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K Smith

Publications and source records attributed to K Smith.

At least 145 records · Page 8Linked to original sources
PubMed1999

Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1.

Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-overexpressing mice were resistant to leaks caused by inflammatory agents. Coexpression of Ang1 and VEGF had an additive effect on angiogenesis but resulted in leakage-resistant vessels typical of Ang1. Ang1 therefore may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated VEGF and, in combination with VEGF, for promoting growth of nonleaky vessels.

Angiopoietin-1↗
PubMed1999

Physiological adjustments and arteriolar remodelling within skeletal muscle during acclimation to chronic hypoxia in the rat.

1. We have investigated the physiological and structural changes that occur in skeletal muscle vasculature during acclimation to chronic hypoxia in rats exposed to 12 % O2 in a hypoxic chamber for 7 or 18 days (7CH and 18CH rats, respectively) and in age-matched normoxic (7N and 18N) rats. 2. Under anaesthesia and breathing 12 % O2, 7CH and 18CH rats had lower arterial blood pressure (ABP) than 7N and 18N rats breathing air, but the haematocrit of the CH rats was increased so that their arterial O2 content equalled that of N rats. Blood flow recorded from the iliac or femoral artery and used to compute muscle vascular conductance (MVC: blood flow/ABP) showed that, in 18CH rats, MVC was comparable with that of 18N rats. 3. Maximal MVC induced by infusion of sodium nitroprusside (SNP) was used as an index of structural vascular conductance and compared with the MVC evoked by acute hypoxia (breathing 8 % O2). Hypoxia induced similar increases in MVC in 7N and 7CH rats and in 18N and 18CH rats, even though N rats were switched from air to 8 % O2 and CH rats were switched from 12 to 8 % O2. The MVCs attained with 8 % O2 and SNP were similar in 7N and 18N rats. However, the MVCs attained with 8 % O2 in 7CH and 18CH rats were only approximately 60 % of those evoked by SNP, while the MVC attained with SNP was greater in 18CH than in 18N rats. 4. Vascular casts of the spinotrapezius muscle analysed ex vivo showed that interbranch intervals along primary, secondary and terminal arterioles (22-50, 13-18 and 7-13 microm diameter, respectively) were 30-50 % shorter in 7CH and 18CH rats than in 7N and 18N rats. Further, the proportions of branches that were of the secondary and terminal arteriolar categories were increased such that the mean diameter of the branches was lower in 7CH than in 7N rats and lower in 18CH than in 18N rats. 5. These results indicate that arteriolar remodelling and angiogenesis occurs in skeletal muscle during acclimation to chronic hypoxia, beginning by the 7th day and progressing at least until the 18th day, so that the number of small arterioles and the functional size of the vascular bed is increased. We propose that these structural and functional changes enhance the ability of skeletal muscle to respond to acute hypoxia by facilitating the increase in vascular conductance, blood flow and thereby the O2 that can be delivered to muscle.

Adaptation, Physiological↗
PubMed1999

CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control.

MyD118 and Gadd45 are two related genes which encode for proteins that play important roles in negative growth control, including both growth suppression and apoptosis. A strategy was employed to clone new members of the MyD118 and Gadd45 family of genes. Based on alignment of the deduced amino acid sequences, one cDNA clone was found to encode for the murine homologue of human CR6, originally cloned as an IL-2 immediate-early response gene. The murine and human CR6 proteins were observed to be 97% identical, indicating that CR6 is an evolutionarily conserved protein. Analysis of CR6 expression during hematopoietic cell development associated with growth arrest and apoptotic cell death, upon exposure of hematopoietic cells to a variety of growth arrest and apoptotic stimuli, and in a variety of murine tissues, has revealed that CR6 expression differs significantly from the expression of the related MyD118 and Gadd45 genes. Nevertheless, CR6, like MyD118 and Gadd45, suppressed colony formation of human lung carcinoma H1299 cells. These data suggest that CR6 plays similar, but not identical, roles to MyD118 and Gadd45 in negative control of cell growth.

Amino Acid Sequence↗
PubMed1999

Sequence-tagged connectors: a sequence approach to mapping and scanning the human genome.

The sequence-tagged connector (STC) strategy proposes to generate sequence tags densely scattered (every 3.3 kilobases) across the human genome by arraying 450,000 bacterial artificial chromosomes (BACs) with randomly cleaved inserts, sequencing both ends of each, and preparing a restriction enzyme fingerprint of each. The STC resource, containing end sequences, fingerprints, and arrayed BACs, creates a map where the interrelationships of the individual BAC clones are resolved through their STCs as overlapping BAC clones are sequenced. Once a seed or initiation BAC clone is sequenced, the minimum overlapping 5' and 3' BAC clones can be identified computationally and sequenced. By reiterating this "sequence-then-map by computer analysis against the STC database" strategy, a minimum tiling path of clones can be sequenced at a rate that is primarily limited by the sequencing throughput of individual genome centers. As of February 1999, we had deposited, together with The Institute for Genomic Research (TIGR), into GenBank 314,000 STCs ( approximately 135 megabases), or 4.5% of human genomic DNA. This genome survey reveals numerous genes, genome-wide repeats, simple sequence repeats (potential genetic markers), and CpG islands (potential gene initiation sites). It also illustrates the power of the STC strategy for creating minimum tiling paths of BAC clones for large-scale genomic sequencing. Because the STC resource permits the easy integration of genetic, physical, gene, and sequence maps for chromosomes, it will be a powerful tool for the initial analysis of the human genome and other complex genomes.

Chromosome Mapping↗
PubMed1999

Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo.

In the present paper, we characterize an antibody, mAb BV13, directed to mouse vascular endothelial (VE)-cadherin, a major adhesive protein of interendothelial adherens junctions. When added to cultured endothelial cells, BV13 induces a redistribution of VE-cadherin from intercellular junctions. VE-cadherin redistribution did not change the localization of platelet endothelial cell adhesion molecule or tight junction markers such as zonula occludens 1, cingulin, and junctional adhesion molecule. Intravenous administration of mAb BV13 induced a concentration- and time-dependent increase in vascular permeability in heart and lungs. By electron microscopy, interstitial edema and accumulation of mixed types of inflammatory cells in heart and lungs were observed. Injection of (rhodamine-labeled) Ricinus communis I lectin showed focal spots of exposed basement membrane in the alveolar capillaries and in some larger pulmonary vessels. These data indicate that VE-cadherin is required for vascular integrity and normal organ functions.

Animals↗
PubMed1999

Sheep scab outbreaks in Great Britain between 1973 and 1992: spatial and temporal patterns.

In January 1973, the mange mite Psoroptes ovis was found in a sheep flock in Lancashire, UK after a 20 year period of eradication. Over the next 20 years, a total of 1480 flock outbreaks were reported, until June 1992 when the control of sheep scab was deregulated. The spatial and temporal patterns of the number of outbreaks in each month over this period were analysed using time series methods, a geographical information system (GIS) and second order approaches to the exploration of space-time interaction (K-function analysis). The monthly time series displays clear evidence of seasonal cyclicity, with most outbreaks being reported in the winter months. After removal of the summer compulsory dip in 1988 however, there is evidence of a change in the seasonal pattern, with more cases being reported in the autumn months. There is also evidence of a contribution from a sinusoidal wave with a period of 8 years, which roughly corresponds to the major changes in the national control policy. The spatial pattern also appears to expand and contract on a roughly 4 year cycle, again reflecting the oscillating periods of success and failure. Examination of the spatial and temporal pattern revealed strong evidence of space-time clustering (p < 0.001) and a major contribution to the pattern from very local (< 12 km) spread within 5 months of an arbitrary outbreak.

Animals↗
PubMed1999

Frameless stereotaxy and anterior cervical surgery.

OBJECTIVE: The role of a frameless image guidance system for anterior cervical surgery was evaluated in 40 patients with cervical spondylosis. An assessment was made of the challenges posed in achieving accurate three-dimensional image registration in the absence of multiple fixed anatomical landmarks, and a solution to this problem is outlined using a novel registration tracking device. MATERIALS AND METHODS: Patients underwent preoperative CT scanning of the surgical field of interest, and the image data was reconstructed on a StealthStation (Sofamor Danek, Memphis, Tennessee, USA). An image guidance tracking device was attached to a modified Caspar retractor. Point matching and surface mapping were used for registration. RESULTS: It was not possible to achieve accurate registration in the first 7 patients. In the next 5 patients, the time taken to achieve registration was prolonged. For 28 patients, registration was achieved in an acceptable time with an accuracy of 0.74 +/- 0.4 mm. Anatomical resection margins were accurately identified and 36 anterior cervical screws were precisely placed. CONCLUSIONS: Frameless stereotaxy can now be applied to procedures involving the anterior cervical spine. Potential benefits include accurate definition of the anatomy, demonstration of resection margins, and intraoperative guidance. The technique may prove particularly useful in cases of complex or disrupted anatomy.

Adult↗
PubMed1999

Historical and biomechanical analysis of integration and dissociation in molluscan feeding, with special emphasis on the true limpets (Patellogastropoda: Gastropoda).

Modifications of the molluscan feeding apparatus have long been recognized as a crucial feature in molluscan diversification, related to the important process of gathering energy from the environment. An ecologically and evolutionarily significant dichotomy in molluscan feeding kinematics is whether radular teeth flex laterally (flexoglossate) or do not (stereoglossate). In this study, we use a combination of phylogenetic inference and biomechanical modeling to understand the transformational and causal basis for flexure or lack thereof. We also determine whether structural subsystems making up the feeding system are structurally, functionally, and evolutionarily integrated or dissociated. Regarding evolutionary dissociation, statistical analysis of state changes revealed by the phylogenetic analysis shows that radular and cartilage subsystems evolved independently. Regarding kinematics, the phylogenetic analysis shows that flexure arose at the base of the Mollusca and lack of flexure is a derived condition in one gastropod clade, the Patellogastropoda. Significantly, radular morphology shows no change at the node where kinematics become stereoglossate. However, acquisition of stereoglossy in the Patellogastropoda is correlated with the structural dissociation of the subradular membrane and underlying cartilages. Correlation is not causality, so we present a biomechanical model explaining the structural conditions necessary for the plesiomorphic kinematic state (flexoglossy). Our model suggests that plesiomorphically the radular teeth must flex laterally as they pass over the bending plane as a result of the mechanical restrictions in the flexible but inelastic subradular membrane and close association between subradular membrane and cartilages. Relating this model to the specific character states of the clades, we conclude that lack of flexure in patellogastropods is caused by the dissociation of the subradular membrane and cartilage supports.

Animals↗
PubMed1999

Characteristics of protein and energy metabolism in neonates with necrotizing enterocolitis--a pilot study.

BACKGROUND/PURPOSE: It is assumed that neonates with necrotizing enterocolitis (NEC) are hypermetabolic. However, the dynamics of protein and energy metabolism in neonates with NEC have not been characterized. The purpose of this study was to test the hypothesis that protein turnover and energy expenditure are increased during the acute stage of NEC and later return to normal values. METHODS: A pilot study was performed on six neonates with proven NEC (Bell's stage II or III). Patients were studied in two phases: (1) in the acute stage of their disease and (2) when their clinical condition had stabilized. Whole-body protein turnover was calculated using an intravenous infusion of [1-13C] leucine and by measuring the isotopic enrichment of plasma [13C]alpha-ketoisocaproic acid and 13CO2. Respiratory gas exchange was measured simultaneously by computerized indirect calorimetry. RESULTS: Median gestational age was 36 weeks (range, 28 to 40) with a median postnatal age of 21 days (range, 6 to 47). All patients recovered from the acute episode, although three patients died after recovering from the acute disease from other conditions. The patients studied showed marked variability in protein metabolism kinetics. However, there was no difference in whole-body protein flux between the acute phase (7.6 g/kg/d; range, 5.6 to 18.2) and the recovery phase (7.0 g/kg/d; range, 6.9 to 12.2; P = .89). Furthermore, there was no difference in any of the component parts of wholebody protein turnover. Resting energy expenditure did not change between the acute phase (42.8 kcal/kg/d; range, 34.4 to 52.5) and the recovery phase (51.0 kcal/kg/d; range, 34.9 to 55.3; P = .18). CONCLUSIONS: This pilot study shows that the rates of protein and energy metabolism in neonates with NEC are comparable with reported values in stable neonates. There was no difference in protein or energy dynamics between study phases. The authors speculate that neonates with NEC may divert the products of protein synthesis from growth to tissue repair.

Calorimetry, Indirect↗
PubMed1999

Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist.

OBJECTIVE: Hypothalamic obesity is a rare sequela of cranial insult, for which pathogenesis and treatment remain obscure. In rodents ventromedial hypothalamic damage causes hyperphagia, obesity, hyperinsulinism, and insulin resistance. Reduction of insulin secretion in humans may attenuate weight gain. METHODS: Eight children with intractable obesity after therapy for leukemia or brain tumors underwent oral glucose tolerance testing (OGTT) with simultaneous insulin levels before and after treatment with octreotide for 6 months. RESULTS: In comparison with a 6-month pre-study observation period, patients exhibited weight loss (+6.0 +/- 0.7 kg vs -4.8 +/- 1.8 kg; P =.04) and decrease in body mass index (+2.1 +/- 0.3 kg/m(2) vs -2.0 +/- 0.7 kg/m(2); P =.0001). Recall calorie count decreased during the 6 months of treatment (P =. 015). OGTT demonstrated biochemical glucose intolerance in 5 of 8 patients initially and in 2 of 7 at study end, whereas insulin response was decreased (281 +/- 47 microU/mL vs 114 +/- 35 microU/mL; P =.04). Percent weight change correlated with changes in insulin response (r = 0.72, P =.012) and changes in plasma leptin r = 0.76, P =.0004). CONCLUSIONS: Patients with hypothalamic obesity demonstrate excessive insulin secretion. Octreotide administration promoted weight loss, which correlated with reduction in insulin secretion on OGTT and with reduction in leptin levels. Pre-study biochemical glucose tolerance improved in several patients while they were receiving octreotide. These results suggest that normalization of insulin secretion may be an effective therapeutic strategy in this syndrome.

Adolescent↗
PubMed1999

Adenosine and pediatric supraventricular tachycardia in the emergency department: multicenter study and review.

STUDY OBJECTIVE: To determine the frequency of successful cardioversion and the adverse effects of adenosine treatment in pediatric emergency department patients with supraventricular tachycardia (SVT). METHODS: This was a multicenter descriptive study with both prospective (convenience sample) and retrospective (chart review) patient entry. The setting was 7 urban pediatric EDs with a yearly census range of 22,000 to 70,000 visits. Pediatric patients 18 years of age and younger who received intravenous adenosine for presumed SVT were eligible. RESULTS: Six investigators from 7 pediatric EDs entered 82 patients with 98 presumed SVT episodes (52 prospective and 46 retrospective) into the study. Twenty-five episodes occurred in children younger than 1 year of age. Eight patients had congenital heart disease, 59 had a history of SVT, 43 were taking cardiac medications (digoxin in 27), 13 had a history of asthma, and 25 presented in compensated cardiogenic shock. A total of 193 intravenous doses of adenosine were administered; doses were classified as low (<.1 mg/kg [n=18]), medium (.1 to <.2 mg/kg [n=116]), or high (>/=.2 mg/kg [n=59]). The dose range was.03 to.5 mg/kg, and only 2 doses were higher than.3 mg/kg. A total of 95 patient-events were determined to be SVT, all but 5 of which were atrioventricular (AV) node-dependent; 3 events were ventricular tachycardia. The overall cardioversion success rate of adenosine was 72% (71/98), and that for AV node-dependent SVT was 79% (71/90). Cardioversion was successful for 4 patient-events at a low dose, 44 at a medium dose, and 23 at a high dose of adenosine. Adverse effects occurred in 22 patients, and no patient had bronchospasm or hemodynamically significant arrhythmia. CONCLUSION: Intravenous administration of adenosine led to successful cardioversion in 72% of pediatric ED patient-events that were presumed to be SVT. A dose range of.1 to.3 mg/kg was found to be most effective. Adenosine was not associated with significant adverse effects.

Adenosine↗
PubMed1999

Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival.

BACKGROUND: Angiogenesis, the process whereby endothelial cells divide and migrate to form new blood capillaries, has been assessed in tumours by measuring microvessel density. High microvessel density is a significant adverse prognostic factor in breast cancer. The angiogenic factor, basic fibroblast growth factor (bFGF), has been associated with tumourigenesis and metastasis in several human cancers. There are few quantitative studies of bFGF expression in normal tissues compared to cancer. PATIENTS AND METHODS: We have measured bFGF levels in 149 human primary breast carcinomas and assessed the findings in relation to microvessel density, oestrogen receptor (ER) and epidermal growth factor receptor (EGFR). Basic FGF levels were measured by ELISA. Western blotting and immunohistochemistry were carried out to confirm the presence of bFGF. RESULTS: Levels of bFGF were more than 10-fold higher in tumour cytosols compared to reduction mammoplasty tissue and 3-fold compared to non neoplastic cytosols from the same breast as the tumour (P < 0.0001). Immunohistochemistry showed bFGF protein was localised exclusively in the stroma whereas no bFGF staining was observed in the epithelial cells. High bFGF levels were significantly related to high ER (P = 0.01). Similarly, high bFGF levels were significantly related to low grade (P = 0.046) and to small tumour size (P = 0.04). No significant relationship was observed between bFGF and microvessel count, EGFR or age. In univariate analysis and in a Cox proportional hazard model bFGF did not reach significance for overall or relapse free survival. CONCLUSIONS: Our results show that although bFGF is elevated in breast carcinomas compared to normal breast tissue it is not related to microvessel density and it is not an independent predictor of survival in breast cancer patients. Basic FGF may be one of multiple factors that synergise with other growth factors such as VEGF to enhance angiogenesis.

Adult↗
PubMed1999

Transcriptional profiling of human microvascular endothelial cells in the proliferative and quiescent state using cDNA arrays.

Endothelial cells are known to be a rich source of transcriptional gene expression. Recent technological advances now permit the detailed profiling of mRNA expression using arrays of known cDNAs on blots. We have used such arrays to examine expression of mRNA by primary isolates of human foreskin microvascular endothelial cells in the proliferative and quiescent state. Cells were stimulated by a combination of known growth factors for these cells including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and 'endothelial cell growth supplement (ECGS)' either alone or in combination. Analysis showed the expression of many mRNAs but of the 588 examined, only one, namely monocyte chemotactic protein-1 (MCP-1), showed a decrease on treatment with EGF. A combination of image grabbing followed by subtractive densitometry enabled identification of the mRNAs upregulated in proliferating endothelium. In consideration of the possibility of selective vascular targeting, of particular interest was the increase in expression of the mRNA for the cell surface proteins vascular endothelial (VE-) and neural (N-) cadherin and alpha5, alphav, beta1 and beta3 integrins. The alpha5 integrin offers a previously unrecognized opportunity for vascular targeting.

Journal Article↗
PubMed1999

Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.

Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.

Adult↗
PubMed1999

Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study.

A case control study of Scottish children aimed to identify risk factors for leukaemia and other cancers operating in the prenatal environment, during delivery and neonatally. Cases (0-14 years) were age-and sex- matched to two population-based controls and details abstracted from the mother's hospital obstetric notes. Analyses of 144 leukaemias (124 acute lymphoblastic leukaemias (ALL)), 45 lymphomas, 75 central nervous system (CNS) tumours and 126 'other solid tumours' were conducted using conditional logistic regression. The presence of a neonatal infection significantly reduced the risk of ALL (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.26-0.95), particularly in 0- to 4-year-olds. Positive swab tests confirmed 47% of ALL cases with any infection and 46% of controls. This is consistent with the hypothesis that early exposure to infections may reduce the risk of childhood ALL. Asphyxia at birth significantly increased the risk of leukaemia, which was accounted for by ALL. For the 'other solid tumours' higher levels of maternal education were inversely associated with risk (OR 0.59, 95% CI 0.37-0.94) but positively associated with antibiotics (OR 2.16 95% CI 1.10-4.25) and respiratory tract infections (OR 14.1, 95% CI 1.76-113.7) in pregnancy. No obvious plausible patterns of risk were detected either within or across disease subgroups.

Adolescent↗
PubMed1999

Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer.

Defects in the APC-beta-catenin pathway are common in colon cancer. We investigated whether aberrant regulation of upstream ligands stimulating this pathway occur in colon cancer. Using RNAase protection analysis, six out of eight wnt genes were expressed in 14 matched cases of normal, adenomatous and malignant colorectal tissues. Wnt 2 and wnt 5a were significantly up-regulated in the progression from normal through adenoma to carcinoma. Transcripts for wnts 4, 7b, 10b and 13, but not wnt 2 and wnt 5a were detected in several colorectal cell lines. In situ hybridization demonstrated that wnt 2 and wnt 5a transcripts were mainly in the lamina propria/stroma region with labelling predominantly in macrophages. Immunostaining with CD68 confirmed the wnt-expressing cells as macrophages. These results show a major difference in wnt expression in colon cancer compared to colon adenomas and suggest stromal wnt expression may play a role in tumour progression.

Adenocarcinoma↗