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Biomedical subjects

J P Wood

Publications and source records attributed to J P Wood.

At least 19 recordsLinked to original sources
PubMed2003

Performance of stentless versus stented aortic valve bioprostheses in the elderly patient: a prospective randomized trial.

OBJECTIVES: Although stentless aortic bioprostheses are believed to offer improved outcomes, benefits remain unsubstantiated. The aim of our study was to compare stentless with stented bioprostheses, with regard to postoperative changes in left ventricular mass and hemodynamic performance, in the elderly patient. METHODS: Forty patients with aortic stenoses, over the age of 75 years, were randomized to receive either the stented Perimount (n=20) or the stentless Prima Plus (n=20) bioprosthesis. Left ventricular mass regression, effective orifice area, ejection fraction and mean gradients were evaluated at discharge, 6 months and 1 year after surgery. RESULTS: Overall a significant decrease in left ventricular mass was found 1 year postoperatively. However, there was no significant difference in the rate of left ventricular mass regression between the groups. Furthermore, 1 year postoperatively, the hemodynamic performance of the valves and the change in the ejection fraction did not differ between the groups. CONCLUSIONS: Our study shows that in a randomized cohort of elderly patients with aortic stenosis, we were not able to detect significant differences, with regard to hemodynamic performance and regression of left ventricular mass, between the stentless and stented valve groups. To our surprise, previously reported findings of non-randomized trials that showed faster and more complete regression of left ventricular mass and hemodynamic benefits of stentless valves were not reproducible.

Aged↗
PubMed2002

A recently described polymorphism in the CD28 gene on chromosome 2q33 is not associated with susceptibility to type 1 diabetes.

Type 1 diabetes mellitus is an autoimmune disease with a strong genetic background. The CTLA4 gene region (IDDM12) has been implicated in genetic susceptibility to type 1 diabetes by genome scanning and both family- and population-based analyses. As the genes encoding the costimulatory molecules CTLA4 and CD28, which compete for the receptor B7, reside close together on chromosome 2q33 and have high sequence homology, we investigated a recently described polymorphism in intron 3 of the CD28 gene and the CLTA4 codon 17 polymorphism in 176 patients with type 1 diabetes and 220 healthy controls. Whereas CTLA4 was found to be associated with type 1 diabetes, the frequency of the CD28 polymorphism did not differ between patients and controls, either in the entire sample or after stratification for CTLA4 genotype. Thus, the CD28 intron 3 polymorphism does not appear to be associated with susceptibility to type 1 diabetes.

Abatacept↗
PubMed2001

Topically applied betaxolol attenuates ischaemia-induced effects to the rat retina and stimulates BDNF mRNA.

It has previously been reported that the beta(1)-adrenoceptor antagonist, betaxolol, can protect retinal neurones from ischaemia when applied topically. It has further been shown that betaxolol can reduce influx of both sodium or calcium into neurones through interaction at neurotoxin site 2 of the sodium channel and the L-type calcium channel, respectively. The present study sought to further investigate the neuroprotective mode of action of betaxolol in the rat retina. Rats were treated topically with L-betaxolol for 10, 5 and 1 min before ischaemia, induced by raising the intraocular pressure above systolic blood pressure for 45 min. This was followed by reperfusion of 3 or 5 days where L-betaxolol was applied topically twice daily. Ischaemia plus reperfusion caused both a loss of immunoreactivity for choline acetyl transferase (ChAT) and a marked reduction of the b-wave of the electroretinogram (ERG). Treatment, as described, with topical L-betaxolol, completely blunted the effects upon ChAT immunoreactivity and caused a significant reversal of the ERG changes. Furthermore, other rats treated topically with commercially available racemic betaxolol (Betoptic Solution, 0.5%) for 6 hr had raised levels of mRNA for brain derived neurotrophic factor (BDNF) but not for basic fibroblast growth factor (bFGF) in their retinas. The combined data provide further evidence that betaxolol can blunt the effects of ischaemia to the rat retina when applied topically just before the insult. Furthermore, the finding that retinal levels of BDNF mRNA are raised following topical betaxolol treatment shows that not only can this drug reach the retina but that it can also induce changes in expression of factors which are known, themselves, to provide neuroprotection to retinal neurones.

Adrenergic beta-Antagonists↗
PubMed2001

Vasovagal syncope and anaesthetic practice.

We surveyed anaesthetists working in North-West England and in North Wales concerning episodes of vasovagal syncope encountered in their practice. Eighty-eight anaesthetists described 109 such events occurring in either patients or their relatives and the estimated frequency of syncope was 1 in 5000 anaesthetic episodes. The patient syncopal episodes were triggered by venous cannulation in 16 instances and regional or local techniques in 20 instances. Thirty-three of the 53 patients were in the upright position when syncope occurred. Thirty-nine of the 56 relatives were male partners of female patients and four of these partners suffered some morbidity. The results of the survey are consistent with our current knowledge of the pathophysiology of vasovagal syncope, which is summarized, and also highlight the common anaesthetic scenarios where fainting is most likely to occur. Given this information anaesthetists will be in a better position to avoid such potentially harmful episodes in the future.

Adult↗
PubMed2001

The influence of zinc on caspase-3 and DNA breakdown in cultured human retinal pigment epithelial cells.

OBJECTIVES: To investigate the role of extracellular zinc on the death process of cultured human retinal pigment epithelial (RPE) cells. METHODS: Confluent cells on borosilicate glass coverslips were treated with substances in serum-free growth medium for various times and were analyzed for death by means of changes in morphologic features, numbers of attached cells, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) procedure. Some cultures were also exposed to experimental ischemia (defined as a lack of oxygen, glucose, and serum). Electrophoresis and Western blotting and enzyme assays were used to investigate changes in expression of the protease enzyme, caspase-3. RESULTS: Experimental ischemia caused death of RPE cells. Zinc sulfate had no effect on these cells at low concentrations (100 pmol/L to 10 nmol/L), but protected them at higher concentrations (< or = 10 micromol/L) and appeared to exacerbate cell death at still greater concentrations. Moreover, zinc compounds (>10 micromol/L) also induced death of cells in control cultures that could be blocked by zinc chelators and partially by the caspase-3 inhibitor, DEVD-FMK. Zinc also increased the amount of the active form of caspase-3 in RPE cells. CONCLUSIONS: Zinc salts protect RPE cells from experimental ischemia-induced death at low concentrations (100 pmol/L-10 nmol/L). However, at higher concentrations, zinc causes cell death and alters the cellular level of caspase-3. These observations are consistent with the death process being apoptosis. CLINICAL RELEVANCE: Zinc supplements are taken by many individuals. Low doses of zinc can protect RPE cells against ischemic-type insults as may occur in certain ocular complaints. Furthermore, high concentrations of zinc can damage RPE cells. Because zinc ions are known to be taken up by RPE cells from the choroidal circulation, the actual therapeutic dose taken by patients is critical.

Adult↗
PubMed2000

An investigation into the potential mechanisms underlying the neuroprotective effect of clonidine in the retina.

alpha(2)-adrenoceptor agonists, such as clonidine, attenuate hypoxia-induced damage to brain and retinal neurones by a mechanism of action which likely involves stimulation of alpha(2)-adrenoceptors. In addition, the neuroprotective effect of alpha(2)-adrenoceptor agonists in the retina may involve stimulation of bFGF production. The purpose of this study was to examine more thoroughly the neuroprotective properties of clonidine. In particular, studies were designed to ascertain whether clonidine acts as a free radical scavenger. It is thought that betaxolol, a beta(1)-adrenoceptor antagonist, acts as a neuroprotective agent by interacting with sodium and L-type calcium channels to reduce the influx of these ions into stressed neurones. Studies were therefore undertaken to determine whether clonidine has similar properties. In addition, studies were undertaken to determine whether i.p. injections of clonidine or betaxolol affect retinal bFGF mRNA levels. In vitro data were generally in agreement that clonidine and bFGF counteracted the effect of NMDA as would occur in hypoxia. No evidence could be found that clonidine interacts with sodium or L-type calcium channels, reduces calcium influx into neurones or acts as a free radical scavenger at concentrations below 100 microM. Moreover, i.p. injection of clonidine, but not betaxolol, elevated bFGF mRNA levels in the retina. The conclusion from this study is that the neuroprotective properties of alpha(2)-adrenoceptor agonists, like clonidine, are very different from betaxolol. The fact that both betaxolol and clonidine blunt hypoxia-induced death to retinal ganglion cells suggests that combining the two drugs may be a way forward to producing more effective neuroprotection.

Adrenergic alpha-Agonists↗
PubMed2000

Flupirtine ameliorates ischaemic-like death of rat retinal ganglion cells by preventing calcium influx.

The effect of flupirtine on the loss of retinal ganglion cells following transient elevation of intraocular pressure (experimental ischaemia) or NMDA-induced excitotoxicity was studied. Ischaemia (60 min) or intravitreal injection of NMDA (20 nmol) caused a decrease in Thy-1 mRNA and Thy-1 immunoreactivity which are associated with ganglion cells. Administration of flupirtine counteracted these changes. Moreover, flupirtine dose-dependently inhibited NMDA-induced 45Ca(2+) influx into cultured cortical neurones and retinal pieces in vitro with maximal inhibition being observed at 200 microM. A similar concentration of flupirtine failed to inhibit kainate-stimulated calcium influx into cultured cortical neurones. In addition, flupirtine had no significant effect on [3H]nitrendipine or [3H]diltiazem binding to cortical membranes. The present studies are consistent with previous findings which suggested flupirtine to act as a NMDA antagonist by a mechanism that still remains to be clarified.

Aminopyridines↗
PubMed2000

5-Hydroxytryptamine1A agonists: potential use in glaucoma. Evidence from animal studies.

Various classes of compounds exist to lower intraocular pressure (IOP) in the treatment of glaucoma. None of them is ideal since some patients respond better than others and the side effects vary between individuals. New classes of compounds need to be introduced to allow the clinician greater scope for effective treatment of all patients. It is now generally agreed that the cause of ganglion cell dysfunction in glaucoma is likely to be multifactorial and that concentrating solely on reducing IOP is inadequate. Irrespective of the reason for the dysfunction, the future goal must be to attenuate cell death. This may be achieved with drugs that interact with components of the retina, and is termed 'neuroprotection'. Thus, drugs that can both reduce IOP and act as neuroprotectants would be ideal for the treatment of glaucoma. In this article we summarise studies on animals which show serotonergic 5-HT1A agonists to both reduce IOP when topically applied to the rabbit eye and blunt the damaging effect to the rat retina and ganglion cells induced by glutamate toxicity or ischaemia. Reduction of IOP occurs via stimulation of 5-HT1A receptors associated with the ciliary processes. Neuroprotection of retinal neurones appears to involve the interaction of 5-HT1A agonists with membrane sodium channels and/or 5-HT1A or even possibly 5-HT7 receptors. Various 5-HT1A agonists are used in patients to treat depression, so classes of these drugs have a proven safety profile for use in patients. The animal studies summarised in this article suggest that 5-HT1A agonists need to be considered as a new class of drugs for the treatment of glaucoma.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Lower-extremity Doppler for deep venous thrombosis--can emergency physicians be accurate and fast?

UNLABELLED: Clinical diagnosis of lower-extremity (LE) deep venous thrombosis (DVT) requires confirmation by an imaging study before committing the patient to anticoagulation therapy. Studies have shown that demonstrating compressibility of leg veins under ultrasound is accurate for ruling out DVTs when performed by vascular specialists. Although LE Doppler has become the preferred test for diagnosing DVTs, it is not always available 24 hours per day. OBJECTIVES: To evaluate the accuracy and speed with which emergency physicians (EPs) could perform LE color duplex ultrasonography for the detection of DVT. METHODS: Patients presenting to an urban community emergency department (ED) between August 1, 1998, and March 3, 1999, were enrolled into this prospective study. The EPs, who underwent brief and standardized training, scanned patients at high risk for DVT with leg pain, swelling, or both. Physicians performed color duplex ultrasound examinations with compression at the common femoral and popliteal veins. The time until completion of the ED scan was recorded with a standardized method. The vascular laboratory performed a complete duplex ultrasound examination within eight hours. RESULTS: One hundred twelve patients were enrolled in the study, with 34 positive for DVT. The median examination time was 3 minutes 28 seconds (95% CI = 2 min 45 sec to 4 min 2 sec; IQR 3 min 9 sec). Times ranged from 1:02 to 18:20 minutes. The ED results had a high correlation with vascular laboratory studies, giving a kappa of 0.9 and a 98% agreement (95% CI = 95.4% to 100%). CONCLUSION: Emergency physicians can perform LE duplex ultrasound examinations accurately and quickly.

Clinical Competence↗
PubMed1999

Betaxolol, a beta1-adrenoceptor antagonist, has an affinity for L-type Ca2+ channels.

The effect of betaxolol on the specific binding of [3H]diltiazem and [3H]nitrendipine to rat cortical membranes was examined. Betaxolol inhibited specific [3H]diltiazem and [3H]nitrendipine binding with IC50 values of 19.7 and 46.3 microM, respectively. The effect of betaxolol on L-type Ca2+ channels showed little stereospecificity, since similar inhibitions of radioligand binding were observed with both racemic betaxolol and L-betaxolol. The dissociation kinetics of [3H]diltiazem were unaffected by 30 microM betaxolol, whereas it increased the [3H]nitrendipine dissociation rate, thus suggesting that betaxolol directly interacts with the benzothiazepine binding site and allosterically modulates the dihydropyridine binding site. Carteolol, propranolol and timolol were also found to inhibit both specific [3H]diltiazem and [3H]nitrendipine binding to rat cortical membranes, but with less potency than betaxolol. The ability of betaxolol to interact with L-type Ca2+ channels may have a role in its therapeutic effects in the management of systemic hypertension and in reducing neuronal death as occurring in glaucoma.

Adrenergic beta-Antagonists↗
PubMed1999

Topically applied betaxolol attenuates NMDA-induced toxicity to ganglion cells and the effects of ischaemia to the retina.

The present results show that topically applied Betoptic(R)(0.5% betaxolol) to the rabbit or rat eye reaches the retina and can counteract the detrimental effects caused by ischaemia/reperfusion or N -methyl- d -aspartate (NMDA)-induced insults to the retina. Betaxolol is a beta(1)-adrenergic blocker but its neuroprotective action is generally thought to be due to its calcium channel blocking properties. Support for this view comes from studies on cultures of cortical neurones where it was found that betaxolol attenuated the NMDA-induced influx of(45)Ca(2+)while beta-adrenoreceptor agonists were ineffective. Topically applied Betoptic(R)to the rabbit eye was observed to reach the retina in maximal amounts within 60 min. Some of the substance was also found in the contralateral retina of the untreated eye suggesting that the agent reaches the retina by local systemic and retinal circulation. Concurrent treatment with Latanoprost(R)did not result in a greater amount of betaxolol reaching the retina. An ophthalmodynamometric procedure, which raises the intraocular pressure, was used to apply an ischaemic insult to the rabbit retina. After three days of reperfusion the b-wave of the electroretinogram was reduced by an average of 59% and the choline acetyltransferase immunoreactivity in the retina was almost obliterated. However, when experiments were carried out on animals which had been treated with one drop of Betoptic(R) twice daily for 4 weeks before ischaemia and also during the reperfusion phase, the reductions in both the b-wave of the electroretinogram and retinal choline acetyltransferase immunoreactivity due to ischaemia/reperfusion were greatly attenuated. Intravitreal injection of NMDA into the rat eye caused a decrease in the immunostaining for Thy-1 antigen which is associated with ganglion cells. The Thy-1 mRNA level was also reduced as was the mRNA for the common subunit of the NMDA receptor, the NR1 subunit. However, in animals subjected to a topical Betoptic(R)regime, before and after intravitreal injection of NMDA, the decreases in the mRNA levels of Thy-1 and NR1 were significantly attenuated.

Administration, Topical↗
PubMed1999

Neuroprotection in relation to retinal ischemia and relevance to glaucoma.

Management of glaucoma is directed at the control of intraocular pressure (IOP), yet it is recognized now that increased IOP isjust an important risk factor in glaucoma. Therapy that prevents the death of ganglion cells is the main goal of treatment, but an understanding of the causes of ganglion cell death and precisely how it occurs remains speculative. Present information supports the working hypothesis that ganglion cell death may result from a particular form of ischemia. Support for this view comes from the fact that not all types of retinal ischemia lead to the pathologic findings seen in glaucomatous retinas or to cupping in the optic disk area. Moreover, in animal experiments in which ischemia is caused by elevated IOP, a retinal abnormality similar to that seen in true glaucoma is produced, whereas after occlusion of the carotid arteries a different pattern of damage is found. In ischemia, glutamate is released, and this initiates the death of neurons that contain ionotropic glutamate (NMDA) receptors. Elevated glutamate levels exist in the vitreous humor of patients with glaucoma, and NMDA receptors exist on ganglion cells and a subset of amacrine cells. Experimental studies have shown that a variety of agents can be used to prevent the death of retinal neurons (particularly ganglion cells) induced by ischemia. These agents are generally those that block NMDA receptors to prevent the action of the released glutamate or substances that interfere with the subsequent cycle of events that lead to cell death. The major causes of cell death after activation of NMDA receptors are the influx of calcium into cells and the generation of free radicals. Substances that prevent this cascade of events are, therefore, often found to act as neuroprotective agents. For a substance to have a role as a neuroprotective agent in glaucoma, it would ideally be delivered topically to the eye and used repeatedly. It is, therefore, of interest that betaxolol, a beta-blocker presently used to reduce IOP in humans, also has calcium channel-blocking functions. Moreover, experimental studies show that betaxolol is an efficient neuro protective agent against retinal ischemia in animals, when injected directly into the eye or intraperitoneally.

Adrenergic beta-Antagonists↗