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Biomedical subjects

S Holloway

Publications and source records attributed to S Holloway.

At least 37 records · Page 2Linked to original sources
PubMed1998

Localization of the somatostatin sst2(a) receptor in human cerebral cortex, hippocampus and cerebellum.

The distribution and cellular localization of the somatostatin sst2(a) receptor was investigated in selected human brain areas using an anti-peptide antibody raised against a carboxy-terminal portion of the receptor protein. The sst2(a) receptor was found to be present on neurones and processes in the deep layers of the cerebral cortex, in the subicular complex and the hippocampal formation. Further signals were obtained in the molecular and granular layer of the cerebellum, with occasional weakly stained Purkinje cells. The regional distribution of the receptor protein was compared with quantitative autoradiography using a sst2 receptor selective ligand [125I]BIM23027.

Autoradiography↗
PubMed1998

Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study.

BACKGROUND: Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families. METHODS: We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all "normal" offspring were examined by a paediatric cardiologist. FINDINGS: The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring--a recurrence risk of 4.1%. This result differed significantly from sibling risk (2.1%; p=0.021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0.047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0.032). We found an excess of miscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occurred in seven (3.1%) of 223 offspring, 12 (2.2%) of 539 siblings, five (0.3%) of 1575 second-degree relatives, and eight (0.3%) of 2728 third-degree relatives. INTERPRETATION: Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.

Adult↗
PubMed1998

Acute and late clinical outcome after rotational atherectomy for complex coronary disease.

Rotational atherectomy is effective acutely in treating complex coronary disease, but less is known about its long-term clinical outcome. We examined the acute results and late clinical outcome in 178 patients undergoing treatment with this device. Rotational atherectomy was used to treat 240 lesions in 178 individual patients. Nineteen percent had multilesion or staged multivessel procedures, and 71% had AHA-ACC Type B2/C lesions. The procedure was completed successfully in 94% of patients. Major complications occurred in 6% (death 1%, Q-MI 2.8%, and emergency bypass surgery 2.2%). Clinical follow-up was available for 167 (94%) patients at 13+/-6 months. Thirty-five percent required additional catheterization because of recurrent symptoms or an abnormal stress test. Clinical restenosis was confirmed in 18%, and an additional 2.2% of patients had progression of disease in previously untreated segments. At the end of 1 year, 14% had undergone repeat target vessel revascularization. Cumulatively at follow-up, approximately 80% had avoided an acute major complication and repeat revascularization for restenosis. Rotational atherectomy provides excellent acute and good late clinical results. At 1 year follow-up, the likelihood of developing clinical restenosis or significant progression of disease was 1 in 5, and patients had a 1 in 7 chance of requiring revascularization because of restenosis. These findings are encouraging and indicate that rotational atherectomy can be performed safely and with a high degree of acute and late clinical success in complex coronary disease characterized by multivessel or multilesion involvement and a predominance of B2 and C lesions.

Aged↗
PubMed1998

The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies.

The incidence of cystic fibrosis (CF) has previously been calculated from epidemiological surveys and from neonatal screening. With the cloning of the CF gene it has become possible to derive incidence figures from heterozygote frequencies, provided that the distribution of mutant alleles among healthy carriers is the same as among affected people. We have estimated the allele frequencies for four CF mutations, AF508, G551D, G542X and R117H, in 14360 unselected women undergoing antenatal heterozygote screening. The proportion of R117H, an allele of known mild effect, was much greater for heterozygotes than for homozygotes. The incidence of CF was therefore calculated from the heterozygote frequencies of AF508, G551D and G542X in a larger cohort of 27 161 successively screened women. The point estimate for the incidence of CF in the Scottish population was 1 in 1984, with 95% confidence intervals of 1 in 1692 to 1 in 2336.

Alleles↗
PubMed1998

A chromosomal deletion map of human malformations.

Malformations are common causes of pediatric morbidity and mortality, and genetic factors are a significant component of their etiology. Autosomal deletions, in almost all cases, cause a nonspecific embryopathy that presents after birth as growth failure, mental retardation, and multiple malformations. We have constructed a chromosome map of autosomal deletions associated with 47 different congenital malformations, using detailed clinical and cytogenetic information on 1,753 patients with nonmosaic single contiguous autosomal deletions. The 1,753 deletions involved 258 (89%) of 289 possible autosomal bands (by the use of ISCN 400-band nomenclature), giving a total of 4,190 deleted autosomal bands for analysis. We compared the band distributions of deletions associated with common major malformations with the distribution of all 1,753 deletions. We noted 283 positive associations between deleted bands and specific malformations, of which 199 were significant (P<.05, P>.001) and 84 were highly significant (P<.001). These "malformation-associated bands" (MABs) were distributed among 137 malformation-associated chromosome regions (MACRs). An average of 6 MABs in 2.9 MACRs were detected per malformation studied; 18 (6%) of 283 MABs contain a locus known to be associated with the particular malformation. A further 18 (6%) of 283 are in seven recognized specific malformation-associated aneuploid regions. Therefore, 36 (26%) of 137 of the MACRs contain an MAB coinciding with a previously recognized locus or malformation-associated aneuploid region. This map should facilitate identification of genes important in human development.

Chromosome Aberrations↗
PubMed1997

The uptake of particulates by an urban woodland: site description and particulate composition.

Woodlands may improve local air quality by increasing the uptake rates of gaseous, particulate and aerosol pollutants from the atmosphere and can also act as relatively permanent sinks for some pollutants. Rough Wood, Walsall was selected for a study of the material which accumulates on tree foliage because of its location in a densely populated urban area, and its proximity to a motorway with high traffic flow (the M6) and to other pollutant sources. Methods were developed for leaf washing to allow determination of the quantity of dust and the identification of the dust particles present on oak leaves. Elemental analysis of particles was also undertaken using scanning electron microscopy coupled with electron probe microanalysis. A large proportion of particles were organic in origin. Of the inorganic particles, the majority contained silicon and aluminium in varying proportions suggesting that they were soil derived. Some particles were clearly identified as the products of combustion, and sea or road salt was present on leaf surfaces. Some particles contained copper, tin and titanium which may reflect the proximity of Rough Wood to local metal workings. The number of particles counted on leaf surfaces decreased as distance from the motorway increased.

Journal Article↗
PubMed1997

Pretreatment with inhaled nitric oxide inhibits neutrophil migration and oxidative activity resulting in attenuated sepsis-induced acute lung injury.

OBJECTIVE: To determine if, and by what mechanisms, inhaled nitric oxide attenuates acute lung injury in a porcine model of adult respiratory distress syndrome induced by Gram-negative sepsis. DESIGN: Nonrandomized, controlled study. SETTING: Laboratory at a university medical center. SUBJECTS: Thirty pathogen-free Yorkshire swine (15 to 20 kg). INTERVENTIONS: Four groups of swine were anesthetized, mechanically ventilated, and studied for 5 hrs. Both control-nitric oxide and septic-nitric oxide animals received inhaled nitric oxide at 20 parts per million throughout the study. Control (n = 10) and control-nitric oxide (n = 5) animals received a 1-hr infusion of sterile saline. Sepsis was induced in septic (n = 10) and septic-nitric oxide (n = 5) animals with a 1-hr intravenous infusion of live Pseudomonas aeruginosa. MEASUREMENTS AND MAIN RESULTS: Untreated septic animals developed a progressive decrease in Pao2 that was prevented in septic-nitric oxide animals (73 +/- 4 vs. 214 +/- 23 torr [9.7 +/- 0.5 vs. 28.5 +/- 3.1 kPa], respectively, at 5 hrs, p < .05). Untreated septic animals showed a significant increase in bronchoalveolar lavage protein and neutrophil count at 5 hrs, compared with the baseline value, indicating acute lung injury. Septic-nitric oxide animals showed no significant increase in these parameters. Peripheral blood neutrophils from untreated septic animals and septic-nitric oxide animals exhibited significant (p < .05) up-regulation of CD18 receptor expression and oxidant activity (10.5 +/- 0.9 and 5.0 +/- 0.9 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively) compared with both control and control-nitric oxide animals (3.0 +/- 0.6 and 2.6 +/- 0.2 nmol of superoxide anion/10(6) neutrophils/10 mins, respectively). Also, priming for the oxidant burst at 5 hrs was decreased by 50% in septic-nitric oxide animals compared with untreated septic animals. Both untreated septic and septic-nitric oxide animals showed a significant increase in pulmonary arterial pressure at 30 mins (47.5 +/- 2.4 and 51.0 +/- 3.0 mm Hg, respectively), followed by a progressive decrease (32.8 +/- 2.6 and 31.3 +/- 5.4 mm Hg, respectively, at 5 hrs). Both of these changes were significant (p < .05) compared with baseline values and compared with the control groups. There was no significant difference in pulmonary arterial pressure or systemic arterial pressure at any time between untreated septic and septic-nitric oxide animals. CONCLUSIONS: These results demonstrate that inhaled nitric oxide attenuates alveolar-capillary membrane injury in this porcine model of Gram-negative sepsis but does not adversely affect systemic hemodynamics. The data suggest that inhaled nitric oxide preserves alveolar-capillary membrane integrity by the following means: a) inhibiting transendothelial migration of activated, tightly adherent neutrophils; and b) possibly by attenuating the neutrophil oxidant burst.

Administration, Inhalation↗
PubMed1997

Protective role of synthetic sialylated oligosaccharide in sepsis-induced acute lung injury.

Proper engagement of leukocyte and endothelial cell selectins with their counterreceptors is an initial step in neutrophil trafficking to sites of inflammation. Certain fucosylated carbohydrate determinants such as sialyl Lewis-x are proposed to act as these counterreceptors. We studied the effects of a synthetic sialyl Lewis-x analog, CY-1503, on the course of hemodynamic derangements and acute lung injury during experimental gram-negative sepsis. Anesthetized ventilated swine were made septic with an infusion of live Pseudomonas aeruginosa. A treatment group received an initial bolus of CY-1503 (60 mg/kg) before sepsis, followed by continuous infusion of CY-1503 (15 mg.kg-1.h-1). Treatment with CY-1503 did not prevent the development of pulmonary hypertension, systemic hypotension, decline in cardiac output, or severe neutropenia. However, CY-1503 significantly attenuated lung injury, demonstrated by decreased bronchoalveolar lavage protein content and neutrophil influx, lowered lung myeloperoxidase activity, and improved arterial oxygenation. Neutrophils from septic and CY-1503 animals showed significant activation, reflected by upregulated CD18 expression and priming for oxidant burst compared with control animals. This study suggests blockade of selectin interactions as a potential therapeutic intervention in sepsis-induced lung injury.

Animals↗
PubMed1997

Absolute and comparative subcutaneous bioavailability of ardeparin sodium, a low molecular weight heparin.

Ardeparin sodium (Normiflo, Wyeth-Ayerst) is a low molecular weight heparin undergoing clinical evaluation as an antithrombotic agent. The objective of this study was to evaluate the absolute and comparative bioavailability of ardeparin following subcutaneous administration of three different formulations [two formulations of ardeparin at 10,000 anti-factor Xa (aXa) U/ml, but with different preservatives, and a 20,000 aXa U/ml formulation]. The study was conducted using a randomized 4-period crossover design (three subcutaneous treatments and one intravenous treatment) in 24 healthy subjects, and the pharmacokinetics of ardeparin were characterized by plasma anti-factor IIa (aIIa) and anti-factor Xa (aXa) activities. The mean absolute bioavailability of ardeparin based on aIIa activity ranged from 62% to 64% and the mean absolute bioavailability based on aXa activity ranged from 88% to 97%. Based on bioequivalence testing criteria, the three ardeparin formulations were bioequivalent.

Adult↗
PubMed1996

A quantitative autoradiographical study on the distribution of somatostatin sst2 receptors in the rat central nervous system using [125I]-BIM-23027.

The kinetic properties, steady state binding characteristics and autoradiographic distribution of the somatostatin (SRIF) sst2 receptor-selective ligand, [125I]-BIM-23027, have been investigated in the rat central nervous system. Analysis of kinetic, saturation and competition binding data in rat hippocampal membranes was consistent with [125I]-BIM-23207 binding to a single population of non-interacting binding sites. Competition studies, using different SRIF ligands suggested that [125I]-BIM-23027 was binding to sites similar to that of the recombinant sst2 receptor. The rank order of affinity for displacing specific binding was BIM-23027 = SRIF > L-362855 > > BIM-23056. There was a widespread distribution of [125I]-BIM-23027 binding sites in the rat central nervous system. The highest density of binding was observed in the dentate gyrus, medial habenular, amygdala, claustrum and lateral septum as well as in the piriform, cingulate and parietal cortex. The cervical and lumbar spinal cord also displayed moderate levels of binding localized to the substantia gelatinosa. The cellular localization of [125I]-BIM-23027 binding was found to be associated with dendritic terminal fields. In contrast, the cellular signal for sst2 receptor mRNA was restricted to cell somata. The widespread distribution of [125I]-BIM-23027 binding sites within the brain suggests that receptors similar to the recombinant sst2 receptor may mediate a variety of different physiological effects within the central nervous system.

Animals↗
PubMed1995

Sepsis-induced acute lung injury is attenuated by selectin blockade following the onset of sepsis.

OBJECTIVE: To determine the effect of infusion with a dual-binding antibody to E- and L-selectin, EL-246, in a postonset model of sepsis. DESIGN: Nonrandomized controlled study. STUDY SUBJECTS: Young Yorkshire swine. INTERVENTIONS: Three groups were studied. Controls (n = 8) received saline solution only. Untreated animals with sepsis (n = 8) received a 1-hour intravenous infusion of live Pseudomonas aeruginosa. Animals treated with EL-246 (n = 6) received the same bacterial infusion and a 2-mg/kg bolus of EL-246 at 30 minutes. OUTCOME MEASURES: Systemic and pulmonary hemodynamics, arterial blood gas determination, bronchoalveolar lavage protein and neutrophil content, neutrophil integrin and selectin expression, neutrophil oxidant burst, and organ myeloperoxidase content. RESULTS: Treatment with EL-246 significantly reduced lung injury, as indicated by improved bronchoalveolar lavage protein and neutrophil content, resulting in a significant improvement in arterial oxygenation. This reduction in lung injury was produced by a reduction in lung myeloperoxidase content. Treatment with EL-246 failed to prevent the development of pulmonary hypertension and systemic hypotension. Neutrophils from animals with sepsis exhibited significant activation and upregulation of CD18, shedding of L-selectin, and production of increased levels of oxidants compared with controls. CONCLUSION: Treatment of animals with EL-246 soon the onset of sepsis produced significant protection against acute lung injury but failed to attenuate hemodynamic derangements associated with sepsis.

Animals↗
PubMed1995

The dose proportionality of the pharmacokinetics of ardeparin, a low molecular weight heparin, in healthy volunteers.

Ardeparin is a low molecular weight heparin currently being evaluated as an antithrombotic agent. The objective of this investigation was to assess the effects of dose on the pharmacokinetics of ardeparin after subcutaneous administration. Eighteen healthy subjects received doses of 30 U/kg, 60 U/kg, and 100 U/kg antifactor Xa (aXa) of ardeparin by subcutaneous injection. Plasma antifactor IIa (aIIa) activity levels after the 30- and 60-U/kg doses of ardeparin were too low to reliably characterize the disposition of the drug. However, the pharmacokinetics of ardeparin could be characterized by using pharmacodynamic measurements of plasma aXa activity. The rate of absorption of ardeparin after subcutaneous administration did not change with increasing dose. The volume of distribution (Vd) of ardeparin was small, reflecting minimal distribution outside the intravascular space, and was independent of dose. The total clearance of ardeparin, however, decreased with increasing dose, and half-life (t1/2) was prolonged at the higher doses. Within the observed dose range, a doubling of the ardeparin dose resulted in an area under the plasma aXa activity-versus-time curve (AUC) that was approximately 25% greater than expected on the basis of linear disposition. The differences in AUC and clearance between the three doses suggest that the mechanism of elimination of ardeparin is saturable.

Adult↗
PubMed1994

A single allele from the polymorphic CCG rich sequence immediately 3' to the unstable CAG trinucleotide in the IT15 cDNA shows almost complete disequilibrium with Huntington's disease chromosomes in the Scottish population.

The CCG rich sequence immediately 3' to the CAG repeat that is expanded in Huntington's disease (HD) has recently been shown to be polymorphic with at least 4 alleles differing by multiples of 3 bp being found in the normal population. We have studied the allele distribution in 180 HD families resident in Scotland and have found very strong evidence for disequilibrium in this population. For the 131 families where phase was unambiguously determined, 130 were shown to have a CCG repeat allele of 176 bp cosegregating with the HD chromosome. This observation is significantly different to the normal population distribution where 31% of people have an allele of 185 bp. The evidence for and against a possible founder effect in the Scottish HD population is discussed. We propose the hypothesis that we may have identified a region of the IT15 gene that is critical in Huntington's disease.

Alleles↗
PubMed1994

Predictive testing for Huntington disease: social characteristics and knowledge of applicants, attitudes to the test procedure and decisions made after testing.

An investigation has been made of the social characteristics and knowledge and experience of Huntington disease (HD) for the first 80 individuals considering presymptomatic testing (applicants) at the medical genetics centres in Edinburgh and Glasgow and of attitudes to the test procedure and decisions made after testing for those who received a result. Sixty-one percent of applicants were female and 31% were over 40 years old. Almost all had a symptomatic parent but 38% did not know HD was in their family until they were over 25 years old and 48% had never received genetic counselling. Thirty-eight percent of applicants first heard of the test at the genetic clinic, 20% from a relative and 20% from the media, but none had received information from their GP. Thirty-one applicants did not have the test because they voluntarily withdrew (17 individuals), their family structure was unsuitable or no informative result was possible (11 individuals), or they were diagnosed clinically as being affected (3 individuals). Those who voluntarily withdrew did not differ significantly from the 49 who received a result in social characteristics or knowledge and experience of HD. Twenty-two individuals were found to be at increased risk (IR) (> 50% of becoming affected) and 27 to be at decreased risk (DR) (< 50% of becoming affected). There was a median period of 9 months between entering the test procedure and receiving a result and the main criticism of the procedure was that it took too long to complete and several individuals experienced considerable anxiety while awaiting their result.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗