (33%) of the foot ulcer group (NS in all groups). Duration of symptoms was < 12 mo in 12 (40%) neuropathic and 15 (38%) foot ulcer patients (NS). CONCLUSIONS: We conclude that painful symptoms are frequent in diabetic neuropathy, irrespective of the presence or absence of foot ulceration and that these symptoms can occur at any stage of the disease. These results suggest that there is a spectrum of neuropathic syndromes from the painful to the patients with foot ulceration, and that much overlap exists.

Adult↗
PubMed1993

Role of experimental socks in the care of the high-risk diabetic foot. A multicenter patient evaluation study. American Group for the Study of Experimental Hosiery in the Diabetic Foot.

OBJECTIVE: To assess the acceptability of specially designed socks to provide satisfactory pressure relief in the insensitive, high-risk, diabetic foot. We have conducted a longitudinal multicenter patient evaluation study to assess the acceptability of such hosiery in neuropathic diabetic patients. RESEARCH DESIGN AND METHODS: A group of 86 neuropathic diabetic patients (69 males, 14 with type I diabetes) with a mean age of 63 yr (range 34-85 yr), and a diabetes duration of 16 yr (range 1-45 yr) participated in the study. Peripheral vascular disease was present in 28 (33%) patients, previous foot ulceration in 39 (44%) patients, and active ulceration was present in 11 (13%) patients. All patients were provided with three pairs of specially designed socks and 80 patients with extra-depth shoes. Evaluation and foot examination were performed at 3 and 6 mo. RESULTS: Socks were worn for a mean of 6 days/wk (range 1-7 days/wk). Patient satisfaction evaluated at both visits was good or very good in 85%, average in 12%, and poor in 3% of patients. Ten ulcers healed during this period, and seven new ulcers occurred. Intention to continue wearing the socks, most or all of the time, was expressed by 84% of patients. CONCLUSIONS: We conclude that the experimental socks have a high level of patient satisfaction when worn with suitable shoes, and may be an acceptable and inexpensive addition to existing methods of protecting the high-risk insensitive diabetic foot.

Adult↗
PubMed1992

The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study.

Foot ulceration results in substantial morbidity amongst diabetic patients. We have studied prospectively the relationship between high foot pressures and foot ulceration using an optical pedobarograph. A series of 86 diabetic patients, mean age 53.3 (range 17-77) years, mean duration of diabetes 17.1 (range 1-36) years, were followed-up for a mean period of 30 (range 15-34) months. Clinical neuropathy was present in 58 (67%) patients at baseline examination. Mean peak foot pressure was higher at the follow-up compared to baseline (13.5 kg.cm-2 +/- 7.1 SD vs 11.2 +/- 5.4, p less than 0.001) with abnormally high foot pressures (greater than 12.3) being present in 55 patients at follow-up and 43 at the baseline visit (p = NS). Plantar foot ulcers developed in 21 feet of 15 patients (17%), all of whom had abnormally high pressures at baseline; neuropathy was present in 14 patients at baseline. Non-plantar ulcers occurred in 8 (9%) patients. Thus, plantar ulceration occurred in 35% of diabetic patients with high foot pressures but in none of those with normal pressures. We have shown for the first time in a prospective study that high plantar foot pressures in diabetic patients are strongly predictive of subsequent plantar ulceration, especially in the presence of neuropathy.

Diabetes Mellitus, Type 1↗