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Biomedical subjects

Sarah Nelson

Publications and source records attributed to Sarah Nelson.

At least 19 recordsLinked to original sources
PubMed2006

GATA2 is associated with familial early-onset coronary artery disease.

The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance.

Adult↗
PubMed2006

TE-averaged two-dimensional proton spectroscopic imaging of glutamate at 3 T.

Glutamate and glutamine are important neurochemicals in the central nervous system and the neurotoxic properties of excess glutamate have been associated with several neurodegenerative diseases. The TE-Averaged PRESS technique has been shown by our group to detect an unobstructed glutamate signal at 3 T that is resolved from glutamine and NAA at 2.35 ppm. TE-Averaged PRESS therefore provides an unambiguous measurement of glutamate as well as other metabolites such as NAA, choline, creatine, and myo-inositol. In this study, we extend the single voxel TE-Averaged PRESS technique for two-dimensional (2D) spectroscopic imaging (TE-Averaged MRSI) to generate 2D glutamate maps. To facilitate TE-Averaged MRSI within a reasonable time, a fast encoding trajectory was used. This enabled rapid acquisition of TE-Averaged spectral arrays with good spectral bandwidth (977 Hz) and resolution (approximately 2 Hz). MRSI data arrays of 10 x 16 were acquired with 1.8 cm3 spatial resolution over a approximately 110 cm3 volume in a scan time of approximately 21 min. Two-dimensional metabolite maps were obtained with good SNR and clear differentiation in glutamate levels was observed between gray and white matter with significantly higher glutamate in gray matter relative to white matter as anticipated.

Aspartic Acid↗
PubMed2005

Hedgehog signaling is required for cranial neural crest morphogenesis and chondrogenesis at the midline in the zebrafish skull.

Neural crest cells that form the vertebrate head skeleton migrate and interact with surrounding tissues to shape the skull, and defects in these processes underlie many human craniofacial syndromes. Signals at the midline play a crucial role in the development of the anterior neurocranium, which forms the ventral braincase and palate, and here we explore the role of Hedgehog (Hh) signaling in this process. Using sox10:egfp transgenics to follow neural crest cell movements in the living embryo, and vital dye labeling to generate a fate map, we show that distinct populations of neural crest form the two main cartilage elements of the larval anterior neurocranium: the paired trabeculae and the midline ethmoid. By analyzing zebrafish mutants that disrupt sonic hedgehog (shh) expression, we demonstrate that shh is required to specify the movements of progenitors of these elements at the midline, and to induce them to form cartilage. Treatments with cyclopamine, to block Hh signaling at different stages, suggest that although requirements in morphogenesis occur during neural crest migration beneath the brain, requirements in chondrogenesis occur later, as cells form separate trabecular and ethmoid condensations. Cell transplantations indicate that these also reflect different sources of Shh, one from the ventral neural tube that controls trabecular morphogenesis and one from the oral ectoderm that promotes chondrogenesis. Our results suggest a novel role for Shh in the movements of neural crest cells at the midline, as well as in their differentiation into cartilage, and help to explain why both skeletal fusions and palatal clefting are associated with the loss of Hh signaling in holoprosencephalic humans.

Animals↗
PubMed2005

Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy.

BACKGROUND AND PURPOSE: After radiotherapy (RT), children with diffuse intrinsic pontine gliomas (DIPG) are followed with sequential magnetic resonance imaging (MRI). However, MRI changes do not necessarily reflect tumor progression, and therefore additional noninvasive tools are needed to improve the definition of progression vs. treatment-related changes. In this study, we determined the feasibility and accuracy of multivoxel proton magnetic resonance spectroscopic imaging (1H-MRSI) for monitoring pediatric patients with DIPG. METHODS AND PATIENTS: Twenty-four serial examinations of MRI/MRSI (7 2D-MRSI and 17 3D-MRSI) were performed on 8 patients with DIPG who received local RT. A total of 1635 voxels were categorized as "normal" or "abnormal" based on corresponding imaging findings on contrast-enhanced T1- and T2-weighted MRI. The choline to N-acetyl-aspartate ratio (Cho:NAA) and choline to creatine ratios (Cho:Cr) within each category of MRI abnormality were compared to their counterpart in normal surrounding tissues. The changes in these ratios corresponding to each type of abnormality were evaluated before RT, at response, and at recurrence, as determined by the clinical status of the patients. The presence or absence of lactate and lipid peaks was noted for each voxel. MRI/MRSI was performed on posterior fossa and supratentorial tissue of 3 volunteer pediatric patients. RESULTS: The Cho:NAA and Cho:Cr values within the imaging abnormalities (3.8 +/- 0.93 and 3.55 +/- 1.37, respectively) were significantly higher than the mean values in normal-appearing regions (0.93 +/- 0.2 and 1.13 +/- 0.38, respectively) (p < 0.005). Cho:NAA values decreased from studies at diagnosis to the time of response to RT (3.12 +/- 0.5 and 2.08 +/- 0.73, respectively), followed by an increase at the time of relapse (from 1.83 +/- 0.92 to 4.29 +/- 1.08). Loss of lactate and lipid peaks correlated with response, and their presence and stability with relapse. In 3 patients, increased spectral abnormalities preceded the radiological and clinical deterioration by 2-5 months. CONCLUSION: Multivoxel MRSI is a feasible and reproducible noninvasive tool for assessing pediatric DIPG. Longitudinal multivoxel MRSI measurements have potential value in assessing response to radiation or other therapies, because they offer more coverage than single-voxel techniques and provide reliable spectral data.

Aspartic Acid↗
PubMed2005

Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T.

Histopathological reports of multiple sclerosis and its animal models have shown evidence of a link between axonal injury in active lesions and impaired glutamate metabolism. Mature oligodendrocytes play a role in glutamate uptake to maintain glutamate homeostasis but in multiple sclerosis white matter the loss of expression of glutamate transporters in the lesion vicinity results in ineffective glutamate removal. Using a magnetic resonance spectroscopy technique that isolates the glutamate resonance at 3 T, we compared glutamate levels between normal subjects and multiple sclerosis patients in different brain areas. Metabolite concentrations (glutamate, glutamine, N-acetyl-aspartate, myo-inositol, choline, creatine) were derived from LCmodel and corrected for T1 relaxation time. Glutamate concentrations were found to be elevated in acute lesions (P = 0.02) and normal-appearing white matter (P = 0.03), with no significant elevation in chronic lesions (P = 0.77). The N-acetyl-aspartate level in chronic lesions was significantly lower (P < 0.001) than in acute lesions and normal-appearing white matter. The choline level in acute lesions was significantly higher (P < 0.001) than in chronic lesions. Evidence was also found for increased glial activity in multiple sclerosis, with significantly higher (P < 0.001) myo-inositol levels in acute lesions compared with control white matter. These in vivo results support the hypothesis that altered glutamate metabolism is present in brains of multiple sclerosis patients.

Acute Disease↗
PubMed2005

Prevalence of the group 1 Dermatophagoides allergens Der p 1 and Der f 1 in homes with no dogs, healthy dogs and Dermatophagoides-sensitized atopic dogs in Liverpool.

Dermatophagoides farinae is a frequent allergen in canine atopic dermatitis despite its reported scarcity in the UK, and the aim of this study was to determine whether dogs were uniquely exposed to this species. Der f 1 and Der p 1 in dust collected from living room carpets, bedroom carpets and dog beds of 13 houses with no dogs, 13 with healthy dogs, and 16 with Dermatophagoides-sensitized atopic dogs were quantified by ELISA. Der p 1 levels (microg g(-1) house dust) were significantly higher than Der f 1 in living rooms (Der p 1 median = 1.9, 95% CI = 2.05-6.32, n = 42; Der f 1 median = 0.07, 95% CI = 0.01-0.06, n = 42), bedrooms (Der p 1 median = 4.35, SD = 5.52; Der f 1 median = 0.01, 95% CI = 0.001-0.1, n = 42) and dog beds (Der p 1 median = 1.04, 95% CI = 1.4-8.1, n = 29; Der f 1 median = 0.008, 95% CI = 0.01-0.04, n = 29) (P < 0.0001). Living rooms in houses without dogs had significantly greater Der p 1 levels (median = 7.0, 95% CI = 3.53-15.8, n = 13) than houses with healthy (median = 1.19, 95% CI = 0.44-3.49, n = 13) or atopic dogs (median = 0.78, 95% CI = 0.63-2.42, n = 16) (P = 0.0004). Environmental flea control in living rooms and washing dog beds was associated with significantly reduced Der p 1 levels. This confirms that D. pteronyssinus is common but D. farinae is rare in the sampling area. Apparent sensitization to D. farinae is probably due to cross-reaction. A combination of environmental measures could reduce allergen exposure.

Animals↗
PubMed2005

AP2-dependent signals from the ectoderm regulate craniofacial development in the zebrafish embryo.

AP2 transcription factors regulate many aspects of embryonic development. Studies of AP2a (Tfap2a) function in mice and zebrafish have demonstrated a role in patterning mesenchymal cells of neural crest origin that form the craniofacial skeleton, while the mammalian Tfap2b is required in both the facial skeleton and kidney. Here, we show essential functions for zebrafish tfap2a and tfap2b in development of the facial ectoderm, and for signals from this epithelium that induce skeletogenesis in neural crest cells (NCCs). Zebrafish embryos deficient for both tfap2a and tfap2b show defects in epidermal cell survival and lack NCC-derived cartilages. We show that cartilage defects arise after NCC migration during skeletal differentiation, and that they can be rescued by transplantation of wild-type ectoderm. We propose a model in which AP2 proteins play two distinct roles in cranial NCCs: an early cell-autonomous function in cell specification and survival, and a later non-autonomous function regulating ectodermal signals that induce skeletogenesis.

Animals↗
PubMed2004

Skeletal and pigment cell defects in the lockjaw mutant reveal multiple roles for zebrafish tfap2a in neural crest development.

Members of the AP-2 transcription factor family have critical roles in many aspects of embryonic development. The zebrafish tfap2a mutant lockjaw (low) displays defects in skeletal and pigment cell derivatives of the neural crest. Here we show essential roles for tfap2a in subsets of embryonic cartilages and pigment cells. Defects in cartilage of the hyoid arch in low correlate with a loss of Hox group 2 gene expression and are suggestive of a transformation to a mandibular fate. In contrast, loss of joints in the mandibular arch and defects in certain types of pigment cells suggest a requirement for tfap2a independent of Hox regulation. Early melanophores do not develop in low mutants, and we propose that this results in part from a loss of kit function, leading to defects in migration, as well as kit-independent defects in melanophore specification. Iridophores are also reduced in low, in contrast to xanthophores, revealing a role for tfap2a in the development of pigment subpopulations. We propose a model of tfap2a function in the neural crest in which there are independent functions for tfap2a in specification of subpopulations of pigment cells and segmental patterning of the pharyngeal skeleton through the regulation of Hox genes. Developmental Dynamics 229:87-98, 2004.

Animals↗
PubMed2004

A comparative study of myo-inositol quantification using LCmodel at 1.5 T and 3.0 T with 3 D 1H proton spectroscopic imaging of the human brain.

Myo-inositol is a strongly coupled system and resonates at four chemical shift positions. At 1.5 T, only the singlet component at 3.57 ppm is detected. However, at 3 T this resonance is resolved into its components at 3.55 ppm and 3.61 ppm. Due to the increased spectral resolution and signal-to-noise ratio, it is anticipated that the quantification of myo-inositol should improve at 3 T. Using data from normal controls and the LCmodel quantification procedure, we found that the quantification precision, reproducibility and detection sensitivity of myo-inositol is significantly better at 3 T relative to 1.5 T.

Aspartic Acid↗
PubMed2004

Mice heterozygous for Atp10c, a putative amphipath, represent a novel model of obesity and type 2 diabetes.

Atp10c is a novel type IV P-type ATPase and is a putative phospholipid transporter. The purpose of this study was to assess the overall effect of the heterozygous deletion of Atp10c on obesity-related phenotypes and metabolic abnormalities in mice fed a high-fat diet. Heterozygous mice with maternal inheritance of Atp10c were compared with heterozygous mice with paternal inheritance of Atp10c and wild-type controls. Body weight, adiposity index, and plasma insulin, leptin and triglyceride concentrations were significantly greater in the mutants inheriting the deletion maternally compared with their sex- and age-matched control male mice fed a 10% fat (% energy) diet and female mice fed a 45% fat (% energy) diet. Glucose and insulin tolerance tests were performed after mice consumed the diets for 4 and 8 wk. Mutants had altered glucose tolerance and insulin response compared with controls, suggesting insulin resistance in both sexes. Mice were killed at 12 wk and routine gross and histological evaluations of the liver, pancreas, adipose tissue, and heart were performed. Histological evaluation showed micro- and macrovesicular lipid deposition within the hepatocytes that was more severe in the mutant mice than in age-matched controls. Although sex differences were observed, our data suggest that heterozygous deletion along with an unusual pattern of maternal inheritance of the chromosomal region containing the single gene, Atp10c, causes obesity, type 2 diabetes, and nonalcoholic fatty liver disease in these mice.

Adenosine Triphosphatases↗
PubMed2004

The unique impact of changes in normal appearing brain tissue on cognitive dysfunction in secondary progressive multiple sclerosis patients.

OBJECTIVE: The purpose of this study was to examine the relationships between cognitive functioning, whole brain magnetic transfer ratio (MTR) imaging, supratentorial 1H-magnetic resonance spectroscopy imaging (1HMRSI), and conventional T1 and T2 imaging in a homogenous sample of SPMS patients. METHODS: Nineteen patients underwent a single 90-min imaging session that obtained T1-and T2-weighted images and MTR. 1HMRSI was obtained on 14 of these patients. Patients underwent a neuropsychological battery, which was used to create an integrated measure of cognitive impairment. Cognitive impairment was the dependent variable in two hierarchical multiple regression analyses in which T2 lesion load, T1 lesion load, and MTR or NAA/Cr were entered sequentially. RESULTS: MTR was significantly related to cognitive functioning (deltaR2 = 0.22, P = 0.02) after accounting for T2 lesion load (deltaR2 = 0.33, P = 0.01) and T1 lesion load (deltaR2 = 0.00, P = 0.98). NAA/Cr was not significantly related to cognitive functioning. CONCLUSIONS: Cognitive dysfunction may act as a clinical marker of normal appearing brain tissue pathology in multiple sclerosis.

Adult↗
PubMed2003

Brain lesion volume and neuropsychological function predict efficacy of treatment for depression in multiple sclerosis.

This study examined the effects of brain lesions and neuropsychological impairment on the efficacy of treatment for depression in patients with comorbid diagnoses of multiple sclerosis (MS) and major depressive disorder (MDD). Thirty patients meeting criteria for MS and MDD received 1 of 3 16-week treatments for depression and were followed for 6 months following treatment cessation. T2-weighted magnetic resonance imaging and neuropsychological evaluations were also obtained. End-of-treatment Beck Depression Inventory (BDI; A. T. Beck, C. H. Ward, M. Mendelson, J. Mock, & J. Erbaugh, 1961) results residualized for baseline BDI were related to right temporal periventricular lesion volume (R2=.32, p=.002) and left temporal grey-white junction lesion volume (R2=.19, p=.02) but were not statistically related to lesion volume in any other brain region or to neuropsychological function. BDI results at 6-month follow-up, residualized for end-of-treatment BDI, were predicted by total lesion volume (R2=.22, p=.005), lesion volume in many discrete areas, and neuropsychological functioning (R2=.29, p=.0009). The effect of total lesion volume on 6-month follow-up BDI results was fully mediated by neuropsychological function.

Adult↗
PubMed2003

Aging and repetition effects: separate specific and nonspecific influences.

The research reported in this article focuses on processes that contribute to the repetition effect in 2-alternative forced-choice tasks and on how these processes change with age. An analytical approach is presented that allows researchers to discriminate between 2 components of performance. The results of Experiment 1 show that differences in the relative contributions of these 2 processes can produce differences in repetition effects between younger and older adults. Furthermore, as in the negative priming domain, increasing the contribution of 1 of these 2 components can eliminate this age difference. Together, the results argue against the practice of attributing age differences in repetition effects to deficits in any single cognitive process.

Adolescent↗
PubMed2003

Standardized, reproducible, high resolution global measurements of T1 relaxation metrics in cases of multiple sclerosis.

BACKGROUND AND PURPOSE: We herein present a methodology for standardized and clinically applicable measurement of T1 relaxation maps with high resolution and volumetric coverage by using the commercially available 3D spoiled gradient-echo sequence. The reproducibility of the T1 metrics derived from these maps and their sensitivity to distinguish between control participants and patients with multiple sclerosis are evaluated. METHODS: Axial view 3D RF spoiled data sets with two flip angles were acquired at 1.5 T to generate the T1 maps, with all other imaging parameters (27/6 ms [TR/TE]; field of view, 180 x 240 x 186 mm(3); matrix, 192 x 256 x 124) kept identical between the two acquisitions. T1 maps were collected from 20 normal control participants and 32 patients with multiple sclerosis. An automated and operator-independent method was developed to segment the relaxation maps and define T1 metrics. RESULTS: We showed that the metrics derived from these maps to represent tissue characteristics were highly reproducible (coefficient of variation, approximately 1% to 4%) and were significantly different between normal control participants and patients with multiple sclerosis (P <.001) for the small cohort of patients in this study. CONCLUSION: The commercially accessible 3D spoiled gradient-echo sequence can be used to generate T1 relaxation maps with high resolution and volumetric coverage. The metrics derived from the relaxation maps are reproducible and have been shown to be sensitive to qualitative and quantitative differences between subgroups of patients with multiple sclerosis and control participants, with strong statistical significance. The use of a commercially available sequence enables the standardization and comparison of T1 metrics across different multiple sclerosis centers.

Artifacts↗
PubMed2002

Dissociating perceptual and conceptual implicit memory in multiple sclerosis patients.

Previous studies indicate that Multiple Sclerosis (MS) patients exhibit deficits in tests of explicit memory such as free recall, but show normal priming on implicit tests of memory such as word stem completion. However, the memory performance of patients with different MS disease subtypes has not been fully examined. In the current study, memory was assessed in Primary Progressive (PPMS), Relapsing Remitting (RRMS), and Secondary Progressive (SPMS) MS subgroups. Explicit memory as well as perceptual and conceptual implicit memory were examined using free recall, word fragment completion, and exemplar generation tests, respectively. All three groups of MS patients exhibited free recall deficits and normal priming on the exemplar generation test. However, the PPMS group exhibited a deficit in word fragment completion priming, whereas the RRMS and SPMS groups exhibited normal levels of priming on this task. Lesion load was assessed using magnetic resonance imaging and was negatively correlated with explicit memory performance, but it did not account for the observed deficits in perceptual implicit memory. The results indicate that PPMS patients exhibit a pattern of memory impairment that is distinct from that of the RRMS and SPMS groups. Moreover, the results indicate that perceptual implicit memory can be neurologically dissociated from conceptual implicit memory.

Adult↗
PubMed2002

Preventing early adolescent substance use: a family-centered strategy for the public middle school.

The Adolescent Transitions Program (ATP) promotes student adjustment and reduces risk within a public school setting, focusing primarily on parenting practices using a tiered, multilevel prevention strategy. A description is given of the program, levels of engagement, and intervention effects. Within each school, multiethnic students (N = 672) and their families were randomly assigned at the individual level to a control condition or the ATP intervention. Analyses focus on the longitudinal effects of the ATP intervention on self-reported substance use through middle school and the 1st year of high school (Grades 6, 7, 8, and 9). Levels of engagement in the selected and indicated interventions were somewhat less than expected. Despite relatively low levels of engagement, the intervention reduced initiation of substance use in both at-risk and typically developing students. These findings are discussed with respect to lessons learned about parent engagement, optimizing strategies for schoolwide implementation, and the promise of embedding family interventions within the public school ecology.

Adolescent↗