Biomedical subjects

Stephen M Smith

Publications and source records attributed to Stephen M Smith.

At least 19 recordsLinked to original sources

PubMed2007

Manifestations of early brain recovery associated with abstinence from alcoholism.

Chronic alcohol abuse results in morphological, metabolic, and functional brain damage which may, to some extent, be reversible with early effects upon abstinence. Although morphometric, spectroscopic, and neuropsychological indicators of cerebral regeneration have been described previously, the overall amount and spatial preference of early brain recovery attained by abstinence and its associations with other indicators of regeneration are not well established. We investigated global and local brain volume changes in a longitudinal two-timepoint study with T1-weighted MRI at admission and after short-term (6-7 weeks) sobriety follow-up in 15 uncomplicated, recently detoxified alcoholics. Volumetric brain gain was related to metabolic and neuropsychological recovery. On admission and after short-term abstinence, structural image evaluation using normalization of atrophy (SIENA), its voxelwise statistical extension to multiple subjects, proton MR spectroscopy (1H-MRS), and neuropsychological tests were applied. Upon short-term sobriety, 1H-MRS levels of cerebellar choline and frontomesial N-acetylaspartate (NAA) were significantly augmented. Automatically detected global brain volume gain amounted to nearly two per cent on average and was spatially significant around the superior vermis, perimesencephalic, periventricular and frontal brain edges. It correlated positively with the percentages of cerebellar and frontomesial choline increase, as detected by 1H-MRS. Moreover, frontomesial NAA gains were associated with improved performance on the d2-test of attention. In 10 age- and gender-matched healthy control subjects, no significant brain volume or metabolite changes were observed. Although cerebral osmotic regulations may occur initially upon sobriety, significant increases of cerebellar choline and frontomesial NAA levels detected at stable brain water integrals and creatine concentrations, serum electrolytes and red blood cell indices in our patient sample suggest that early brain recovery through abstinence does not simply reflect rehydration. Instead, even the adult human brain and particularly its white matter seems to possess genuine capabilities for regrowth. Our findings emphasize metabolic as well as regionally distinct morphological capacities for partial brain recovery from toxic insults of chronic alcoholism and substantiate early measurable benefits of therapeutic sobriety. Further understanding of the precise mechanisms of this recovery may become a valuable model of brain regeneration with relevance for other disorders.

Adult↗

PubMed2007

N-acetylcysteine for patients with prolonged hypotension as prophylaxis for acute renal failure (NEPHRON).

BACKGROUND: Acute renal failure is a common complication in critically ill patients and carries an increased morbidity and mortality. N-acetylcysteine is an antioxidant and anti-inflammatory agent that may counteract some of the pathophysiologic derangements in shock states. OBJECTIVE: To test whether the administration of N-acetylcysteine, compared with placebo, reduces the incidence of acute renal failure in hypotensive patients. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study. SETTING: Intensive care units of a university tertiary care hospital. PATIENTS: One hundred forty-two patients with new onset (within 12 hrs) of at least>or=30 consecutive minutes of hypotension and/or vasopressor requirement. INTERVENTIONS: Patients were randomized to receive either N-acetylcysteine or placebo for 7 days, in addition to standard supportive therapy. MEASUREMENTS AND MAIN RESULTS: Patients who received N-acetylcysteine had an incidence of acute renal failure (>or=0.5 mg/dL increase in creatinine) of 15.5%, compared with 16.9% in those receiving placebo (p=.82, not significant). There were no significant differences between treatment arms in any of the secondary outcomes examined, including incidence of a 50% increase in creatinine, maximal rise in creatinine, recovery of renal function, length of intensive care unit and hospital stay, requirement for renal replacement therapy, and mortality. Among patients receiving N-acetylcysteine, there were trends toward reduced incidence of acute renal failure in patients with baseline Sequential Organ Failure Assessment (SOFA) score>8 (p=.12), lower SOFA scores during the first 4 days of treatment (p=.28), and reduced mortality in patients<65 yrs of age (p=.20). CONCLUSIONS: There were no significant differences in any of our primary or secondary end points between patients treated with N-acetylcysteine or placebo. Trends toward reduced incidence of acute renal failure in patients with baseline SOFA score >8, reduced SOFA scores during the first 4 days, and reduced mortality in patients<65 yrs of age are provocative but require further study to determine their clinical significance.

Acetylcysteine↗

PubMed2006

Characterization of the particulate methane monooxygenase metal centers in multiple redox states by X-ray absorption spectroscopy.

The integral membrane enzyme particulate methane monooxygenase (pMMO) converts methane, the most inert hydrocarbon, to methanol under ambient conditions. The 2.8-A resolution pMMO crystal structure revealed three metal sites: a mononuclear copper center, a dinuclear copper center, and a nonphysiological mononuclear zinc center. Although not found in the crystal structure, solution samples of pMMO also contain iron. We have used X-ray absorption spectroscopy to analyze the oxidation states and coordination environments of the pMMO metal centers in as-isolated (pMMO(iso)), chemically reduced (pMMO(red)), and chemically oxidized (pMMO(ox)) samples. X-ray absorption near-edge spectra (XANES) indicate that pMMO(iso) contains both Cu(I) and Cu(II) and that the pMMO Cu centers can undergo redox chemistry. Extended X-ray absorption fine structure (EXAFS) analysis reveals a Cu-Cu interaction in all redox forms of the enzyme. The Cu-Cu distance increases from 2.51 to 2.65 A upon reduction, concomitant with an increase in the average Cu-O/N bond lengths. Appropriate Cu2 model complexes were used to refine and validate the EXAFS fitting protocols for pMMO(iso). Analysis of Fe EXAFS data combined with electron paramagnetic resonance (EPR) spectra indicates that Fe, present as Fe(III), is consistent with heme impurities. These findings are complementary to the crystallographic data and provide new insight into the oxidation states and possible electronic structures of the pMMO Cu ions.

Copper↗

PubMed2006

The pathogenesis of HIV infection: stupid may not be so dumb after all.

In the mid-1990's, researchers hypothesized, based on new viral load data, that HIV-1 causes CD4+ T-cell depletion by direct cytopathic effect. New data from non-human primate studies has raised doubts about this model of HIV-1 pathogenesis. Despite having high levels of viremia, most SIV infections are well tolerated by their natural hosts. Two recent studies of these models provide information, which may be useful in determining how HIV-1 causes CD4+ T-cell loss. A full understanding of pathogenesis may lead to novel therapies, which preserve the immune system without blocking virus replication.

Animals↗

PubMed2006

Vasopressin inhibits glutamate release via two distinct modes in the brainstem.

The hypothalamus coordinates autonomic responses in part through arginine vasopressin (AVP) released in medial nucleus tractus solitarius (NTS). However, the mechanisms and sites of AVP action within NTS pathways are uncertain. In brainstem slices, we activated solitary tract (ST) primary afferents to release glutamate and tested whether AVP modulated synaptic transmission to second-order neurons. NTS neurons were classified as second order by ST synaptic characteristics or the presence of anterograde tracers from peripheral baroreceptor afferents. Stimulus recruitment curves indicated ST-EPSCs on individual neurons were evoked by stimulation of single ST axons. Variance-mean (V-M) analysis of ST-EPSCs in individual neurons revealed uniformly high release probability (p approximately 0.9) from an average of 19 release sites (N) and a quantal size (q) of 34.0 +/- 4.7 pA. In 26 of 49 neurons, AVP inhibited afferent synaptic transmission. In most neurons, AVP reduced ST-EPSC amplitudes (n = 20) by decreasing p to 0.65, whereas q, N, and conduction times were unaffected. The V1a antagonist SR49059 alone decreased ST-EPSC V and increased M, suggesting tonic AVP actions, and blocked exogenous AVP action (n = 4). In other neurons with identical ST release properties, AVP induced synaptic failures and increased conduction time without altering the V-M relationship of successful ST-EPSCs (n = 6). Interestingly, frequency-depressed ST-EPSCs were not affected by AVP. AVP failed to alter holding or voltage-dependent potassium currents. Thus, AVP regulates NTS neurons by two distinct novel and state-dependent mechanisms: one, an analog, graded presynaptic inhibition of terminal glutamate release and the other, a binary, extraterminal block of conducted excitation.

Animals↗

PubMed2006

Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data.

There has been much recent interest in using magnetic resonance diffusion imaging to provide information about anatomical connectivity in the brain, by measuring the anisotropic diffusion of water in white matter tracts. One of the measures most commonly derived from diffusion data is fractional anisotropy (FA), which quantifies how strongly directional the local tract structure is. Many imaging studies are starting to use FA images in voxelwise statistical analyses, in order to localise brain changes related to development, degeneration and disease. However, optimal analysis is compromised by the use of standard registration algorithms; there has not to date been a satisfactory solution to the question of how to align FA images from multiple subjects in a way that allows for valid conclusions to be drawn from the subsequent voxelwise analysis. Furthermore, the arbitrariness of the choice of spatial smoothing extent has not yet been resolved. In this paper, we present a new method that aims to solve these issues via (a) carefully tuned non-linear registration, followed by (b) projection onto an alignment-invariant tract representation (the "mean FA skeleton"). We refer to this new approach as Tract-Based Spatial Statistics (TBSS). TBSS aims to improve the sensitivity, objectivity and interpretability of analysis of multi-subject diffusion imaging studies. We describe TBSS in detail and present example TBSS results from several diffusion imaging studies.

Amyotrophic Lateral Sclerosis↗

PubMed2006

A peptide-loaded dendritic cell based cytotoxic T-lymphocyte (CTL) vaccination strategy using peptides that span SIV Tat, Rev, and Env overlapping reading frames.

CTL based vaccine strategies in the macaque model of AIDS have shown promise in slowing the progression to disease. However, rapid CTL escape viruses can emerge rendering such vaccination useless. We hypothesized that such escape is made more difficult if the immunizing CTL epitope falls within a region of the virus that has a high density of overlapping reading frames which encode several viral proteins. To test this hypothesis, we immunized macaques using a peptide-loaded dendritic cell approach employing epitopes in the second coding exon of SIV Tat which spans reading frames for both Env and Rev. We report here that autologous dendritic cells, loaded with SIV peptides from Tat, Rev, and Env, induced a distinct cellular immune response measurable ex vivo. However, conclusive in vivo control of a challenge inoculation of SIVmac239 was not observed suggesting that CTL epitopes within densely overlapping reading frames are also subject to escape mutations.

Animals↗

PubMed2006

Applying FSL to the FIAC data: model-based and model-free analysis of voice and sentence repetition priming.

This article presents results obtained from applying various tools from FSL (FMRIB Software Library) to data from the repetition priming experiment used for the HBM'05 Functional Image Analysis Contest. We present analyses from the model-based General Linear Model (GLM) tool (FEAT) and from the model-free independent component analysis tool (MELODIC). We also discuss the application of tools for the correction of image distortions prior to the statistical analysis and the utility of recent advances in functional magnetic resonance imaging (FMRI) time series modeling and inference such as the use of optimal constrained HRF basis function modeling and mixture modeling inference. The combination of hemodynamic response function (HRF) and mixture modeling, in particular, revealed that both sentence content and speaker voice priming effects occurred bilaterally along the length of the superior temporal sulcus (STS). These results suggest that both are processed in a single underlying system without any significant asymmetries for content vs. voice processing.

Brain Mapping↗

PubMed2006

High-resolution FMRI at 1.5T using balanced SSFP.

The resolution in conventional BOLD FMRI is considerably lower than can be achieved with other MRI methods, and is insufficient for many important applications. One major difficulty in robustly improving spatial resolution is the poor image quality in BOLD FMRI, which suffers from distortions, blurring, and signal dropout. This work considers the potential for increased resolution with a new FMRI method based on balanced SSFP. This method establishes a blood oxygenation sensitive steady-state (BOSS) signal, in which the frequency sensitivity of balanced SSFP is used to detect the frequency shift of deoxyhemoglobin. BOSS FMRI is highly SNR efficient and does not suffer from image distortions or signal dropout, making this method an excellent candidate for high-resolution FMRI. This study presents the first demonstration of high-resolution BOSS FMRI, using an efficient 3D stack-of-segmented EPI readout and combined acquisition at multiple center frequencies. BOSS FMRI is shown to enable high-resolution FMRI data (1 x 1 x 2 mm(3)) in both visual and motor systems using standard hardware at 1.5 T. Currently, the major limitation of BOSS FMRI is its sensitivity to temporal and spatial field drift.

Brain Mapping↗

PubMed2005

Valproic acid and HIV-1 latency: beyond the sound bite.

A recent publication in Lancet by Dr. David Margolis and colleagues raised the prospect that HIV infection may be curable. In this pilot study, which received much attention from the press, Dr. Margolis'group found that valproic acid plus enfuvirtide reduces the pool of CD4+ T-cells, which are latently infected with HIV-1, the so-called viral reservoir. This commentary critically addresses current data on this topic.

CD4-Positive T-Lymphocytes↗

PubMed2005

HIV vaccine development.

For the past two decades, scientists have aggressively pursued the development of a vaccine against human immunodeficiency virus (HIV). The magnitude of this effort is unprecedented in the history of infectious diseases. However, difficulties in finding promising candidate vaccines have limited the number of clinical efficacy trials. The macaque model is well suited for the evaluation of potential vaccines, but comparison of results among studies is often complicated by the use of different macaque species and/or challenge viruses. This review discusses current results obtained in the macaque model and human vaccine trials.

AIDS Vaccines↗

PubMed2005

Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study.

BACKGROUND: Converging evidence from several theories of the development of incentive-sensitization to smoking-related environmental stimuli suggests that the ventral striatum plays an important role in the processing of smoking-related cue reactivity. METHODS: Twenty-six healthy right-handed volunteers (14 smokers and 12 nonsmoking controls) underwent functional magnetic resonance imaging (fMRI) during which neutral and smoking-related images were presented. Region of interest analyses were performed within the ventral striatum/nucleus accumbens (VS/NAc) for the contrast between smoking-related (SR) and nonsmoking related neutral (N) cues. RESULTS: Group activation for SR versus N cues was observed in smokers but not in nonsmokers in medial orbitofrontal cortex, superior frontal gyrus, anterior cingulate cortex, and posterior fusiform gyrus using whole-brain corrected Z thresholds and in the ventral VS/NAc using uncorrected Z-statistics (smokers Z = 3.2). Region of interest analysis of signal change within ventral VS/NAc demonstrated significantly greater activation to SR versus N cues in smokers than controls. CONCLUSIONS: This is the first demonstration of greater VS/NAc activation in addicted smokers than nonsmokers presented with smoking-related cues using fMRI. Smokers, but not controls, demonstrated activation to SR versus N cues in a distributed reward signaling network consistent with cue reactivity studies of other drugs of abuse.

Adult↗

PubMed2005

Prevalence of GB virus type C in urban Americans infected with human immunodeficiency virus type 1.

GBV-C virus infection has been linked to improved clinical outcome in HIV-1 co-infected individuals. The epidemiology of GBV-C has, thus far, been limited to the gay male, HIV+ population. Here we describe the prevalence of antibodies against GBV-C envelope glycoprotein E2 and GBV-C viremia in an HIV+ inner city population. This study group is predominantly African-American; 41% of the participants are women. The major risk factor for HIV infection is intravenous drug use. Overall, 56% of the study population had evidence of current or past infection with GBV-C. GBV-C exposure was not associated with hepatitis C virus infection. The group of participants, who had GBV-C viremia and anti-E2 antibodies, had high percentage of patients with an undetectable HIV-1 viral load. These data provide increased insight into the prevalence of GBV-C co-infection in the HIV epidemic in this understudied population.

Female↗

PubMed2005

Investigations into resting-state connectivity using independent component analysis.

Inferring resting-state connectivity patterns from functional magnetic resonance imaging (fMRI) data is a challenging task for any analytical technique. In this paper, we review a probabilistic independent component analysis (PICA) approach, optimized for the analysis of fMRI data, and discuss the role which this exploratory technique can take in scientific investigations into the structure of these effects. We apply PICA to fMRI data acquired at rest, in order to characterize the spatio-temporal structure of such data, and demonstrate that this is an effective and robust tool for the identification of low-frequency resting-state patterns from data acquired at various different spatial and temporal resolutions. We show that these networks exhibit high spatial consistency across subjects and closely resemble discrete cortical functional networks such as visual cortical areas or sensory-motor cortex.

Brain↗

PubMed2005

New York City HIV superbug: fear or fear not?

On February 11, 2005, the New York City Department of Health and Mental Hygiene announced that a city resident had recently been infected with a multi-drug resistant form of HIV and rapidly progressed to AIDS. The Health Commissioner, Thomas R. Frieden, called for increased vigilance against this new strain. Is this situation an emerging crisis or simply an unusual case report of rapid HIV progression?

Acquired Immunodeficiency Syndrome↗

PubMed2005

Variability in fMRI: a re-examination of inter-session differences.

We revisit a previous study on inter-session variability (McGonigle et al. [2000]: Neuroimage 11:708-734), showing that contrary to one popular interpretation of the original article, inter-session variability is not necessarily high. We also highlight how evaluating variability based on thresholded single-session images alone can be misleading. Finally, we show that the use of different first-level preprocessing, time-series statistics, and registration analysis methodologies can give significantly different inter-session analysis results.

Adult↗

PubMed2005

Mixture models with adaptive spatial regularization for segmentation with an application to FMRI data.

Mixture models are often used in the statistical segmentation of medical images. For example, they can be used for the segmentation of structural images into different matter types or of functional statistical parametric maps (SPMs) into activations and nonactivations. Nonspatial mixture models segment using models of just the histogram of intensity values. Spatial mixture models have also been developed which augment this histogram information with spatial regularization using Markov random fields. However, these techniques have control parameters, such as the strength of spatial regularization, which need to be tuned heuristically to particular datasets. We present a novel spatial mixture model within a fully Bayesian framework with the ability to perform fully adaptive spatial regularization using Markov random fields. This means that the amount of spatial regularization does not have to be tuned heuristically but is adaptively determined from the data. We examine the behavior of this model when applied to artificial data with different spatial characteristics, and to functional magnetic resonance imaging SPMs.

Algorithms↗

PubMed2004

Topical estrogen protects against SIV vaginal transmission without evidence of systemic effect.

BACKGROUND: Accumulating data suggest that the state of the vaginal epithelium affects a woman's risk of HIV vaginal transmission and several human and non-human primate studies have shown that the rate of HIV or SIV vaginal transmission is decreased when estrogen is dominant. Systemic estrogen can protect against SIV vaginal transmission. OBJECTIVE: To determine the safety and efficacy of topical estrogen in preventing SIV vaginal transmission. DESIGN: The non-human primate model of HIV vaginal transmission was used to assess vaginal estriol cream in ovariectomized macaques. METHODS: Twelve macaques were treated intravaginally with estriol and eight with placebo cream twice a week. The vaginal and systemic effects of estriol were determined by colposcopy and serum luteinizing hormone, levels of which would decline in the presence of systemic estrogen. After 5 weeks of therapy, the animals were challenged vaginally with pathogenic SIVmac251. RESULTS: Vaginal estriol resulted in minimal serum estriol levels and had no effect on serum luteinizing hormone levels. Vaginal epithelia cornified and thickened significantly in response to estriol therapy. One of the estriol-treated animals became infected after this single challenge, while six of the control animals became infected (P = 0.0044). CONCLUSIONS: These data demonstrate that topical vaginal estriol can strongly protect against SIV vaginal transmission, while having no detectable systemic effect. These results support the study of topical vaginal estriol in preventing HIV vaginal transmission in at-risk women.

Administration, Topical↗