Biomedical subjects

S M Resnick

Publications and source records attributed to S M Resnick.

At least 19 recordsLinked to original sources

PubMed2001

Accuracy and sensitivity of detection of activation foci in the brain via statistical parametric mapping: a study using a PET simulator.

Statistical parametric mapping (SPM) is currently the most widely used method for analysis of functional activation images. This paper reports a quantitative evaluation of the sensitivity and accuracy of SPM, using a realistic simulator of PET image formation, which accounted for the main physical processes involved in PET, including attenuation, scatter, randoms, Poisson noise, and limited detector resolution. Activation foci of the brain were simulated by placing spheres of specified activities in particular locations. Using these data, the sensitivity and accuracy of SPM in detecting activation foci was measured for different versions of the SPM spatial normalization method and for an elastic warping method referred to as STAR (spatial transformation algorithm for registration). The STAR method resulted in relatively better registration and hence better detection of the activation foci. A secondary goal of the paper was to evaluate the improvement in detection sensitivity obtained by applying an atlas-based adaptive smoothing method instead of the usual Gaussian filtering method. The results indicate some limitations of statistical parametric mapping, assist in the correct interpretation of the SPM maps, and point to future research directions in functional image analysis.

Adolescent↗

PubMed2001

Effects of estrogen on patterns of brain activity at rest and during cognitive activity: a review of neuroimaging studies.

Animal and human studies provide evidence of systematic effects of estrogen on cerebral activity and cognitive function. In this article, we review studies of the activational effects of estrogen on cerebral activity during rest and during the performance of cognitive tasks in pre- and postmenopausal women. The goal is twofold--to better understand evidence suggesting that estrogen influences brain functioning and argue for the importance of considering hormone effects when designing neuroimaging studies. Hormone-related increases in blood flow during the resting state have been documented in healthy elderly women, elderly women with cerebrovascular disease, and middle-aged postmenopausal women with early menopause. There is no reliable influence of estrogen on blood flow during the resting state in women with Alzheimer's disease. Hormone therapy has been associated with changes in brain activation patterns in middle-aged and elderly postmenopausal women during performance of verbal and figural memory tasks, providing critical biological support for the view that estrogen might protect against age-associated changes in cognition and lower the risk of Alzheimer's disease. There is a paucity of studies examining changes in brain activation patterns across the menstrual cycle and a need for randomized studies of hormone therapy in postmenopausal women to confirm findings from observational studies. General procedural guidelines for controlling and investigating hormone effects in neuroimaging studies are discussed.

Aged↗

PubMed2001

Voxel-based morphometry using the RAVENS maps: methods and validation using simulated longitudinal atrophy.

Statistical analysis of anatomical maps in a stereotaxic space has been shown to be a useful tool in population-based studies for quantifying local anatomical differences or changes, without a priori assumptions about the location and extent of the regions of interest. This paper presents an extension and validation of a previously published methodology, referred to as RAVENS, for characterizing regional atrophy in the brain. A new method for elastic, volume-preserving spatial normalization, which allows for accurate quantification of very localized atrophy, is used. The RAVENS methodology was tested on images with simulated atrophy within two gyri: precentral and superior temporal. It was found to accurately determine the regions of atrophy, despite their localized nature and the interindividual variability of cortical structures. Moreover, it was found to perform substantially better than the voxel-based morphology method of SPM'99. Improved sensitivity was achieved at the expense of human effort involved in defining a number of sulcal curves that serve as constraints on the 3D elastic warping.

Atrophy↗

PubMed2001

Growth of the purple bacterium Rhodobacter capsulatus on the aromatic compound hippurate.

The purple nonsulfur bacterium Rhodobacter capsulatus strain B10 grew phototrophically on the aromatic compound hippurate (N-benzoyl-L-glycine) and related benzoyl amino acids. Absorption spectra, extraction, and GC/MS analysis of culture supernatants showed that hippurate was stoichiometrically converted to benzoate and glycine, with the latter used as a carbon or nitrogen source for growth. This conclusion was supported by detection of the enzyme hippuricase in permeabilized intact cells. Chemotrophic growth on hippurate by Rba. capsulatus, either at full or reduced oxygen tensions, was not observed. The type strain of Rhodobacter sphaeroides as well as four strains of Rhodopseudomonas palustris also grew phototrophically on hippurate, while several other aromatic-degrading species of purple bacteria did not.

Benzoates↗

PubMed2001

Effects of hormone replacement therapy on cognitive and brain aging.

Recent reports suggest that hormone therapy may be associated with a reduced risk for Alzheimer's disease and may offer some protection against age-associated declines in specific cognitive functions. The majority of these reports are based on observational studies, which are confounded by the "healthy user" bias--the tendency for women receiving hormone therapy to be younger, better educated, and have fewer medical problems. In one attempt to address these limitations, we conducted a series of studies examining effects of hormone therapy on cognitive and brain functioning in nondemented postmenopausal women in the Baltimore Longitudinal Study of Aging (BLSA). In this sample, women receiving hormone therapy and women who never received hormone therapy were comparable with respect to educational attainment, general medical health, and performance on a test of verbal knowledge. Despite these similarities, women receiving hormone therapy performed better on tests of verbal and visual memory compared to never-treated women. The two groups also differed in the patterns of regional brain activation evoked during performance of delayed verbal and figural memory tasks. Furthermore, longitudinal comparisons revealed greater relative blood flow increases over two years in women receiving hormone therapy for the hippocampus and other mesial temporal lobe structures that subserve memory. These observational findings from our studies in the BLSA have led to the development of a large-scale randomized clinical trial of hormone therapy and cognitive aging, the ancillary Women's Health Initiative Study of Cognitive Aging (WHISCA), and have important implications for studies of the effects of SERM's on cognitive and brain functioning.

Aging↗

PubMed2001

Enhanced verbal memory in nondemented elderly women receiving hormone-replacement therapy.

OBJECTIVE: This study examined the effects of hormone-replacement therapy on memory and other cognitive abilities in cognitively intact older women. METHOD: This prospective observational study in nondemented postmenopausal women aged 50-89 from the Baltimore Longitudinal Study of Aging involved study groups consisting of 103 women who were receiving oral or transdermal estrogen-replacement therapy (44 of whom were receiving adjuvant progesterone) and 81 women who had never received such therapy. Groups were naturally matched on education, health status, depressive symptoms, annual income, and general verbal ability. To restrict the study group to cognitively healthy women, prospective clinical data were used to exclude women who developed dementia up to 5 years after assessment. Data were cross-sectional. Multivariate analysis of variance and follow-up univariate analyses of variance were performed to compare those women who were receiving and those who had never received hormone-replacement therapy on measures of verbal memory, figural memory, mental rotations, attention, and working memory. RESULTS: The women receiving hormone-replacement therapy performed significantly better on measures of verbal learning and memory than did those who had never received hormones, but there were no significant differences in scores on other cognitive tests. Specific aspects of memory performance, including encoding and retrieval, were superior among the women receiving hormone therapy. CONCLUSIONS: These findings, based on groups of women who were receiving and had never received hormone-replacement therapy and who were naturally matched on health and cognitive status, suggest that hormone-replacement therapy may have a selective beneficial effect on verbal memory in older nondemented women.

Aged↗

PubMed2000

The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men.

BACKGROUND: The observation that dehydroepiandrosterone (DHEA) concentrations decrease markedly with age has led to the hypothesis that declining DHEA concentrations may contribute to age-related changes in cognition. In the United States, DHEA is widely available as an over-the-counter supplement that individuals are using in an effort to ameliorate age-related cognitive and physical changes. OBJECTIVE: To investigate the relationship between age-associated decreases in endogenous DHEA sulfate (DHEA-S) concentrations and declines in neuropsychological performance in a prospective, longitudinal study. METHODS: The subjects were 883 men from a community-dwelling volunteer sample in the Baltimore Longitudinal Study of Aging. The men were aged 22 to 91 years at the initial visit, and they were followed up for as long as 31 years (mean, 11. 55 years), with biennial reassessments of multiple cognitive domains and contemporaneous measurement of serum DHEA-S concentrations. Outcome measures were the results of cognitive tests of verbal and visual memory, 2 tests of mental status, phonemic and semantic word fluency tests, and measures of visuomotor scanning and attention. Serum DHEA-S concentrations were determined by standard radioimmunoassay. RESULTS: Neither the rates of decline in mean DHEA-S concentrations nor the mean DHEA-S concentrations within individuals were related to cognitive status or cognitive decline. A comparison between the highest and lowest DHEA-S quartiles revealed no cognitive differences, despite the fact that these groups differed in endogenous DHEA-S concentration by more than a factor of 4 for a mean duration of 12 years. CONCLUSION: Our longitudinal results augment those of previous prospective studies by suggesting that the decline in endogenous DHEA-S concentration is independent of cognitive status and cognitive decline in healthy aging men.

Adult↗

PubMed2000

Longitudinal change in hippocampal volume as a function of apolipoprotein E genotype.

The epsilon4 allele of the apolipoprotein E (APOE) gene confers an increased risk for the development of AD. The authors compared longitudinal rates of change in hippocampal volume as a function of APOE genotype in nondemented elderly individuals. Rate of volumetric loss was significantly greater among epsilon4+ compared with epsilon4- individuals. These results indicate that individuals positive for the APOE epsilon4 allele may show a greater rate of hippocampal atrophy than their epsilon4- counterparts, even in the absence of a diagnosis of AD.

Age Factors↗

PubMed2000

One-year age changes in MRI brain volumes in older adults.

Longitudinal studies indicate that declines in cognition and memory accelerate after age 70 years. The neuroanatomic and neurophysiologic underpinnings of cognitive change are unclear, as there is little information on longitudinal brain changes. We are conducting a longitudinal neuroimaging study of nondemented older participants in the Baltimore Longitudinal Study of Aging. This report focuses on age and sex differences in brain structure measured by magnetic resonance imaging during the first two annual evaluations. Cross-sectional results from 116 participants aged 59-85 years reveal significantly larger ventricular volumes and smaller gray and white matter volumes in older compared with younger participants and in men compared with women. Regional brain volumes show that the effects of age and sex are not uniform across brain regions. Age differences are greatest for the parietal region. Sex differences tend to be larger for frontal and temporal than parietal and occipital regions. Longitudinal analysis demonstrates an increase of 1526 mm(3) in ventricular volume over 1 year, but no detectable change in total or regional brain volumes. Definition of the pattern and rate of longitudinal brain changes will facilitate the detection of pathological brain changes, which may be predictors of dementia.

Age Factors↗

PubMed2000

In vitro ATP regeneration from polyphosphate and AMP by polyphosphate:AMP phosphotransferase and adenylate kinase from Acinetobacter johnsonii 210A.

In vitro enzyme-based ATP regeneration systems are important for improving yields of ATP-dependent enzymatic reactions for preparative organic synthesis and biocatalysis. Several enzymatic ATP regeneration systems have been described but have some disadvantages. We report here on the use of polyphosphate:AMP phosphotransferase (PPT) from Acinetobacter johnsonii strain 210A in an ATP regeneration system based on the use of polyphosphate (polyP) and AMP as substrates. We have examined the substrate specificity of PPT and demonstrated ATP regeneration from AMP and polyP using firefly luciferase and hexokinase as model ATP-requiring enzymes. PPT catalyzes the reaction polyP(n) + AMP --> ADP + polyP(n-1). The ADP can be converted to ATP by adenylate kinase (AdK). Substrate specificity with nucleoside and 2'-deoxynucleoside monophosphates was examined using partially purified PPT by measuring the formation of nucleoside diphosphates with high-pressure liquid chromatography. AMP and 2'-dAMP were efficiently phosphorylated to ADP and 2'-dADP, respectively. GMP, UMP, CMP, and IMP were not converted to the corresponding diphosphates at significant rates. Sufficient AdK and PPT activity in A. johnsonii 210A cell extract allowed demonstration of polyP-dependent ATP regeneration using a firefly luciferase-based ATP assay. Bioluminescence from the luciferase reaction, which normally decays very rapidly, was sustained in the presence of A. johnsonii 210A cell extract, MgCl(2), polyP(n=35), and AMP. Similar reaction mixtures containing strain 210A cell extract or partially purified PPT, polyP, AMP, glucose, and hexokinase formed glucose 6-phosphate. The results indicate that PPT from A. johnsonii is specific for AMP and 2'-dAMP and catalyzes a key reaction in the cell-free regeneration of ATP from AMP and polyP. The PPT/AdK system provides an alternative to existing enzymatic ATP regeneration systems in which phosphoenolpyruvate and acetylphosphate serve as phosphoryl donors and has the advantage that AMP and polyP are stabile, inexpensive substrates.

Acinetobacter↗

PubMed2000

Regioselectivity and enantioselectivity of naphthalene dioxygenase during arene cis-dihydroxylation: control by phenylalanine 352 in the alpha subunit.

The naphthalene dioxygenase (NDO) system catalyzes the first step in the degradation of naphthalene by Pseudomonas sp. strain NCIB 9816-4. The enzyme has a broad substrate range and catalyzes several types of reactions including cis-dihydroxylation, monooxygenation, and desaturation. Substitution of valine or leucine at Phe-352 near the active site iron in the alpha subunit of NDO altered the stereochemistry of naphthalene cis-dihydrodiol formed from naphthalene and also changed the region of oxidation of biphenyl and phenanthrene. In this study, we replaced Phe-352 with glycine, alanine, isoleucine, threonine, tryptophan, and tyrosine and determined the activity with naphthalene, biphenyl, and phenanthrene as substrates. NDO variants F352W and F352Y were marginally active with all substrates tested. F352G and F352A had reduced but significant activity, and F352I, F352T, F352V, and F352L had nearly wild-type activities with respect to naphthalene oxidation. All active enzymes had altered regioselectivity with biphenyl and phenanthrene. In addition, the F352V and F352T variants formed the opposite enantiomer of biphenyl cis-3,4-dihydrodiol [77 and 60% (-)-(3S,4R), respectively] to that formed by wild-type NDO [>98% (+)-(3R,4S)]. The F352V mutant enzyme also formed the opposite enantiomer of phenanthrene cis-1,2-dihydrodiol from phenanthrene to that formed by biphenyl dioxygenase from Sphingomonas yanoikuyae B8/36. A recombinant Escherichia coli strain expressing the F352V variant of NDO and the enantioselective toluene cis-dihydrodiol dehydrogenase from Pseudomonas putida F1 was used to produce enantiomerically pure (-)-biphenyl cis-(3S,4R)-dihydrodiol and (-)-phenanthrene cis-(1S,2R)-dihydrodiol from biphenyl and phenanthrene, respectively.

Anthracenes↗

PubMed2000

Substrate specificity of naphthalene dioxygenase: effect of specific amino acids at the active site of the enzyme.

The three-component naphthalene dioxygenase (NDO) enzyme system carries out the first step in the aerobic degradation of naphthalene by Pseudomonas sp. strain NCIB 9816-4. The three-dimensional structure of NDO revealed that several of the amino acids at the active site of the oxygenase are hydrophobic, which is consistent with the enzyme's preference for aromatic hydrocarbon substrates. Although NDO catalyzes cis-dihydroxylation of a wide range of substrates, it is highly regio- and enantioselective. Site-directed mutagenesis was used to determine the contributions of several active-site residues to these aspects of catalysis. Amino acid substitutions at Asn-201, Phe-202, Val-260, Trp-316, Thr-351, Trp-358, and Met-366 had little or no effect on product formation with naphthalene or biphenyl as substrates and had slight but significant effects on product formation from phenanthrene. Amino acid substitutions at Phe-352 resulted in the formation of cis-naphthalene dihydrodiol with altered stereochemistry [92 to 96% (+)-1R,2S], compared to the enantiomerically pure [>99% (+)-1R,2S] product formed by the wild-type enzyme. Substitutions at position 352 changed the site of oxidation of biphenyl and phenanthrene. Substitution of alanine for Asp-362, a ligand to the active-site iron, resulted in a completely inactive enzyme.

Amino Acid Substitution↗

PubMed1998

Effects of estrogen replacement therapy on PET cerebral blood flow and neuropsychological performance.

Reports that estrogen may protect against age-associated memory decline and Alzheimer's Disease have kindled interest in the effects of estrogen replacement therapy (ERT) on cognition and brain function. As part of a 9-year study in the Baltimore Longitudinal Study of Aging, we are performing annual magnetic resonance imaging, positron emission tomography (PET), and neuropsychological assessments to examine brain structure and function in individuals aged 55 and older. PET measurements of regional cerebral blood flow (rCBF) are obtained under 3 conditions: rest and verbal and figural delayed recognition memory tasks. Fifteen women receiving ERT (with or without the addition of progesterone) were compared with a matched sample of 17 untreated women. There were no significant differences between groups in regional brain volumes or ventricular size. However, ERT users and nonusers showed significant differences in PET-rCBF relative activation patterns during the memory tasks. During verbal memory processing, there were significant interactions in rCBF activations for the right parahippocampal gyrus, right precuneus, right frontal regions, and left hypothalamus. During figural memory processing, significant interactions were observed for right parahippocampal and inferior parietal regions and for left visual association and anterior thalamic regions. ERT users also showed better performance on neuropsychological tests of figural and verbal memory and on some aspects of the PET activation tests, although the two groups did not differ in education, overall verbal ability, or performance on other neuropsychological tests. These findings confirm our previous observation of the beneficial effects of ERT on figural memory. Moreover, differences in rCBF activation patterns between ERT users and nonusers suggest an area for future research to examine mechanisms through which ERT may influence memory and other cognitive abilities.

Aged↗

PubMed1998

Enzyme specificity of 2-nitrotoluene 2,3-dioxygenase from Pseudomonas sp. strain JS42 is determined by the C-terminal region of the alpha subunit of the oxygenase component.

Biotransformations with recombinant Escherichia coli expressing the genes encoding 2-nitrotoluene 2,3-dioxygenase (2NTDO) from Pseudomonas sp. strain JS42 demonstrated that 2NTDO catalyzes the dihydroxylation and/or monohydroxylation of a wide range of aromatic compounds. Extremely high nucleotide and deduced amino acid sequence identity exists between the components from 2NTDO and the corresponding components from 2,4-dinitrotoluene dioxygenase (2,4-DNTDO) from Burkholderia sp. strain DNT (formerly Pseudomonas sp. strain DNT). However, comparisons of the substrates oxidized by these dioxygenases show that they differ in substrate specificity, regiospecificity, and the enantiomeric composition of their oxidation products. Hybrid dioxygenases were constructed with the genes encoding 2NTDO and 2,4-DNTDO. Biotransformation experiments with these hybrid dioxygenases showed that the C-terminal region of the large subunit of the oxygenase component (ISP alpha) was responsible for the enzyme specificity differences observed between 2NTDO and 2,4-DNTDO. The small subunit of the terminal oxygenase component (ISP beta) was shown to play no role in determining the specificities of these dioxygenases.

Amino Acid Sequence↗

PubMed1997

Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia.

Males are more likely than females to show aggressive behavior across species, ages, and situations, and these differences may be partly influenced by early hormones. We studied aggression in three samples of subjects with congenital adrenal hyperplasia (CAH), who were exposed to high levels of androgen in the prenatal and early postnatal periods. Controls were siblings and first cousins similar in age. In Sample 1, adolescents and adults completed the Multidimensional Personality Questionnaire (MPQ), which includes an Aggression scale. In Sample 2, adolescents and adults completed the MPQ and a paper-and-pencil version of Reinisch's Aggression Inventory. In Sample 3, parents rated the aggression of children aged 3-12, using a modification of Reinisch's Inventory. In all three samples, control males had higher aggression scores than control females. Further, as predicted, females with CAH had higher aggression than control females, but the difference was significant only in adolescents and adults. These results suggest that early androgens contribute to variability in human aggression.

Adolescent↗

PubMed1997

Stereospecific oxidation of (R)- and (S)-1-indanol by naphthalene dioxygenase from Pseudomonas sp. strain NCIB 9816-4.

A recombinant Escherichia coli strain which expresses naphthalene dioxygenase (NDO) from Pseudomonas sp. strain NCIB 9816-4 oxidized (S)-1-indanol to trans-(1S,3S)-indan-1,3-diol (95.5%) and (R)-3-hydroxy-1-indanone (4.5%). The same cells oxidized (R)-1-indanol to cis-1,3-indandiol (71%), (R)-3-hydroxy-1-indanone (18.2%), and cis-1,2,3-indantriol (10.8%). Purified NDO oxidized (S)-1-indenol to both syn- and anti-2,3-dihydroxy-1-indanol.

Dioxygenases↗

PubMed1997

Estrogen replacement therapy and longitudinal decline in visual memory. A possible protective effect?

Estrogen replacement therapy (ERT) is increasingly recommended for postmenopausal women due to its beneficial effects on physical health in older women. Recent studies have suggested that ERT may have a protective effect on cognitive function and may reduce the risk of Alzheimer's disease. In the present study we test the hypothesis that ERT may have a protective effect on memory in nondemented women. Data on hormonal status and memory were examined in 288 postmenopausal women in the Baltimore Longitudinal Study of Aging. One hundred sixteen women who reported that they were receiving ERT during a cognitive assessment were compared with 172 women who had never received ERT. Women who were receiving ERT had fewer errors on the Benton Visual Retention Test (BVRT), a measure of short-term visual memory, visual perception, and constructional skills. Furthermore, ERT appeared to protect against age changes in BVRT performance in a subgroup of 18 women for whom BVRT data were available before and during treatment with ERT. These findings suggest that ERT may protect against memory decline in nondemented postmenopausal women and offer further support for a beneficial role of estrogen on cognitive function in aging women.

Aged↗

PubMed1996

Regio- and stereospecific oxidation of fluorene, dibenzofuran, and dibenzothiophene by naphthalene dioxygenase from Pseudomonas sp. strain NCIB 9816-4.

The regio- and stereospecific oxidation of fluorene, dibenzofuran, and dibenzothiophene was examined with mutant and recombinant strains expressing naphthalene dioxygenase from Pseudomonas sp. strain NCIB 9816-4. The initial oxidation products were isolated and identified by gas chromatography-mass spectrometry and nuclear magnetic resonance spectrometry. Salicylate-induced cells of Pseudomonas sp. strain 9816/11 and isopropyl-beta-D-thiogalactopyranoside-induced cells of Escherichia coli JM109(DE3)(pDTG141) oxidized fluorene to (+)-(3S,4R)-cis-3,4-dihydroxy-3,4-dihydrofluorene (80 to 90% relative yield; > 95% enantiomeric excess [ee]) and 9-fluorenol (< 10% yield). The same cells oxidized dibenzofuran to (1R,2S)-cis-1,2-dihydroxy-1, 2-dihydrodibenzofuran (60 to 70% yield; > 95% ee) and (3S,4R)-cis-3, 4-dihydroxy-3,4-dihydrodibenzofuran (30 to 40% yield; > 95% ee). Induced cells of both strains, as well as the purified dioxygenase, also oxidized dibenzothiophene to (+)-(1R,2S)-cis-1,2-dihydroxy-1, 2-dihydrodibenzothiophene (84 to 87% yield; > 95% ee) and dibenzothiophene sulfoxide (< 15% yield). The major reaction catalyzed by naphthalene dioxygenase with each substrate was stereospecific dihydroxylation in which the cis-dihydrodiols were of identical regiochemistry and of R configuration at the benzylic center adjacent to the bridgehead carbon atom. The regiospecific oxidation of dibenzofuran differed from that of the other substrates in that a significant amount of the minor cis-3,4-dihydrodiol regioisomer was formed. The results indicate that although the absolute stereochemistry of the cis-diene diols was the same, the nature of the bridging atom or heteroatom influenced the regiospecificity of the reactions catalyzed by naphthalene dioxygenase.

Benzofurans↗