Biomedical subjects

Stephen Smith

Publications and source records attributed to Stephen Smith.

At least 19 recordsLinked to original sources

PubMed2006

Vascular development is disrupted by endothelial cell-specific expression of the anti-apoptotic protein Bcl-2.

Endothelial cell (EC) apoptosis has been detected in remodelling blood vessels in vivo, and inhibition of EC apoptosis appears to alter vascular morphogenesis in vitro, suggesting that EC apoptosis may play a role in blood vessel remodelling. However, apoptotic EC are difficult to quantify in vivo, and studies of the incidence of EC apoptosis and the sites at which it occurs in vivo have produced contradictory results. Therefore, the specific biological roles played by EC apoptosis remain unclear. Here, we have used a transgenic approach to determine the biological function of EC apoptosis in vivo. Anti-apoptotic Bcl-2 transgenes were expressed in mice under control of the EC-specific tie2 promoter. These transgenic mice died during the second half of gestation. While the development and remodelling of large vessels including aortic arch arteries and great veins proceeded normally, abnormally dense and disorganised networks of small vessels were present in the skin and internal organs. In addition, vessel organisation and lumen formation were disrupted in the placental labyrinth. This study provides direct experimental evidence that endothelial cell apoptosis plays an essential role during embryogenesis. Our results suggest that EC apoptosis plays an important role in determining the structure of the microcirculation but may be dispensable for large vessel development.

Animals↗

PubMed2006

Alphabetical prejudice in team discussions (or would Zebedee ever get seen on a ward round).

PURPOSE: To ascertain whether the order in which patients are discussed in a team meeting determines the time spent on discussion. DESIGN: Prospective study over 18 consecutive multidisciplinary team meetings. SETTING/SUBJECTS: Multidisciplinary team meetings on a Brain Injury Rehabilitation Unit, Edinburgh. MAIN OUTCOME MEASURE: Time spent discussing each case. RESULTS: Patients discussed early on received 3-4 minutes more discussion time than those later on. This was highly significant on a one-way analysis of variance (P < 0.001). CONCLUSIONS: Preferential treatment of patients who come at the start of the team meeting is a real phenomenon. Such alphabetical prejudice, where it exists, should be addressed.

Bias↗

PubMed2006

Meaningful design and contrast estimability in FMRI.

Optimising the efficiency of an experimental design is known to be of great importance. However, existing methods for calculating design rank deficiency and contrast estimability (an important aspect of experimental design) relate to computational precision rather than image noise and are therefore not very meaningful. For example, a contrast between two experimental conditions may be mathematically "estimable" while requiring a huge differential BOLD response for statistical significance to be reached. In this paper we formulate standard efficiency equations in terms of required BOLD effect, and use this to generate measures of rank/estimability which are meaningful. This takes into account the strength and smoothness of the timeseries noise and is applicable to complex contrasts; we show how to re-express several regressors and an associated contrast vector as a single equivalent regressor, so that we can calculate the contrast's effective peak-peak height unambiguously. We also present some example results on typical designs, and characterise noise results from a range of typical FMRI acquisitions, in order to allow experimenters to apply efficiency estimation in advance of acquiring data.

Artifacts↗

PubMed2006

A potent human anti-eotaxin1 antibody, CAT-213: isolation by phage display and in vitro and in vivo efficacy.

The CC chemokine, eotaxin1 (CCL11) is an important regulator of eosinophil function. A marked accumulation of eosinophils in tissues has been correlated with the up-regulation of eotaxin1 expression in several diseases. The potential therapeutic value of neutralizing the effects of eotaxin1 in inflammatory conditions (including asthma) is under investigation. A human single-chain fragment variable antibody that neutralizes human eotaxin1 (CAT-212) was produced using antibody phage display and converted to whole antibody IgG4 format (CAT-213). A novel approach to lead optimization in which the length of the variable heavy chain complementarity-determining region 3 was reduced by one amino acid resulted in an increase in potency of >1000-fold compared with the parent anti-eotaxin1 antibody. The optimized antibody binds eotaxin1 with high affinity (80.4 pM) and specificity. CAT-213 and CAT-212 do not bind or neutralize a range of other human proteins including human monocyte chemoattractant protein-1, a structurally similar chemokine. CAT-213 neutralizes the ability of eotaxin1 to cause an increase in intracellular calcium signaling (with an IC(50) value of 2.86 nM), migration of CCR3-expressing L1.2 cells (with an IC(50) value of 0.48 nM), and inhibition of the eotaxin1-evoked shape change of human eosinophils in vitro (with an IC(50) of 0.71 nM). Local administration of CAT-213 to mice (1-100 microg kg(-1)) attenuates dermal eosinophilia induced by human eotaxin1, achieving >90% inhibition of eosinophil influx. CAT-213 may therefore be of therapeutic value in inhibiting diseases in which eotaxin1 and eosinophils play a major role, for example, severe asthma.

Algorithms↗

PubMed2006

Lesion probability maps of white matter hyperintensities in elderly individuals: results of the Austrian stroke prevention study.

OBJECTIVE: White matter hyperintensities (WMH) are common on brain MRI of the elderly. Their size ranges from punctate to early confluent to confluent lesions. While this increase in extension is frequently seen as evidence for a continuum of changes, histological data and clinical follow-up suggest differences in underlying pathology and their progression. METHODS: We tested this hypothesis by exploring the distributions of punctuate and confluent lesions using lesion probability maps (LPM) generated from MRI scans of 189 participants (mean age 60.8+/-6.2 years) in the Austrian Stroke Prevention Study. We dichotomised WMH according to the classification by Fazekas et al. [punctate (n=143) vs. early confluent and confluent (n=33)] to run voxel-based t-tests using permutation-based nonparametric inference. To test alternative hypotheses, we created similar LPM for age and arterial hypertension. RESULTS: We observed significant differences in the spatial distribution of lesions for the two WMH groups (p<0.01). Punctate lesions were more diffusely distributed throughout the cerebral white matter (peak probability approximately 5%) relative to confluent lesions (peak probability 45%). Confluent lesions had greatest likelihood of being found in perfusion "watershed" regions. These differences in distribution could not be explained by differences in age or hypertension only, as both greater age and the diagnosis of hypertension were associated with WMH abutting the occipital horns. CONCLUSIONS: Punctate and early confluent to confluent WMH show distinguishable differences in their spatial distribution within a normal elderly population. The pattern of punctate WMH is probably a consequence of mixed etiologies. Preferential localization of the more confluent WMH with arterial watershed areas implies a stronger ischemic component in their development.

Age Factors↗

PubMed2005

Blood oxygenation level dependent contrast resting state networks are relevant to functional activity in the neocortical sensorimotor system.

The relevance of correlations between blood oxygenation level dependent (BOLD) signal changes across the brain acquired at rest (resting state networks, or RSN) to functional networks was tested using two quantitative criteria: (1) the localisation of major RSN correlation clusters and the task-related maxima defined in BOLD fMRI signal changes from the same subjects; and (2) the relative hemispheric lateralisation (LI) of BOLD fMRI signal changes in sensorimotor cortex. RSN were defined on the basis of signal changes correlated with that of a "seed" voxel in the primary sensorimotor cortex. We found a generally close spatial correspondence between clusters of correlated BOLD signal change in RSN and activation maxima associated with hand movement. Conventional BOLD fMRI during active hand movement showed the expected wide variation in relative hemispheric lateralisation of LI for sensorimotor cortex across the subjects. There was a good correlation between LIs for the active hand movement task and the RSN (r=0.74, p<0.001). The RSN thus define anatomically relevant regions of motor cortex and change with functionally relevant variations in hemispheric lateralisation of sensorimotor cortical interactions with hand movement.

Adult↗

PubMed2005

Insulin-mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by rosiglitazone.

BACKGROUND: Obesity-associated hypertension is likely to be due to multiple mechanisms. Identification of the renin-angiotensin system (RAS) within adipose tissue does, however, suggest a potential causal role for it in obesity-associated hypertension. Obese patients are often hyperinsulinemic, but mechanisms underlying insulin upregulation of the RAS in adipose tissue are unclear. Tumor necrosis factor-alpha (TNF-alpha), an inducer of angiotensinogen in hepatocytes, is elevated in hyperinsulinemic, obese individuals and may provide a link in mediating insulin upregulation of the RAS in adipose tissue. Furthermore, thiazolidinediones lower blood pressure in vivo, and downregulation of the RAS in adipose tissue may contribute to this effect. We therefore examined the effect of rosiglitazone (RSG) on the insulin-mediated upregulation of the RAS. METHODS AND RESULTS: Sera were obtained from the arterial circulation and from venous blood by draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (n=12) were treated with insulin (1 to 1000 nmol/L), insulin in combination with RSG (10 nmol/L), and RSG (10 nmol/L) alone to determine angiotensinogen expression and angiotensin II, bradykinin, and TNF-alpha secretion. Subcutaneous adipocytes were also treated with TNF-alpha (10 to 100 ng/mL) to examine the direct effect on angiotensinogen expression and angiotensin II secretion. The findings showed that the arteriovenous difference in angiotensin II levels was significant (>23%; P<0.001). Insulin increased TNF-alpha secretion in a concentration-dependent manner (P<0.01), whereas RSG (10 nmol/L) significantly reduced the insulin-mediated rise in TNF-alpha (P<0.001), as well as angiotensin and angiotensin II. TNF-alpha also increased angiotensinogen and angiotensin II in isolated adipocytes. CONCLUSIONS: The present in vivo data suggest that human subcutaneous adipose tissue is a significant source of angiotensin II. This study also demonstrates a potential TNF-alpha-mediated mechanism through which insulin may stimulate the RAS and may contribute to explain obesity-associated hypertension. RSG downregulates the RAS in subcutaneous adipose tissue, and this effect may contribute to the long-term effect of RSG on blood pressure.

Adipocytes↗

PubMed2005

Potential difference measurements in the lower airway of children with and without cystic fibrosis.

Nasal potential difference measurements are valuable endpoint assays in clinical studies of novel treatments for cystic fibrosis (CF). Similar measurements made on the lower airway via the bronchoscope have been successful in adults, but have not been reported in children, the group most likely to benefit from such therapies. Here we report the design and validation of a small, single-lumen catheter technique allowing baseline potential difference and chloride secretion to be assessed in the distal airways of children as young as 1 year of age. Tracheal baseline values were significantly higher in children with CF than those without, although this was not the case more distally. In airways between the third and seventh generation, perfusion with a zero chloride solution containing isoprenaline led to a significant change in potential difference in children without CF, whereas no change was seen in those with CF. This measure provided a reliable distinguishing test between the two disease groups. We confirm that invasive bronchoscopic techniques can be performed safely and reliably in small children. Potential difference measurements could form a useful functional endpoint assay for future studies of either the CFTR gene or protein-based therapies in future trials in the pediatric age group.

Bronchi↗

PubMed2005

White matter lesion progression, brain atrophy, and cognitive decline: the Austrian stroke prevention study.

White matter lesions progress over time, but the clinical consequences are widely unknown. Three-hundred twenty-nine elderly community-dwelling volunteers underwent serial magnetic resonance imaging scanning and cognitive testing at baseline and at 3- and 6-year follow-up. We measured the changes in white matter lesion and brain parenchymal volumes. After 6 years, the median increase in white matter lesion load was 0.2 cm3 (interquartile range [IQR], 0.0-0.80 cm3) with a maximum of 31.4 cm3. The median loss of brain volume was 2.3% (IQR, 1.13-3.58%). Increasing white matter lesion volume was correlated with loss of brain volume (p < 0.0001) and performance decline in tests of memory (p = 0.022), conceptualization (p = 0.046), and visuopractical skills (p = 0.005). Associations between changes in white matter lesion load and cognitive functioning were no longer significant when adding change in brain volume to the models, suggesting that cognitive decline related directly to loss of brain substance with progression of lesion burden.

Aged↗

PubMed2005

Prioritizing new over old: an fMRI study of the preview search task.

In visual search, observers can successfully ignore temporally separated distractors that are presented as a preview before onset of the search display. Previous behavioral studies have demonstrated the involvement of top-down selection mechanisms in preview search, biasing attention against the old set in favor of the more relevant new set. Using functional magnetic resonance imaging, we replicate and extend findings showing the involvement of superior and inferior parietal areas in the preview task when compared to both a relatively easy single-set search task and a more effortful full-set search task. In contrast, the effortful full-set search showed activation in the dorsolateral prefrontal cortex when compared to the single-set search, suggesting that this area is involved in rejecting additional distractors that could not be separated in time.

Adult↗

PubMed2005

Development and validation of models for the investigation of blood clotting in idealized stenoses and cerebral aneurysms.

An in vitro model of blood clotting is presented using hypercoaguable milk as an analog for blood. Milk clot formation was studied for periods of 2, 5, 10, 20, and 30 min within an idealized stenosis geometry. Clot formation was recorded using photography, clot casting, and clot mass calculation. The distribution of clot within the fluid was seen to be in good agreement with a previous study that used a residence time model to predict areas of clot formation in thrombin solution. A numerical model was formulated within computational fluid dynamics package CFX that allowed local activation of blood clotting to be simulated. This model was applied to the analysis of an idealized cerebral aneurysm geometry. An idealized coil geometry was included within the aneurysm and clotting fluid concentration and fluid residence time were modeled using transport equations within CFX. The viscosity of the fluid was defined as a function of both residence time and clotting fluid concentration. The model was seen to produce features consistent with observations of thrombosis within cerebral aneurysms, while avoiding the unrealistic build up of clot in near-wall regions that is associated with a pure residence time model.

Animals↗

PubMed2005

Intraovarian actions of anti-angiogenic agents disrupt periovulatory events during the menstrual cycle in monkeys.

To determine if anti-angiogenic agents disrupt primate ovarian function, vehicle or a general angiostatic compound (TNP-470), specific antagonists of vascular endothelial growth factor (soluble VEGF receptor-1, sVEGFR-1; anti-VEGF monoclonal antibody, VEGF Ab) and/or an angiopoietin antagonist (Ang-2) were administered to rhesus monkeys: (1) locally via injection into the preovulatory follicle at midcycle or the developing corpus luteum at the midluteal phase; or (2) systemically via subcutaneous injection in the early follicular phase or at midcycle during the natural menstrual cycle. Compared to controls, intrafollicular injection of TNP-470 or sVEGFR-1 decreased circulating progesterone (P) levels in the subsequent luteal phase. Treatment with sVEGFR-1, but not TNP-470, also decreased the incidence of ovulation. Intrafollicular injection of Ang-2 also prevented ovulation, as well as any functional luteal phase. In the absence of elevated P, serum estradiol levels rose to peak levels 11-12 days post-Ang-2 treatment, at which time another large antral follicle was observed on the contralateral (noninjected) ovary. Intraluteal and systemic injection of VEGF antagonists alone or with Ang-2 had minimal effects. Thus, anti-angiogenic factors can act locally in the primate follicle to disrupt the gametogenic (oocyte release) and endocrine (steroid) functions of the ovary. However, further studies are needed to optimize delivery of angiogenic agents before they can be meaningfully evaluated as possible contraceptive agents.

Angiogenesis Inhibitors↗

PubMed2004

Soluble factors from human endometrium promote angiogenesis and regulate the endothelial cell transcriptome.

BACKGROUND: Angiogenesis and vascular remodeling play critical roles in the cyclical growth and regression of endometrium. They also appear to play roles in the pathogenesis of endometriosis. METHODS AND RESULTS: Supernatants were collected from cultured endometrium isolated from women with and without endometriosis. These supernatants induced endothelial cell proliferation and angiogenesis in vitro. They contained vascular endothelial growth factor (VEGF)-A, and their proliferative effects on endothelial cells were partially abrogated by a blocking anti-VEGF-A antibody. Gene array analysis showed that culture supernatants from proliferative phase endometrium, and to a lesser extent secretory phase endometrium, induced significant changes in the transcriptome of endothelial cells. We could not detect any association between endometriosis and the ability of endometrial-derived soluble factors to promote angiogenesis or to regulate the endothelial transcriptome. In addition, we could not detect any association between endometriosis and the concentration of VEGF-A in supernatants from cultured endometrium or in menstrual effluent. CONCLUSIONS: We have shown that endometrium cultured in vitro produced soluble factors, including VEGF-A, that promoted angiogenesis. Proliferative phase endometrium promoted significant endothelial cell transcriptome changes that appear overall to be pro-angiogenic. These transcriptome changes provide insight into the dynamic control of vessel structure on which both eutopic endometrium and endometriotic lesions depend.

Case-Control Studies↗

PubMed2004

Accelerated evolution of brain atrophy and "black holes" in MS patients with APOE-epsilon 4.

Apolipoprotein E (APOE)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of "black holes" (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In APOE-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-epsilon4.

Adult↗

PubMed2004

With demand lacking, smallpox vaccine expiring.

The Bush administration's campaign to vaccinate health care workers against smallpox has proved unpopular, largely because of concerns about the safety of the vaccine and who would pay for any needed medical treatment. State health departments have destroyed about 61,000 doses of expired vaccine--substantially more than the number actually administered.

Humans↗

PubMed2004

Anthrax versus the flu.

As state governments in the United States slash their public health budgets, federal money is pouring in for bioterror preparedness.

Anthrax↗

PubMed2003

Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine.

One explanation for the weak relationship between neuropsychological deficits and conventional measures of disease burden in multiple sclerosis is that brain 'plasticity' allows adaptive reorganization of cognitive functions to limit impairment, despite injury. We have tested this hypothesis. Ten patients with multiple sclerosis and 11 healthy controls were studied using a functional MRI (fMRI) counting Stroop task. The two subject groups had comparable performances, but a predominantly left medial prefrontal region [Brodmann area (BA) 8/9/10] was more active during the task in patients than in controls (corrected P < 0.001), while a right frontal region (including BA 45 and the basal ganglia) was more active in controls than in patients (corrected P = 0.004). The magnitude of the differences correlated with the normalized brain parenchymal volume, a measure of disease burden (r = -0.72, P = 0.02). We then tested the effects of acute administration of rivastigmine, a central cholinesterase inhibitor, on patterns of brain activation. In five out of five multiple sclerosis patients there was a relative normalization of the abnormal Stroop-associated brain activation, although no change in the patterns of brain activation was found in any of four healthy controls given the drug and tested in the same way. We suggest that recruitment of medial prefrontal cortex is a form of adaptive brain plasticity that compensates, in part, for relative deficits in processing related to the reduced right prefrontal cortex activity with multiple sclerosis. This functional plasticity is modulated by cholinergic agonism and must arise from potentially highly dynamic mechanisms such as the 'unmasking' of latent pathways.

Adult↗

PubMed2003

Interpretation of pre- versus postimplant TRUS images.

In order to summarize the inter-observer variability of pre- and postimplant TRUS image interpretation. Ten patients treated with Pd-103 brachytherapy were studied. Preimplant prostatevolumes ranged from 21 to 51 cm3. The number of sources implanted ranged from 74 to 155, and the number of sources per cm3 prostate volume ranged from 3.0 to 4.3. A set of transverse images (6 MHz) were taken immediately prior to and following source placement. Original printer images were sent to four investigators and the prostate outlined independently on a cellophane overlay. The overlays were digitized into a Varian MMS 7.0 treatment planning system (Charlottesville, VA) for volume determinations. There was moderate interobserver variability in TRUS volume determination, accentuated for the postimplant images. The standard deviations varied from 2% to 13% of the mean (median: 7%) for preimplant volumes, versus 7% to 32% (median: 13%) for postimplant volumes. Interobserver prostatic edge (border) localization variability was greatest at the base and apex, with closer agreement along the posterior border. For preimplant images, the majority of edge points were within 1.0 mm of the mean. At each coordinate, with the exception of the anterior base, the majority of points were within 2.0 mm of the mean. In general, border identification variability was greater in the post implant images. While all prostate imaging modalities suffer from interobserver variability, preimplant and postimplant TRUS appears capable of consistently determining prostatic volume and borders. It appears that intraoperative TRUS-based dosimetry is a practical goal, provided that seed location coordinates can be added to the prostatic edge information derived from TRUS images.

Brachytherapy↗