Biomedical subjects

Stephen Smith

Publications and source records attributed to Stephen Smith.

15 recordsLinked to original sources

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

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↗

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↗

PubMed2003

The nurse, M.D. and IT. Executive dialogue series.

Clinical information systems are proven to enhance workflow and outcomes, and yet hospitals often face staff resistance when systems are installed. This roundtable discussion explores how nurses and physicians can collaborate on developing IT systems.

Attitude to Computers↗

PubMed2002

Effects of word form on brain processing of written Chinese.

Both logographic characters and alphabetic pinyins can be used to write words in Chinese. Here we use fMRI to address the question of whether the written form affects brain processing of a word. Fifteen healthy, right-handed, native Chinese-reading volunteers participated in our study and were asked to read silently either Chinese characters (8 subjects) or pinyins (7 subjects). The stimulus presentation rate was varied for both tasks to allow us to identify brain regions with word-load-dependent activation. Rate effects (fast minus slow presentations) for Chinese character reading were observed in striate and extrastriate visual cortex, superior parietal lobule, left posterior middle temporal gyrus, bilateral inferior temporal gyri, and bilateral superior frontal gyri. Rate effects for pinyin reading were observed in bilateral fusiform, lingual, and middle occipital gyri, bilateral superior parietal lobule/precuneus, left inferior parietal lobule, bilateral inferior temporal gyrus, left middle temporal gyrus, and left superior temporal gyrus. These results demonstrate that common regions of the brain are involved in reading both Chinese characters and pinyins, activated apparently independently of the surface form of the word. There also appear to be brain regions in which activation is dependent on word form. However, it is unlikely that these are entirely specific for a given word form; their activation more likely reflects relative functional specializations within broader networks for processing written language.

Adult↗

PubMed2002

Evidence for asymmetric frontal-lobe involvement in episodic memory from functional magnetic resonance imaging and patients with unilateral frontal-lobe excisions.

Recently, there has been considerable debate regarding the involvement of the left and right prefrontal cortices in the encoding and retrieval of episodic memory. In a previous PET study, we found that the use of easily verbalisable material may lead to activation predominantly in the left lateral frontal cortex whilst the use of non-easily verbalisable material may lead to activation predominantly in the right lateral frontal cortex, in both cases irrespective of encoding and retrieval processes. In order to replicate and extend these findings, the same task was modified for use with fMRI. Six healthy volunteers were scanned while encoding and then recalling stimuli that either emphasised visual or verbal processes. It was found that, in comparison to a baseline condition, the encoding of visual stimuli led to a bilateral activation of the prefrontal cortex whilst the encoding of verbal stimuli led to a preferential activation of the left prefrontal cortex. An effect of stimulus type was less evident during retrieval, with both visual and verbal stimuli leading to bilateral prefrontal cortex activation. Overall, encoding and retrieval activated similar regions of the prefrontal cortex suggesting that these areas mediate processes that are fundamental to both aspects of memory. To extend these findings further, the tasks used in the fMRI study were used to assess a group of patients with unilateral frontal lesions and a group of healthy control volunteers. The patients were significantly impaired compared to the healthy volunteers, although no significant differences were found in performance between the right- and left-sided lesioned patients. This result suggests that the memory-related asymmetries observed during functional neuroimaging studies may not be critical for task performance.

Female↗

PubMed2002

Improved optimization for the robust and accurate linear registration and motion correction of brain images.

Linear registration and motion correction are important components of structural and functional brain image analysis. Most modern methods optimize some intensity-based cost function to determine the best registration. To date, little attention has been focused on the optimization method itself, even though the success of most registration methods hinges on the quality of this optimization. This paper examines the optimization process in detail and demonstrates that the commonly used multiresolution local optimization methods can, and do, get trapped in local minima. To address this problem, two approaches are taken: (1) to apodize the cost function and (2) to employ a novel hybrid global-local optimization method. This new optimization method is specifically designed for registering whole brain images. It substantially reduces the likelihood of producing misregistrations due to being trapped by local minima. The increased robustness of the method, compared to other commonly used methods, is demonstrated by a consistency test. In addition, the accuracy of the registration is demonstrated by a series of experiments with motion correction. These motion correction experiments also investigate how the results are affected by different cost functions and interpolation methods.

Acoustic Stimulation↗

PubMed2002

Clinical and genetic characterization of families with triple A (Allgrove) syndrome.

Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype-phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.

Adolescent↗

PubMed2002

Increased macrophage infection upon subcutaneous inoculation of rhesus macaques with simian immunodeficiency virus-loaded dendritic cells or T cells but not with cell-free virus.

Information on the establishment of immunodeficiency virus infection through transmission of infected cells is sparse. Dendritic cells (DCs) and T cells may be central to the onset and subsequent spread of infection following mucosal exposure. To directly investigate the consequences of virus being introduced by DCs or T cells, we reinjected ex vivo simian immunodeficiency virus (SIV)-loaded autologous immature DCs and T cells subcutaneously (s.c.) into healthy macaques. s.c. injection of cell-bound virus was used to mirror what may happen if virus-loaded cells pass through an epithelium or perhaps DCs and T cells that immediately entrap cell-free virus, having just crossed an epithelial barrier. Virus load in the plasma was monitored along with combined in situ hybridization and immunohistochemistry to identify the cells replicating virus in the lymphoid tissues. Both DCs and T cells transmitted infection after being pulsed with either wild-type or nef-defective (delta nef) SIVmac239. As seen in animals infected intravenously, replication of delta nef was attenuated compared to that of wild-type virus when introduced in either cell-bound form. Upon examination of the draining lymph nodes (LNs) during the first days of infection, virus-producing CD4(+) T cells predominated in control animals that received s.c. cell-free virus. In dramatic contrast, both SIV-positive macrophages and T cells were detected in the LNs of monkeys infected with cell-associated SIV. Therefore, although both cell-free and cell-associated viruses are infectious, the initial cells amplifying the virus differ. This may have important implications for the subsequent dissemination of infection and/or induction of antiretroviral immunity.

Animals↗

PubMed1999

Two-Dimensional Echocardiographic Quantitation of Left Ventricular Global and Regional Shape: Validation of an Algorithm Based on Fourier Transformation and Curvature Measurements of Endocardial Contours.

Left ventricular geometry is an important parameter of its function; however, left ventricular function has been conventionally quantified through measurements of volume, ejection fraction, and mass. Left ventricular global shape has been quantified previously using methods that are based on assumptions of idealized cavity shape. Although these indices have been applied to various disease states of the left ventricle, the underlying assumption of an ideal left ventricular geometry is inherently flawed. Regional left ventricular shape using echocardiography has not been previously evaluated, principally because of the difficulty in quantitative regional geometry. Alterations in left ventricular geometry have a direct impact on wall stress and thus the diastolic performance of the left ventricle. We developed an algorithm based on Fourier transformation of traced endocardial borders from two-dimensional echocardiograms that allowed global shape of the left ventricular to be quantified without assumptions of any ideal left ventricular shape. This method is an adaptation of an algorithm defined for cineventriculograms by Marino and colleagues (Am J Physiol 1988;254:H547-H557). We further described a method to quantify regional endocardial curvature as an index of regional shape. In this preliminary validation study, we primarily tested the reproducibility of these two parameters.

Journal Article↗