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Biomedical subjects

S W Davies

Publications and source records attributed to S W Davies.

At least 19 recordsLinked to original sources
PubMed2005

The SV stent study: a prospective, multicentre, angiographic evaluation of the BiodivYsio phosphorylcholine coated small vessel stent in small coronary vessels.

OBJECTIVE: To evaluate the use of the phosphorylcholine (PC) coated BiodivYsio small vessel (SV) stent in native coronary vessels of small calibre. DESIGN AND SETTING: Prospective, multi-centre, multi-national registry with 6-month clinical and core-lab angiographic follow-up. Adverse events were adjudicated by a Clinical Events Committee (CEC) and included peri-procedural analysis of cardiac enzymes. PATIENTS: Patients with signs or symptoms of ischaemia with an identified target lesion in an epicardial vessel with reference diameter 2.0-2.75 mm were enrolled. Intervention in other epicardial territories in the same patient was permitted. RESULTS: Recruitment of 150 consecutive lesions (in 143 patients) was completed in 19 centres in Europe and Israel. The stent was deployed successfully in all but one lesion. At 6 months, 1 patient (1%) had experienced sudden cardiac death, 4 further patients (3%) had a non-Q wave MI, and a further 24 patients (17%) had repeat revascularisation of a study target vessel. The mean reference vessel diameter prior to stenting was 2.2 mm (S.D. 0.4). Mean minimal luminal diameters at pre-procedure, post procedure and follow-up were 0.6 mm (S.D. 0.3), 2.0 mm (S.D. 0.4) and 1.2 mm (S.D. 0.6), respectively. The late lumen loss index was 0.55 (S.D. 0.53) with a binary restenosis rate of 32%. CONCLUSIONS: In stenting of selected lesions in small vessels, the BiodivYsio SV stent demonstrated high rates of implant success. The rates of major adverse cardiac events (MACE), angiographic restenosis and repeat revascularisation are similar to those reported in other small vessel bare metal stent studies.

Adult↗
PubMed2002

Systemic platelet effects of contrast media: implications for cardiologic research and clinical practice.

BACKGROUND: Angiographic contrast media cause platelet activation and decrease aggregability in vitro. We have previously shown in vitro a significant antiplatelet effect of contrast media at the concentrations obtained locally in the coronary artery during angioplasty. It is not known, however, whether a systemic effect is present. METHOD: Thirty patients undergoing diagnostic coronary angiography were prospectively randomized to receive the nonionic medium iohexol, ionic low-molecular-weight medium ioxaglate, or ionic high-molecular-weight medium diatrizoate. Platelet aggregability was measured before and after the investigation with whole blood electrical impedance aggregometry (WBEA) with collagen agonist and the PFA-100 (Dade, Miami, Fla) platelet function analyzer with combined shear, collagen, and adenosine diphosphate as agonists. RESULTS: With WBEA, with iohexol no difference in impedance change was seen: (medians and ranges) before, 9.8 Omega (4.8-19.2 Omega) versus after, 9.6 Omega (2-19.2 Omega) (P not significant [NS]). With ioxaglate a significant fall was seen: before, 8.6 Omega (6.4-15.2 Omega) versus after, 6.6 Omega (0-12.4 Omega) (P =.004). With diatrizoate a significant and greater fall was seen: before, 10.8 Omega (6.4-17.6 Omega) versus after, 6.6 Omega (0-10.8 Omega) (P =.002). With PFA, no difference in closure time was seen with any medium: iohexol before, 99 seconds (79-142 seconds) versus after, 142 seconds (63-128 seconds) (P NS); ioxaglate before, 120 seconds (75-258 seconds) versus after, 95 seconds (74-258 seconds) (P NS); and diatrizoate before, 114.5 seconds (65-250 seconds) versus after, 100.5 seconds (72-300 seconds) (P NS). CONCLUSIONS: Ionic but not nonionic contrast media have a systemic antiplatelet effect at diagnostic angiographic doses when measured with WBEA. Such an effect has not been shown before. This may explain the observed improved clinical outcome with ionic contrast media but also might confound platelet studies in coronary angioplasty.

Adult↗
PubMed2001

Evaluation of free-breathing three-dimensional magnetic resonance coronary angiography with hybrid ordered phase encoding (HOPE) for the detection of proximal coronary artery stenosis.

We evaluated free-breathing, prospective navigator-gated, three-dimensional (3D) magnetic resonance coronary angiography (MRCA) with hybrid ordered phase-encoding (HOPE), in the detection of proximal coronary artery stenosis. The coronary arteries were imaged in 46 patients undergoing cardiac catheterization. The mean scan time was 48 minutes. The mean arterial length (mm) visualized was left main stem (LMS) 11.7 (SD 4.5), left anterior descending (LAD) 30.1 (SD 11.1), circumflex (LCx) 15.5 (SD 8.6), and right (RCA) 56.2 (SD 20.8). Twenty-three patients had coronary artery disease with 47 significant stenoses on cardiac catheterization. All LMS were normal on both catheterization and MRCA. MRCA sensitivity was highest for the LAD (89% CI 65%-99%) and RCA (76% CI 50%-93%), but lower for the LCx (50% CI 21%-79%). Specificity ranged from 72%-100%. Improvements in image quality, length of vessel seen, and specific imaging of the LCx are required for MRCA to become an alternative to cardiac catheterization.

Adult↗
PubMed2001

Coronary artery disease as the cause of incident heart failure in the population.

AIMS: New approaches in the treatment of ischaemic left ventricular dysfunction, including revascularization, make it increasingly important to identify heart failure cases resulting from coronary artery disease. Without angiography these cases may be missed. We investigated the frequency of coronary artery disease in incident cases of heart failure in the population. METHODS AND RESULTS: We identified all incident cases of heart failure in a population of 292 000 in South London, U.K. by monitoring patients admitted to hospital and through a rapid access heart failure clinic. The presence and severity of coronary artery disease was identified by coronary angiography in patients under 75 years. Myocardial perfusion scanning was used to elucidate the aetiological significance of the coronary artery disease and identify hibernating myocardium. Three hundred and thirty-two cases of new heart failure were identified over 15 months. One hundred and thirty-six cases were under 75 years and angiography was undertaken in 99/136 (73%). Coronary artery disease was the aetiology in 71/136 (52%). In 18 of these 71 cases (25%), the aetiology was not recognised to be due to coronary artery disease prior to angiography, including eight cases with hibernating myocardium. CONCLUSION: Coronary artery disease is the cause of 52% (95% CI 43-61%) of incident heart failure in the general population under 75 years. Clinical assessment without angiography under-estimates the proportion of patients with coronary artery disease, and fails to identify those patients who may benefit from revascularization.

Adult↗
PubMed2001

Clinical presentation and diagnosis of coronary artery disease: stable angina.

Angina pectoris is a clinical syndrome of discomfort in the chest, jaw, arm, or other sites which is associated with myocardial ischaemia. The nature of angina has many individual variations, and it is easier first to consider the typical syndrome. It is hard to better the descriptions of William Heberden: There is a disorder of the breast, marked with strong and peculiar symptoms, considerable for the danger belonging to it.... Those who are afflicted with it are seized, while they are walking, and more particularly when they walk soon after eating, with a painful and most disagreeable sensation in the breast.... the moment they stand still all this uneasiness vanishes. After it has continued some months, it will not cease so instantaneous upon standing still ... (most) whom I have seen, who are at least twenty, were men, and almost all above 50 years old, and most of them with a short neck, and inclining to be fat.... But the natural tendency of this illness be to kill the patients suddenly.... The os sterni is usually pointed to as the seat of this malady ... and sometimes there is with it a pain about the middle of the left arm. The usual cause of myocardial ischaemia is coronary atherosclerosis. Other diseases of the coronary arteries (emboli, spasm, vasculitis, Kawasaki disease, congenital anomalies), other cardiac diseases (hypertrophic cardiomyopathy, severe hypertension, severe aortic valve disease), and high output states (severe anaemia, thyrotoxicosis) are all uncommon or rare causes of angina. However, while angina is usually associated with atherosclerotic coronary artery disease, the converse is not always true. The condition of coronary atherosclerosis is very common (fatty streaks and more advanced plaques are almost universal in adults in industrialised countries) but it does not always cause myocardial ischaemia. Furthermore, myocardial ischaemia may present other than with angina - for each presentation there is a wide differential diagnosis.

Aged↗
PubMed2001

Invasive investigations and revascularisation.

Invasive investigation of coronary artery disease is relatively expensive, and carries risks including a mortality of approximately 1 in 2000. It would not be practical or appropriate to perform invasive investigation in all patients with a clinical diagnosis of coronary artery disease, still less in the large numbers with chest pain and possible angina. Clinicians will refer for invasive investigation those: (i) with a high level of angina, needing revascularisation on symptomatic grounds; and (ii) who are likely to have a poor prognosis with medical treatment, and thus likely to benefit from revascularisation. Not all of these patients will have a high level of symptoms.

Angioplasty, Balloon, Coronary↗
PubMed2000

Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by personality changes, motor impairment, and subcortical dementia. HD is one of a number of diseases caused by expression of an expanded polyglutamine repeat. We have developed several lines of mice that are transgenic for exon 1 of the HD gene containing an expanded CAG sequence. These mice exhibit a defined neurological phenotype along with neuronal changes that are pathognomonic for the disease. We have previously observed the appearance of neuronal intranuclear inclusions, but did not find evidence for neurodegeneration. In this study, we report that all lines of these mice develop a late onset neurodegeneration within the anterior cingulate cortex, dorsal striatum, and of the Purkinje neurons of the cerebellum. Dying neurons characteristically exhibit neuronal intranuclear inclusions, condensation of both the cytoplasm and nucleus, and ruffling of the plasma membrane while maintaining ultrastructural preservation of cellular organelles. These cells do not develop blebbing of the nucleus or cytoplasm, apoptotic bodies, or fragmentation of DNA. Neuronal death occurs over a period of weeks not hours. We also find degenerating cells of similar appearance within these same regions in brains of patients who had died with HD. We therefore suggest that the mechanism of neuronal cell death in both HD and a transgenic mouse model of HD is neither by apoptosis nor by necrosis.

Age of Onset↗
PubMed2000

Neuronal intranuclear inclusion disease and juvenile parkinsonism.

Juvenile parkinsonism (onset age <20 yrs) is uncommon and few cases with neuropathologic confirmation have been reported. We present the case of a 17-year-old boy who presented with asymmetric arm tremor and bulbar symptoms. His paternal great aunt had parkinsonism with onset at age 22 years. Examination revealed parkinsonism in the absence of additional neurologic signs except for delayed pupillary responses to light. He responded well to levodopa but developed motor fluctuations and disabling dyskinesias after 3 years of treatment. Following attempted withdrawal of levodopa at age 24 years, he developed severe aspiration pneumonia complicated by cardiorepiratory arrests and he died 6 months later. At autopsy, the dominant histologic feature was wide-spread neuronal hyaline intranuclear inclusions. Neuronal depletion was observed in the substantia nigra, locus ceruleus, and, to a lesser extent, in the frontal cortex, and inclusions were particularly prominent in these areas. Inclusions were immunoreactive for ubiquitin and were typical of those seen in neuronal intranuclear inclusion disease (NIID), a rare, multisytem neurodegenerative disease. NIID should be considered in the differential diagnosis of juvenile parkinsonism. A link between NIID and hereditary neurodegenerative disorders characterized by expanded polyglutamine tracts is supported by the similar appearance of intranuclear inclusions in both conditions and by a family history in some cases of NIID.

Adolescent↗
PubMed2000

Diurnal variation in platelet aggregation iwth the PFA-100 platelet function analyser.

BACKGROUND: Myocardial infarction is commoner in the morning, and previous small studies suggesting diurnal variation in platelet aggregation have been limited to optical aggregometry with platelet-rich plasma and low shear. This phenomenon was studied using whole blood at high shear rates. METHOD: Fifteen healthy volunteers were venesected at 0800 hrs supine in bed immediately before rising, at 0830 hrs 30 min after rising, at 1200 hrs and 1700 hrs. Samples underwent the high shear method of PFA-100 using additional chemical agonists of collagen with ADP or collagen with epinephrine. PFA-100 results are reported as closure time of the experimental aperture in seconds, a longer time indicating less platelet aggregation. RESULTS: With both epinephrine and ADP, a non-significant shortening of closure time was seen on rising. Subsequently, with both agonists the closure time lengthened through the day. With ADP the difference was small (medians 0830 hrs: 85 s, 1700 hrs: 87.5 s) but statistically significant (p = 0.03). With epinephrine it was much more marked (medians 0830 hrs: 114.3 s, 1700 hrs: 140.5 s) and highly significant (p = 0.002). CONCLUSIONS: These findings demonstrate a diurnal rhythm in platelet function using whole blood at high shear rates. This is likely to be more applicable to the in vivo situation than previously reported optical aggregometry studies.

Adult↗
PubMed1999

Transgenic models of Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. A mouse model of this disease has been generated by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line (R6 lines). Transgenic mice develop a progressive neurological phenotype with a movement disorder and weight loss similar to that in HD. We have previously identified neuronal inclusions in the brains of these mice that have subsequently been established as the pathological hallmark of polyglutamine disease. Inclusions are present before symptoms, which in turn occur long before any selective neuronal cell death can be identified. We have extended the search for inclusions to skeletal muscle, which, like brain, contains terminally differentiated cells. We have conducted an investigation into the skeletal muscle atrophy that occurs in the R6 lines, (i) to provide possible insights into the muscle bulk loss observed in HD patients, and (ii) to conduct a parallel analysis into the consequence of inclusion formation to that being performed in brain. The identification of inclusions in skeletal muscle might be additionally useful in monitoring the ability of drugs to prevent inclusion formation in vivo.

Animals↗
PubMed1999

From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is an inherited progressive neurodegenerative disease caused by the expansion of a polyglutamine repeat sequence within a novel protein. Recent work has shown that abnormal intranuclear inclusions of aggregated mutant protein within neurons is a characteristic feature shared by HD and several other diseases involving glutamine repeat expansion. This suggests that in each of the these disorders the affected nerve cells degenerate as a result of these abnormal inclusions. A transgenic mouse model of HD has been generated by introducing exon 1 of the HD gene containing a highly expanded CAG sequence into the mouse germline. These mice develop widespread neuronal intranuclear inclusions and neurodegeneration specifically within those areas of the brain known to degenerate in HD. We have investigated the sequence of pathological changes that occur after the formation of nuclear inclusions and that precede neuronal cell death in these cells. Although the relation between inclusion formation and neurodegeneration has recently been questioned, a full characterization of the pathways linking protein aggregation and cell death will resolve some of these controversies and will additionally provide new targets for potential therapies.

Animals↗
PubMed1999

Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease.

Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the significance of these alterations has been uncertain, possibly reflecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N-methyl-D-aspartate and gamma-aminobutyric acid receptors, are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of specific genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to, the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological mechanism in HD.

Animals↗
PubMed1999

Brain neurotransmitter deficits in mice transgenic for the Huntington's disease mutation.

Huntington's disease (HD) is associated with an expansion in the CAG repeat sequence of a gene on chromosome 4, resulting in a neurodegenerative process particularly affecting the striatum and with profound but selective changes in content of various neurotransmitters. Recently, transgenic mice expressing a fragment of the human HD gene containing a large CAG expansion have been generated; these mice exhibit a progressive neurological phenotype that includes motor disturbances, as well as neuronal deficits. To investigate their underlying neurotransmitter pathology, we have determined concentrations of GABA, glutamate, and the monoamine neurotransmitters in several brain regions in these mice and control animals at times before and after the emergence of the behavioural phenotype. In contrast to the findings in HD, striatal GABA was unaffected, although a deficit was observed in the cerebellum, consistent with a dysfunction of Purkinje cells. Losses of the monoamine transmitters were observed, some of which are not seen in HD. Thus, 5-hydroxytryptamine and, to a greater extent, 5-hydroxyindoleacetic acid levels were diminished in all brain regions studied, and noradrenaline was particularly affected in the hippocampus. Dopamine was decreased in the striatum in older animals, parallelling evidence for diminished dopaminergic activity in HD.

Animals↗
PubMed1999

Evaluation of angiographic contrast media and platelet function with impedance aggregometry and the PFA-100 'platelet function analyser'.

BACKGROUND: Angiographic contrast media are used in balloon angioplasty and may influence thrombotic complications of the procedure. We studied the effect of different media on platelet aggregation in whole blood using impedance aggregometry and the PFA-100 'platelet function analyser' (Dade, USA). METHODS: Venous blood samples from 18 healthy volunteers were split into four aliquots and mixed with 10% normal saline control, non-ionic medium (iohexol), low-molecular weight ionic medium (ioxaglate) and high-molecular weight ionic medium (diatrizoate). Samples were studied with impedance aggregometry and the PFA-100. RESULTS: All media caused significant inhibition of aggregation compared with control with both methods (P<0.001). Antiplatelet potency was greatest with diatrizoate, intermediate with ioxaglate and least with iohexol with both methods (P<0.01). Electron microscopy of the PFA-100 membrane demonstrated occlusion of the experimental aperture with platelet thrombus in the control. Inhibition of platelet thrombus was seen with all media, greatest with diatrizoate, intermediate with ioxaglate and least with iohexol. CONCLUSIONS: The media studied significantly inhibited platelet aggregation in vitro and potency was greater with ionic than non-ionic media. These methods use a combination of shear and chemical agonist with whole blood and may reproduce in vivo arterial conditions better than other techniques.

Journal Article↗
PubMed1999

Formation of polyglutamine inclusions in non-CNS tissue.

Huntington's disease (HD) is one of a class of inherited progressive neurodegenerative disorders that are caused by a CAG/polyglutamine repeat expansion. We have previously generated mice that are transgenic for exon 1 of the HD gene carrying highly expanded CAG repeats which develop a progressive movement disorder and weight loss with similarities to HD. Neuronal inclusions composed of the exon 1 protein and ubiquitin are present in specific brain regions prior to onset of the phenotype, which in turn occurs long before specific neurodegeneration can be detected. In this report we have extended the search for polyglutamine inclusions to non-neuronal tissues. Outside the central nervous system (CNS), inclusions were identified in a variety of post-mitotic cells. This is consistent with a concentration-dependent nucleation and aggregation model of inclusion formation and indicates that brain-specific factors are not necessary for this process. To possibly gain insights into the wasting that is observed in the human disease, we have conducted a detailed analysis of the timing and progression of inclusion formation in skeletal muscle and an investigation into the cause of the severe muscle atrophy that occurs in the mouse model. The formation of inclusions in non-CNS tissues will be particularly useful with respect to in vivo monitoring of pharmaceutical agents selected for their ability to prevent polyglutamine aggregation in vitro, without the requirement that the agent can cross the blood-brain barrier in the first instance.

Animals↗