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Background: Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer disease, but whether these are early or late changes remains unclear. Magnetic resonance imaging is used to assess structure and function in the hippocampal formation., Objective: To estimate differences in the associations of hippocampal and entorhinal cortex volumes and CBV with memory function in the early and late stages of cognitive impairment by relating these measures to memory function in persons with and without dementia who underwent detailed brain imaging and neuropsychological assessment., Design: Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampal volume, and hippocampal CBV to measurements of memory performance. The same measures were related to language function as a reference cognitive domain., Setting: Community-based cohort., Participants: Two hundred thirty-one elderly Medicare recipients (aged > or =65 years) residing in northern Manhattan, New York., Main Outcome Measures: Values for entorhinal cortex volume, hippocampal volume, entorhinal cortex CBV, and hippocampal CBV and their relation to memory performance., Results: No association was noted between entorhinal cortex volume or hippocampal CBV and memory. Decreased hippocampal volume was strongly associated with worse performance in total recall, and lower entorhinal cortex CBV was associated with lower performance in delayed recall. Excluding persons with Alzheimer disease, the association of entorhinal cortex CBV with memory measures was stronger, whereas the association between hippocampal volume and total recall became nonsignificant., Conclusions: In the early stages of Alzheimer disease or in persons without dementia with worse memory ability, functional and metabolic hippocampal hypofunction contributes to memory impairment, whereas in the later stages, functional and structural changes play a role.

Patient motion during an MRI exam can result in major degradation of image quality, and is of increasing concern due to the aging population and its associated diseases. This work presents a general strategy for real-time, intraimage compensation of rigid-body motion that is compatible with multiple imaging sequences. Image quality improvements are established for structural brain MRI acquired during volunteer motion. A headband integrated with three active markers is secured to the forehead. Prospective correction is achieved by interleaving a rapid track-and-update module into the imaging sequence. For every repetition of this module, a short tracking pulse-sequence remeasures the marker positions; during head motion, the rigid-body transformation that realigns the markers to their initial positions is fed back to adaptively update the image-plane-maintaining it at a fixed orientation relative to the head-before the next imaging segment of k-space is acquired. In cases of extreme motion, corrupted lines of k-space are rejected and reacquired with the updated geometry. High-precision tracking measurements (0.01 mm) and corrections are accomplished in a temporal resolution (37 ms) suitable for real-time application. The correction package requires minimal additional hardware and is fully integrated into the standard user interface, promoting transferability to clinical practice., ((c) 2009 Wiley-Liss, Inc.)

Magnetic resonance studies offer a new way through the impasse that now seems to block further progress in disentangling the pathogenesis and improving the treatment of cerebral malaria, a catastrophic neurologic complication of infection with Plasmodium falciparum. The underlying mechanisms responsible for coma in cerebral malaria are still unknown and the relative contributions of the microvascular sequestration of infected erythrocytes, the inflammatory response to P. falciparum, disordered hemostasis, and other factors remain controversial. For more than a century, neuropathologic studies have provided the basis for concepts of causation of cerebral malaria. Magnetic resonance techniques now offer non-invasive means of determining essential anatomic, metabolic, biochemical, and functional features of the brain in patients with cerebral malaria during life that could transform our understanding of the pathogenesis of cerebral malaria and lead to the development of new neuroprotective treatments.

The accuracy of cerebral blood flow (CBF) imaging in humans has been impeded by the partial volume effects (PVE), which are a consequence of the limited spatial resolution. Because of brain atrophy, PVE can be particularly problematic in imaging the elderly and can considerably overestimate the CBF difference with the young. The primary goal of this study was to separate the structural decline from the true CBF reduction in elderly. To this end, a PVE-correction algorithm was applied on the CBF images acquired with spin-echo EPI continuous arterial spin labeling MRI (voxel size = 3.4 x 3.4 x 8 mm(3)). Tissue-specific CBF images that were independent of voxels' tissue fractional volume were obtained in elderly (N = 30) and young (N = 26); mean age difference was 43 years. Globally, PVE-corrected gray matter CBF was 88.2 +/- 16.1 and 107.3 +/- 17.5 mL/100 g min(-1) in elderly and young, respectively. The largest PVE contribution was found in the frontal lobe and accounted for an additional 10% and 12% increase in the age-related CBF difference between men and women, respectively. The GM-to-WM CBF ratios were found to be on average 3.5 in elderly and 3.9 in young. Whole brain voxelwise comparisons showed marked CBF decrease in anterior cingulate (bilateral), caudate (bilateral), cingulate gyrus (bilateral), cuneus (left), inferior frontal gyrus (left), insula (left), middle frontal gyrus (left), precuneus (bilateral), prefrontal cortex (bilateral), and superior frontal gyrus (bilateral) in men and amygdala (bilateral), hypothalamus (left), hippocampus (bilateral), and middle frontal gyrus (right) in women., (2009 Wiley-Liss, Inc.)

The auditory oddball task is a well-studied stimulus paradigm used to investigate the neural correlates of simple target detection. It elicits several classic event-related potentials (ERPs), the most prominent being the P300 which is seen as a neural correlate of subjects' detection of rare (target) stimuli. Though trial-averaging is typically used to identify and characterize such ERPs, their latency and amplitude can vary on a trial-to-trial basis reflecting variability in the underlying neural information processing. Here we simultaneously recorded EEG and fMRI during an auditory oddball task and identified cortical areas correlated with the trial-to-trial variability of task-discriminating EEG components. Unique to our approach is a linear multivariate method for identifying task-discriminating components within specific stimulus- or response-locked time windows. We find fMRI activations indicative of distinct processes that contribute to the single-trial variability during target detection. These regions are different from those found using standard, including trial-averaged, regressors. Of particular note is the strong activation of the lateral occipital complex (LOC). The LOC was not seen when using traditional event-related regressors. Though LOC is typically associated with visual/spatial attention, its activation in an auditory oddball task, where attention can wax and wane from trial to trial, indicates that it may be part of a more general attention network involved in allocating resources for target detection and decision making. Our results show that trial-to-trial variability in EEG components, acquired simultaneously with fMRI, can yield task-relevant BOLD activations that are otherwise unobservable using traditional fMRI analysis.

Purpose: To investigate the feasibility of measuring myocardial T2 at 3 Tesla for assessment of tissue iron in thalassemia major and other iron overloaded patients., Materials and Methods: A single-breathhold electrocardiogram-triggered black-blood multi-echo spin-echo (MESE) sequence with a turbo factor of 2 was implemented at 3 Tesla (T). Myocardial and liver T2 values were measured with three repeated breathholds in 8 normal subjects and 24 patients. Their values, together with the T2 values measured using a breathhold multi-echo gradient-echo sequence, were compared with those at 1.5T in the same patients., Results: At 3T, myocardial T2 was found to be 39.6 +/- 7.4 ms in normal subjects. In patients, it ranged from 12.9 to 50.1 ms. "T2 and T2(*) [corrected] were observed to correlate in heart (rho = 0.93, P [corrected] < 0.0001) and liver (rho = 0.95, P < 0.0001). Myocardial T2 and T2 at 3T were also highly correlated with the 1.5T measurements. Preliminary results indicated that myocardial T2 quantitation was relatively insensitive to B1 variation, and reproducible with 3.2% intra-exam and 3.8% inter-exam variations., Conclusion: Myocardial T2 quantitation is feasible at 3T. Given the substantially decreased T2 and increased B0 inhomogeneity, the rapid myocardial T2 measurement protocol demonstrated here may present a robust alternative to study cardiac iron overload at 3T., ((c) 2009 Wiley-Liss, Inc.)

Background: The validity of a self-reported stroke remains inconclusive., Objective: To validate the diagnosis of self-reported stroke using stroke identified by magnetic resonance imaging (MRI) as the standard., Design, Setting, and Participants: Community-based cohort study of nondemented, ethnically diverse elderly persons in northern Manhattan., Methods: High-resolution quantitative MRIs were acquired for 717 participants without dementia. Sensitivity and specificity of stroke by self-report were examined using cross-sectional analyses and the chi(2) test. Putative relationships between factors potentially influencing the reporting of stroke, including memory performance, cognitive function, and vascular risk factors, were assessed using logistic regression models. Subsequently, all analyses were repeated, stratified by age, sex, ethnic group, and level of education., Results: In analyses of the whole sample, sensitivity of stroke self-report for a diagnosis of stroke on MRI was 32.4%, and specificity was 78.9%. In analyses stratified by median age (80.1 years), the validity between reported stroke and detection of stroke on MRI was significantly better in the younger than the older age group (for all vascular territories: sensitivity and specificity, 36.7% and 81.3% vs 27.6% and 26.2%; P = .02). Impaired memory, cognitive skills, or language ability and the presence of hypertension or myocardial infarction were associated with higher rates of false-negative results., Conclusions: Using brain MRI as the standard, specificity and sensitivity of stroke self-report are low. Accuracy of self-report is influenced by age, presence of vascular disease, and cognitive function. In stroke research, sensitive neuroimaging techniques rather than stroke self-report should be used to determine stroke history.

The prevalence of obesity among children, adolescents and adults has been dramatically increasing worldwide during the last several decades. The obesity epidemic has been recognized as one of the major global health problems, because its health hazard is linked to a number of common diseases including breast and prostate cancers. Obesity is caused by combination of genetic and environmental factors. While genetic contribution to obesity has been known to be significant, the genetic factors remain relatively unchanged. Recent studies have highlighted the involvement of environmental "obesogens", i.e. the xenobiotic chemicals that can disrupt the normal development and homeostatic control over adipogenesis and energy balance. Several lines of evidence suggest that increasing exposure to chemicals with endocrine-disrupting activities (endocrine-disrupting chemicals, EDCs) contributes to the increased obesity. The cellular and molecular mechanisms underlying obesogen-associated obesity are just now being appreciated. In this paper, we comprehensively reviewed current knowledge about the role of estrogen receptors alpha and beta (ERalpha and ERbeta) in regulation of energy metabolism pathways, including glucose transport, glycolysis, tricarboxylic acid (TCA) cycle, mitochondrial respiratory chain (MRC), adenosine nucleotide translocator (ANT) and fatty acid beta-oxidation and synthesis, by estrogens; and then examined the disturbance of E(2)/ER-mediated energy metabolism pathways by environmental obesogens; and finally, we discussed the potential implications of disturbance of energy metabolism pathways by obesogens in obesity and pointed out several key aspects of this area that need to be further explored. A better understanding of the cellular and molecular mechanisms underlying obesogen-associated obesity will lead to new approaches for slow down and/or prevention of the increased trend of obesity associated with exposure to obesogens.

Background: Benign prostatic hyperplasia (BPH) is an age-related enlargement of the prostate, characterized by increased proliferation of stromal and epithelial cells. Despite its prevalence, the etiology of BPH is unknown., Methods: The Brown Norway rat is a model for age-dependent, lobe-specific hyperplasia of the prostate. Histological analyses of the dorsal and lateral lobes from aged rats reveal focal areas characterized by increased numbers of luminal epithelial cells, whereas the ventral lobe is unaffected. This study examined differential gene expression by lobe and age in the Brown Norway rat prostate. The objective was to identify genes with different levels of expression in the prostate lobes from 4-month (young) and 24-month (old) animals, and to subsequently link changes in gene expression to mechanisms of prostate aging., Results: The number of age-dependent differentially expressed genes was greatest in the dorsal compared to the ventral and lateral lobes. Minimal redundancy was observed among the differentially expressed genes in the three lobes. Age-related changes in the expression levels of 14 candidate genes in the dorsal, lateral and ventral lobes were confirmed by quantitative RT-PCR. Genes that exhibited age-related differences in their expression were associated with proliferation, oxidative stress, and prostate cancer progression, including topoisomerase II alpha (Topo2a), aurora kinase B (Aurkb), stathmin 1 (Stmn1), and glutathione S-transferase pi. Immunohistochemistry for Topo2a, Aurkb, and Stmn1 confirmed age-related changes in protein localization in the lateral lobe of young and aged prostates., Conclusion: These findings provide clues to the molecular events associated with aging in the prostate., ((c) 2009 Wiley-Liss, Inc.)

The purpose of this study was to examine cerebral blood flow (CBF) as measured by arterial spin labeling (ASL) in tissue classified as white matter hyperintensities (WMH), normal appearing white matter, and grey matter. Seventeen healthy older adults received structural and ASL MRI. Cerebral blood flow was derived for three tissue types: WMH, normal appearing white matter, and grey matter. Cerebral blood flow was lower in WMH areas relative to normal appearing white matter, which in turn, was lower than grey matter. Regions with consistently lower CBF across individuals were more likely to appear as WMH. Results are consistent with an emerging literature linking diminished regional perfusion with the risk of developing WMH.

An important function of the brain's orienting response is to enable the evaluation of novel, environmental events in order to prepare for potential behavioral action. Here, we assessed the event-related hemodynamic (erfMRI) correlates of this phenomenon using unexpected (i.e., novel) environmental sounds presented within the context of an auditory novelty oddball paradigm. In ERP investigations of the novelty oddball, repetition of the identical novel sound leads to habituation of the novelty P3, an ERP sign of the orienting response. Repetition also leads to an enhancement of a subsequent positivity that appears to reflect semantic analysis of the environmental sounds. In this adaptation for erfMRI recording, frequent tones were intermixed randomly with infrequent target tones and equally infrequent novel, environmental sounds. Subjects responded via speeded button press to targets. To assess habituation, some of the environmental sounds were repeated two blocks after their initial presentation. As expected, novel sounds and target tones led to activation of widespread, but somewhat different, neural networks. Contrary to expectation, however, there were no significant areas in which activation was reduced in response to second compared to first presentations of the novel sounds. Conversely, novel sounds relative to target tones engendered activity in the inferior frontal gyrus (BA 45) consistent with semantic analysis of these events. We conclude that a key concomitant of the orienting response is the extraction of meaning, thereby enabling one to determine the significance of the environmental perturbation and take appropriate goal-directed action., (2008 Wiley-Liss, Inc.)

Background: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis., Methods: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530., Findings: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies., Interpretation: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.

Background: Serum androgen concentrations decline with age in male Brown Norway rats and castration induces apoptosis of luminal secretory epithelial cells in the ventral but not in the dorsal and lateral prostate lobes. Clusterin has been described as an androgen-repressed gene and a protein with either anti- or pro-apoptotic actions., Methods: We measured clusterin mRNA and protein levels, the effects of aging and castration on clusterin protein levels and clusterin immunolocalization within the prostatic ductal network in the prostate lobes of young and aged rats., Results: Whereas levels of clusterin mRNA and protein expression measured by RT-PCR and Western blot, respectively, were higher in the ventral and lateral lobes of aged (24 months) compared to young (4 months) rats, no age-dependent differences were observed in the dorsal lobe. Clusterin expression was localized by immunohistochemistry exclusively to the proximal duct segment of young rats, but extended to the distal segment of the ventral and lateral lobes of aged rats. Despite an age-related decrease in serum testosterone concentration, clusterin gene expression was not altered in the dorsal lobe. After castration, levels of clusterin expression increased significantly in the ventral and lateral lobes despite the absence of epithelial cell apoptosis in the latter. In castrated rats, clusterin expression extended throughout the proximal-distal duct regions of the prostate lobes of young and aged rats., Conclusion: Regulation of clusterin expression in the prostate lobes of aging rats appears complex and is neither directly repressed by androgen nor dependent on apoptotic-induced stress.

Case Description: A 2-year-old spayed female domestic shorthair cat was examined because of bilateral thoracic limb weakness of acute onset., Clinical Findings: Clinical signs included muscle atrophy, paresis, depressed spinal reflexes, hyperesthesia of the thoracic limbs, and reduced jaw muscle tone. Pelvic limb reflexes were normal. Results of a neurologic examination were suggestive of multifocal lesions involving both brachial plexuses and the trigeminal nerves. Abnormal nerve conduction across the brachial plexus and delayed late potentials were found on electrodiagnostic testing, and diffuse subclinical involvement of other regions of the peripheral nervous system was confirmed on the basis of abnormal electromyographic findings for the masticatory muscles and conduction block of the peroneal nerve., Treatment and Outcome: No specific treatments were given, and neurologic signs resolved within a month. A relapse occurred 2 months after the first episode, with clinical signs affecting both the pelvic and the thoracic limbs on this occasion. Again, the condition resolved without specific treatment, and 13 months after the initial episode, the cat reportedly was normal., Conclusions and Clinical Relevance: Findings suggested that brachial plexus neuropathy can be a multifocal disease in cats, even if clinically apparent neurologic deficits are initially subtle or absent, and that electrodiagnostic techniques can be used to identify subclinical involvement of the peripheral nerves.

This case report describes the diagnosis and management of primary femoral nerve sheath tumours in two dogs. Both of the tumours were localised by electromyography (EMG) and magnetic resonance imaging (MRI), and were then surgically resected using a novel approach to the iliopsoas muscle via osteotomy of the ventral ilial wing. This approach should be considered when attempting surgical treatment of conditions affecting the iliopsoas muscle or the femoral nerve because it provides excellent exposure of these structures.

Myocardial elastography (ME), a radio-frequency (RF) based speckle tracking technique, was employed in order to image the entire two-dimensional (2D) transmural deformation field in full echocardiographic views and was validated against tagged magnetic resonance imaging (tMRI) in normal as well as reperfused (i.e., treated myocardial infarction [MI]) human left ventricles. RF ultrasound and tMRI frames were acquired at the papillary muscle level in 2D short-axis (SA) views at the frame rates of 136 (fps; real-time) and 33 fps (electrocardiogram [ECG]-gated), respectively. In ME, in-plane, 2D (lateral and axial) incremental displacements were iteratively estimated using one-dimensional (1D) cross-correlation and recorrelation techniques in a 2D search with a 1D matching kernel. In tMRI, cardiac motion was estimated by a template-matching algorithm on a 2D grid-shaped mesh. In both ME and tMRI, cumulative 2D displacements were obtained and then used to estimate 2D Lagrangian finite systolic strains, from which polar (i.e., radial and circumferential) strains, namely angle-independent measures, were further obtained through coordinate transformation. Principal strains, which are angle-independent and less centroid-dependent than polar strains, were also computed and imaged based on the 2D finite strains using methodology previously established. Both qualitatively and quantitatively, angle-independent ME is shown to be capable of (1) estimating myocardial deformation in good agreement with tMRI estimates in a clinical setting and of (2) differentiating abnormal from normal myocardium in a full left-ventricular view. The principal strains were concluded to be a potential diagnostic measure for detection of cardiac disease with reduced centroid dependence.

Partial volume effects (PVE) are a consequence of limited spatial resolution in brain imaging. In arterial spin labeling (ASL) MRI, the problem is exacerbated by the nonlinear dependency of the ASL signal on magnetization contributions from each tissue within an imaged voxel. We have developed an algorithm that corrects for PVE in ASL imaging. The algorithm is based on a model that represents the voxel intensity as a weighted sum of pure tissue contribution, where the weighting coefficients are the tissue's fractional volume in the voxel. Using this algorithm, we were able to estimate cerebral blood flow (CBF) for gray matter (GM) and white matter (WM) independently. The average voxelwise ratio of GM to WM CBF was approximately 3.2, in good agreement with reports in the literature. As proof of concept, data from PVE-corrected method were compared with those from the conventional, PVE-uncorrected method. As hypothesized, the two yielded similar CBF values for voxels containing >95% GM and differed in proportion with the voxels' heterogeneity. More importantly, the GM CBF assessed with the PVE-corrected method was independent of the voxels' heterogeneity, implying that estimation of flow was unaffected by PVE. An example of application of this algorithm in motor-activation data is also given., ((c) 2008 Wiley-Liss, Inc.)

Objectives: To evaluate the evolutional changes in disease and nonbattle injury in a long-term deployment setting, we investigated trends of selected disease and nonbattle injury (NBI) incidence among US military personnel deployed in ongoing military operations in Southwest Asia and the Middle East., Methods: Participants completed an anonymous questionnaire concerning diarrhea, acute respiratory illness (ARI), and NBIs. We compared incidence, morbidity, and risk associations of disease and NBI incidence with historical data. We analyzed a clinic screening form to describe trends in diarrhea incidence over a 3-year period., Results: Between April 2006 and March 2007, 3374 troops completed deployment questionnaires. Incidence of diarrhea was higher than that of ARI and NBI (12.1, 7.1, and 2.5 episodes per 100 person-months, respectively), but ARI and NBI resulted in more-frequent health system utilization (both P < .001) and decreased work performance (P < .001 and P = .05, respectively) than did diarrhea. Compared with historical disease and NBI incidence rates, diarrhea and NBI incidence declined over a 4-year period, whereas ARI remained relatively constant., Conclusions: Diarrhea, ARI, and NBI are important health concerns among deployed military personnel. Public health and preventive measures are needed to mitigate this burden.

Background: Mild parkinsonian signs (MPS) are a marker of incident dementia. They have been linked with cerebrovascular disease, which can be evaluated using magnetic resonance imaging (MRI). Also, if MPS are a marker for developing Alzheimer-type changes, hippocampal volume on MRI might be diminished in individuals with MPS., Objective: To examine white matter hyperintensity (WMH) volume and total hippocampal volume in elderly individuals with and without MPS., Methods: Community-dwelling elderly persons in northern Manhattan (New York), New York, underwent neurologic examination and brain MRI. The WMH volume (derived from fluid-attenuated inversion recovery-weighted MRIs using a semiautomated thresholding approach) and total hippocampal volume (derived manually) were expressed relative to total cranial volume., Results: Mild parkinsonian signs were present in 111 of 666 participants (16.7%). Mean (SD) relative WMH volume was larger in participants with MPS vs those without MPS (1.70 [1.28] vs 1.17 [1.18]; P<.001). In a multivariate logistic regression analysis adjusting for age, sex, race/ethnicity, years of educational achievement, and depression, relative WMH volume was associated with MPS (odds ratio, 1.26; 95% confidence interval, 1.08-1.47; P=.004). In both unadjusted and adjusted analyses, total relative hippocampal volume was similar in participants with MPS vs those without MPS regardless of cognitive status., Conclusions: In this MRI study of community-dwelling elderly persons, WMH volume was associated with MPS and total relative hippocampal volume was not. These data raise the possibility that vascular disease could have a role in the development of MPS.

Protein S-nitrosation is a reversible post-translation modification critical for redox-sensitive cell signaling that is typically studied using the Biotin Switch method. This method and subsequent modifications usually require avidin binding or Western blot analysis to detect biotin labeled proteins. We describe here a modification of the Biotin Switch assay that eliminates the need for Western blot or avidin enrichment protocols and allows direct comparison of the S-nitrosation state proteins from two different samples in the same gel lane or on the same 2D gel. This S-FLOS method offers detection, identification and quantification of S-nitrosated proteins, with the potential for site-specific identification of nitrosation events.

Objective: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS)., Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk., Results: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose., Conclusions: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.

Background: Aging is accompanied by a decrease in brain volume and by an increase in cerebrovascular disease., Objective: To examine the effects of age, sex, race/ethnicity, and vascular disease history on measures of brain morphology, including relative brain volume, ventricular volume, hippocampus and entorhinal cortex volumes, and white matter hyperintensity (WMH) burden, in a large community-based cohort of racially/ethnically diverse older adults without dementia., Design: The associations of age, sex, race/ethnicity, and self-reported vascular disease history with brain morphology were examined in a cross-sectional study using multiple linear regression analyses. Sex x race/ethnicity interactions were also considered., Setting: The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from 3 racial/ethnic groups (white, Hispanic, and African American) from northern Manhattan., Participants: Beginning in 2003, high-resolution quantitative magnetic resonance (MR) images were acquired in 769 participants without dementia., Main Outcome Measures: Relative brain volume (total brain volume/intracranial volume), ventricular volume, and hippocampus and entorhinal cortex volumes were derived manually on high-resolution MR images. White matter hyperintensities were quantified semiautomatically on fluid-attenuated inversion recovery-T2-weighted MR images., Results: Older age was associated with decreased relative brain volume and with increased ventricular and WMH volumes. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than white participants, but the associations of these variables with age were similar across racial/ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and with higher WMH burden, particularly among African Americans., Conclusions: Older age and vascular disease, particularly among African Americans, are associated with increased brain atrophy and WMH burden. African American and Hispanic subjects have larger relative brain volumes and more WMH than white subjects. Racial/ethnic group differences in WMH severity seem to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.

The spatio-temporal nature of focused ultrasound-induced blood-brain barrier (BBB) opening as a brain drug delivery method was investigated in Alzheimer's disease model mice. The left hippocampus of transgenic (APP/PS1, n = 3) and nontransgenic (n = 3) mice was sonicated (frequency: 1.525 MHz, peak-negative pressure: 600 kPa, pulse length: 20 ms, duty cycle: 20%, duration: 1 min) in vivo, through their intact skin and skull, after intravenous injection of microbubbles (SonoVue; 25 microl). Sequential, high-field MR images (9.4 Tesla) were acquired before and after injection of gadolinium (Omniscan, 0.75 ml, molecular weight: 573.7 Da) on two separate days for each mouse. Gadolinium deposits through the ultrasound-induced BBB opening in the left hippocampus revealed significant contrast-enhancement in the MRI. On the following day, MRI revealed significant BBB closure within the same region. However, the BBB opening extent and BBB closing timeline varied in different regions within the same sonicated location. This indicates that opening and closing were dependent on the brain region targeted. No significant difference in BBB opening or closing behaviors was observed between the APP/PS1 and the nontransgenic mice. In conclusion, a BBB-impermeable molecule was noninvasively, transiently and reproducibly delivered to the hippocampus of Alzheimer's APP/PS1 mice.

Changes in the oxidant/antioxidant environment of aging Leydig cells have been shown to be correlated with the reduced ability of these cells to produce testosterone. With this in mind, we hypothesized that the experimental depletion of glutathione (GSH), an abundant Leydig cell intracellular antioxidant, might result in reduced testosterone production. Incubation of Leydig cells isolated from the testes of adult Brown Norway rats with buthionine sulfoximine (BSO) reduced GSH content by more than 70% and testosterone production by about 40%. The antioxidants vitamin E, N-tert-butyl-alpha-phenylnitrone and Trolox countered BSO's effect on steroidogenesis but not on GSH depletion. Together, BSO and glutathione ethyl ester maintained intracellular GSH and also testosterone production, whereas 1,2-dithiole-3-thione, which increases intracellular GSH, increased testosterone production. In vivo studies also were conducted. Young (4 month old) and old (24 month old) rats were injected with BSO twice a day for 7 d, after which Leydig cells were isolated and analyzed in vitro. BSO treatment reduced Leydig cell GSH content by 70% and the ability of the Leydig cells to produce testosterone by more than 50%. As with aging, decreases were seen in LH-stimulated cAMP production, steroidogenic acute regulatory protein, cholesterol side-chain cleavage, 3beta-hydroxysteroid dehydrogenase, and 17alpha-hydroxylase/17,20-lyase. The results of these studies, taken together, are consistent with the hypothesis that alteration in the oxidant/antioxidant environment may play a significant, causative role in the age-related reduced ability of Leydig cells to produce testosterone.

Continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI) was combined with multivariate analysis for detection of an Alzheimer's disease (AD)-related cerebral blood flow (CBF) covariance pattern. Whole-brain resting CBF maps were obtained using spin echo, echo planar imaging (SE-EPI) CASL in patients with mild AD (n=12, age=70.7+/-8.7 years, 7 males, modified Mini-Mental State Examination (mMMS)=38.7/57+/-11.1) and age-matched healthy controls (HC) (n=20; age=72.1+/-6.5 years, 8 males). A covariance pattern for which the mean expression was significantly higher (P<0.0005) in AD than in HC was identified containing posterior cingulate, superior temporal, parahippocampal, and fusiform gyri, as well as thalamus, insula, and hippocampus. The results from this analysis were supplemented with those from the more standard, region of interest (ROI) and voxelwise, univariate techniques. All ROIs (17/hemisphere) showed significant decrease in CBF in AD (P<0.001 for all ROIs, alphacorrected=0.05). The area under the ROC curve for discriminating AD versus HC was 0.97 and 0.94 for covariance pattern and gray matter ROI, respectively. Fewer areas of depressed CBF in AD were detected using voxelwise analysis (corrected, P<0.05). These areas were superior temporal, cingulate, middle temporal, fusiform gyri, as well as inferior parietal lobule and precuneus. When tested on extensive split-half analysis to map out the replicability of both multivariate and univariate approaches, the expression of the pattern from multivariate analysis was superior to that of the univariate.

Photoreactions of 4-nitroanisole and the 2-halo-4-nitroanisoles (halogen = F, Cl, Br, and I) with the nucleophiles hydroxide ion and pyridine have been investigated quantitatively to extend the findings recently communicated for cyanide ion. The halonitroanisoles on excitation form triplet pi,pi* states, which undergo substitution of the halogen by nucleophiles. Chemical yields of photoproducts, Stern-Volmer kinetic plots, triplet lifetimes, and triplet yields are reported for the five compounds with the three nucleophiles. Following a standard kinetic treatment, 73 rate constants are determined for elementary reactions of the triplets including quenching and various nucleophilic addition processes. The photoadditions are roughly 14 orders of magnitude faster than thermal counterparts. Rate constants for attack at the fluorine-bearing carbon of triplet 2-fluoro-4-nitroanisole are 2.9 x 10(9), 1.3 x 10(9), and 6.3 x 10(8) M(-1) s(-1) for cyanide ion, hydroxide ion, and pyridine, respectively. The relative rates for attack at the halogen-bearing carbons for F/Cl/Br/I are 27:1.9:1.9:1 (cyanide ion), 29:2.6:2.4:1 (hydroxide ion), and 39:3.9:3.5:1 (pyridine), respectively. The relative nucleophilicities vary somewhat with the attack site; they are about 5:2:1 for cyanide ion, hydroxide ion, and pyridine for attack at the halogen-bearing carbons. The trend of the element effect opposes that of aliphatic substitution and elimination but is similar in size and parallel to that of thermal nucleophilic aromatic substitution. Relative nucleophilicities in the photoreactions are also similar to those of comparable but vastly slower thermal reactions. The findings imply that the efficiency-determining step of the halogen photosubstitution is simple formation of a sigma-complex through electron-paired bonding within the triplet manifold.

We demonstrate the development and successful application of immunotargeted superparamagnetic iron oxide nanoparticles (ITSIONs), with in vivo magnetic resonance diagnostic and potential drug delivery capability for kidney disease. Further, the versatility of the conjugation chemistry presents an attractive route to the preparation of a range of biomolecule-nanoparticle conjugates. The ITSION contrast agent is a stable, biocompatible, targeted nanoparticle complex that combines a monodisperse iron oxide nanoparticle core with a functionalized phospholipid coating conjugated to antibodies that is capable of targeting normal cells expressing specific target antigens. The plasma half-life and R1 and R2 relaxivities suggest sufficient time for targeted binding while clearing from the system quick enough for detection of specific contrast enhancement. RT1 anti-MHC Class II antibodies were used to target the renal medulla of the rat, a section of the kidney in which MHC Class II, associated with inflammation, is specifically expressed. For in vivo resonance imaging, we compare phospholipid coated nanoparticles, nonspecific ITSIONs, and RT1 ITSIONs. Enhanced binding of the RT1 ITSIONS indicates specificity for the renal medulla and thus potential for disease detection or drug delivery.

Variance estimates can be used in conjunction with scientifically meaningful effect sizes to design experiments with type II error control. Here we present estimates of intra- and inter-subject variances for region of interest (ROI) from resting cerebral blood flow (CBF) maps obtained using whole brain, spin echo echoplanar (SE-EPI) continuous arterial spin labeling (CASL) imaging on 52 elderly subjects (age=70.5+/-7.9 years, 29 males). There was substantial intrasubject systematic variability in CBF of gray matter ROIs corresponding to a range of standard deviations=[39-168] (ml/(100 g min)). This variability was mainly due to two factors: (1) an expected inverse relationship between ROI volume and intrasubject variance and (2) an increased effective post-labeling delay for more superior slices acquired later in the sequence. For example, intrasubject variance in Brodmann area 4 (BA 4) was approximately 8 times larger than in hippocampus, despite their similar gray matter volumes. Estimated ROI-wise power was computed for various numbers of acquired CBF images, numbers of subjects, and CBF effect sizes for two experimental designs: independent sample t-test and paired t-test. The theoretical effects of pulse sequence and field strength on general applicability of these results are discussed.

Age-dependent epithelial cell hyperplasia in the dorsal and lateral lobes of Brown Norway rats is analogous to benign prostatic hyperplasia in aging men. A major question is whether differential lobe-specific and age-dependent proliferation of cells, rather than cell survival, contributes to the hyperplasia. Although serum testosterone (T) levels decline in aged rats, active cell proliferation was detected as Ki67-positive cells in the dorsal and lateral lobes. We determined whether androgens differentially affect cell proliferation and cell-cycle regulatory proteins in the prostate lobes of young and aged rats. Castrated rats were treated with different doses of T to restore serum levels to those of intact young or aged rats. Rates of cell proliferation, measured by 5-bromodeoxyuridine labeling, peaked after 3-d T treatment in all lobes. 5-bromodeoxyuridine-labeling indices were higher in the dorsal and lateral lobes of aged than of young rats with equivalent serum T levels. No age-dependent difference was seen in the ventral lobe. Cell proliferation was marked by increased levels of cyclins D1 and E and cyclin-dependent kinases 4 and 6, decreased p27 and increased phosphorylation of Rb. Levels of cyclins D1 and E were higher in the dorsal and lateral lobes of intact and T-treated aged than young rats. Confocal immunofluorescent microscopy documented changes in cyclin-dependent kinase 4 and cyclin D1 subcellular localization. Cyclin D1 nuclear localization correlated with the time frame for cell proliferation. In conclusion, rates of cell proliferation and levels of cell-cycle regulatory proteins that control the G1/S transition exhibit lobe-specific and age-dependent differences in response to androgens.

A new approach to MR trabecular bone characterization is presented. This method probes the diffusion of spins through internal magnetic field gradients due to the susceptibility contrast between the bone and water (or marrow) phases. The resulting spin magnetization decay encodes properties of the underlying structure. This method, termed decay due to diffusion in the internal field (DDIF), is well established as a probe of pore size and structure. In the present work its application is shown for in vitro experiments on excised bovine tibiae samples. A comparison with pulsed field gradient (PFG) measurement of restricted diffusion shows a strong correlation of DDIF with the surface-to-volume ratio (SVR) of bones. Calculation of the internal magnetic field within the bone structure also supports this interpretation. These NMR measurements compare well with the image analysis from microscopic computed tomography (muCT). The SVR is not accessible in the clinically standard densitometry measurements, and provides vital information on bone strength and therefore on its fracture risk. The DDIF and PFG methods derive this information from a straightforward pulse sequence that does not employ either high applied field gradients or microimaging, and thus may have clinical potential., (2007 Wiley-Liss, Inc)

CumuIative and excessive exposure to estrogens is associated with increased breast cancer risk. The traditional mechanism explaining this association is that estrogens affect the rate of cell division and apoptosis and thus manifest their effect on the risk of breast cancer by affecting the growth of breast epithelial tissues. Highly proliferative cells are susceptible to genetic errors during DNA replication. The action of estrogen metabolites offers a complementary genotoxic pathway mediated by the generation of reactive estrogen quinone metabolites that can form adducts with DNA and generate reactive oxygen species through redox cycling. In this chapter, we discussed a novel mitochondrial pathway mediated by estrogens and their cognate estrogen receptors (ERs) and its potential implications in estrogen-dependent carcinogenesis. Several lines of evidence are presented to show: (1) mitochondrial localization of ERs in human breast cancer cells and other cell types; (2) a functional role for the mitochondrial ERs in regulation of the mitochondrial respiratory chain (MRC) proteins and (3) potential implications of the mitochondrial ER-mediated pathway in stimulation of cell proliferation, inhibition of apoptosis and oxidative damage to mitochondrial DNA. The possible involvement of estrogens and ERs in deregulation of mitochondrial bioenergetics, an important hallmark of cancer cells, is also described. An evolutionary view is presented to suggest that persistent stimulation by estrogens through ER signaling pathways of MRC proteins and energy metabolic pathways leads to the alterations in mitochondrial bioenergetics and contributes to the development of estrogen-related cancers.

In this article we report on the findings of a two-part project investigating contemporary issues in sexuality researchers' interaction with journalists. The goal of the project was to explore best practices and suggest curricular and training initiatives for sexuality researchers and journalists that would enhance the accurate dissemination of sexuality research results in the media. We present the results of a survey of a convenience sample of 94 sexuality researchers about their experiences and concerns regarding media coverage and a summary of the main themes that emerged from an invitational conference of sexuality researchers and journalists. In addition, we present some preliminary recommendations for training and best practices. Topics assessed include reporting accuracy; sex researchers' comfort with various topics, media, and journalists; researchers' perceptions of the purpose and content of articles; concern about the impact of media coverage; and training for sexuality researchers.

Background: Neurotoxicity related to the Abeta peptide is thought to be a primary mechanism of dysfunction in Alzheimer disease (AD). Although numerous imaging studies have observed brain dysfunction in AD, whether these imaged defects reflect Abeta-related neurotoxicity remains unknown., Objective: To study Abeta-related neurotoxicity by means of functional imaging maps of the hippocampal formation in human patients and mouse models., Design: Cross-sectional study comparing humans with AD and control subjects, cross-sectional study of J20 mice, a transgenic mouse model of AD, and a longitudinal study of flurbiprofen administration to transgenic mice., Setting: Alzheimer disease research center. Subjects Eleven subjects with probable Alzheimer disease and 11 age-matched controls, plus J20 mice and wild-type littermates., Interventions: In the first study, human subjects and controls underwent magnetic resonance imaging. In the second study, mice underwent imaging at 3, 6, 12, 15, and 21 months of age, for a total of 57 imaging experiments. In the third study, 12 J20 mice underwent imaging repeatedly over time; 6 received flurbiprofen to ameliorate Abeta-related neurotoxicity and 6 received vehicle control., Main Outcome Measures: Comparison of hippocampal functional maps., Results: Among all hippocampal subregions, the entorhinal cortex was the dominant site of dysfunction observed in both human patients and J20 mice. Long-term administration of flurbiprofen rescued entorhinal cortex dysfunction in transgenic mice., Conclusion: Our results establish that the neurotoxicity related to the Abeta peptide can be captured in vivo by functional imaging and suggest hippocampal subregions most vulnerable to its toxic effects.

The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 degrees C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison; 25-50 microl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 microm, scan time: 45-180 min) with gadolinium (Omniscan; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.

Purpose: A guide to the appropriate documentation of the critical aspects of the patient medical record to ensure reimbursement and the reduction of medical liability is presented., Summary: Several documentation styles can be adopted to record pharmacist interventions, including unstructured notes, semistructured notes, and systematic notes. Documentation should be clear, concise, legible, nonjudgmental, patient focused, and standardized, and it should ensure patient confidentiality. Systematic documentation styles include SOAP (subjective, objective, assessment, plan), TITRS (title, introduction, text, recommendation, signature), and FARM (findings, assessment, recommendations or resolutions, management). SOAP is the primary form for which payers traditionally reimburse. Systematic documentation should be used to demonstrate how pharmacist interventions improved patient care and should not just be used for reimbursement. Pharmacists have the opportunity to build a collaborative relationship with other professionals and with patients. Documentation can provide evidence of this symbiotic relationship where the pharmacist assists in providing a caring and compassionate environment for the patient's benefit. Professional liability, as it relates to clinical documentation, can be an issue. Documentation provides the necessary information to successfully manage the process of discovery and the review of the conduct of all parties involved in a liability issue., Conclusion: Documentation in a universal format allows for communication among health care practitioners. Written documentation is one key to a successful, open-communication partnership among providers. In addition, accurate, appropriate, and concise documentation is an essential component of ensuring that the patient care provided is evident, not only for patient safety and continuity but also for cases where reimbursement and quality of care are being challenged contractually or legally.

Context: Higher testosterone in black compared with white men has been postulated to explain their higher prostate cancer incidence. Previous studies comparing hormone levels by race might have been limited by size, restricted age variation, or lack of representation of the general population., Objective: Our objective was to compare serum testosterone, estradiol, and SHBG concentrations among non-Hispanic black, non-Hispanic white, and Mexican-American men., Participants, Design, and Setting: A total of 1413 men aged 20+ yr and who attended the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988-1991 were included in this cross-sectional study., Measurement: Serum hormone concentrations were measured by electrochemiluminescence immunoassays., Results: After applying sampling weights and adjusting for age, percent body fat, alcohol, smoking, and activity, testosterone concentrations were not different between non-Hispanic blacks (n = 363; geometric mean, 5.29 ng/ml) and non-Hispanic whites (n = 674; 5.11 ng/ml; P > 0.05) but were higher in Mexican-Americans (n = 376; 5.48 ng/ml; P < 0.05). Non-Hispanic blacks (40.80 pg/ml) had a higher estradiol concentration than non-Hispanic whites (35.46 pg/ml; P < 0.01) and Mexican-Americans (34.11 pg/ml; P < 0.01). Non-Hispanic blacks (36.49 nmol/liter) had a higher SHBG concentration than non-Hispanic whites (34.91 nmol/liter; P < 0.05) and Mexican-Americans (35.04 nmol/liter; P < 0.05)., Conclusions: Contrary to the postulated racial difference, testosterone concentrations did not differ notably between black and white men. However, blacks had higher estradiol levels. Mexican-Americans had higher testosterone than whites but similar estradiol and SHBG concentrations. Given these findings, it may be equally if not more important to investigate estradiol as testosterone in relation to diseases with racial disparity.

With continued debate over the functional significance of adult neurogenesis, identifying an in vivo correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.

Recent neuroimaging studies have converged to show that odorant-induced responses to prolonged stimulation in primary olfactory cortex (POC) are characterized by a rapidly habituating time course. Different statistical approaches have effectively modeled this time course. One approach explicitly modeled rapid habituation using an exponentially decaying reference waveform that decreased to baseline levels within 30 to 40 s. A second approach modeled an early transient response by simply shortening the odorant 'ON' period to be less than the actual stimulation period (i.e., 9 of 40 s). The goal of the current study was to validate, compare, and optimize these methodological approaches by applying them to an olfactory fMRI block-design dataset from 10 healthy young subjects presented with odorants for 12 s (ON), alternating with 30 s of clear air (OFF). Both approaches significantly improved sensitivity to odorant-induced signal changes in POC relative to a square-wave model based on the actual stimulation period. Our findings further demonstrate that the 'optimal' model fit to the data was achieved by shortening the odorant 'ON' period to approximately 6 s. These results suggest that sensitivity to odorant-induced POC activity in block-design experiments can be optimized by modeling an early phasic response followed by a precipitous rather than specific exponential decrease to baseline levels. Notably, whole brain voxel-wise analyses further established that modeling rapid habituation in this way is not only sensitive, but also highly specific to odorant-induced activation in a well-established network of olfactory-related brain areas.

The clinical phenotype of complete androgen insensitivity (CAIS) was associated with a mutation in the human androgen receptor (hAR) gene encoding the amino acid substitution, M745I, in the hAR protein. Transcriptional activation of hAR(M745I) by the synthetic androgen, methyltrienolone (R1881), was reduced compared to wild-type (wt) hAR. The transcriptional co-activator, androgen receptor associated protein 70 (ARA70), failed to enhance transactivation of hAR(M745I) at lower concentrations of R1881 (0.01-0.1 nM), whereas the p160 co-activators, SRC-1 and TIF2, stimulated activity. Transcriptional activity of hAR(M745I) was stimulated by 1 or 10 nM R1881 and activity was further enhanced by co-expression of ARA70 similar to that of the hAR(wt). Transcriptional activity of hAR(wt) was minimally stimulated by estradiol (E2) without or with co-expression of ARA70, whereas 10 or 100 nM E2 increased transactivation by hAR(M745I) of the androgen-responsive MMTV-luciferase reporter gene by 10-fold and activity was further enhanced by ARA70. Increasing concentrations of E2 competed more effectively for binding of R1881 to hAR(M745I) than to hAR(wt), indicative of the preferential binding of E2 to the mutant hAR. Partial tryptic digestion of hAR wt and M745I revealed that activation of the mutant protein was reduced in the presence of R1881. By contrast, tryptic digestion showed that the mutant hAR was activated by the binding of E2. In conclusion, the clinical phenotype of CAIS resulted from a hAR gene mutation encoding hAR(M745I) with reduced binding and transactivation by androgens, but the novel properties of enhanced affinity for and increased transactivation by estradiol.

Unlabelled: The increasing role of metabolomics in system biology is driving the development of tools for comprehensive analysis of high-resolution NMR spectral datasets. This task is quite challenging since unlike the datasets resulting from other 'omics', a substantial preprocessing of the data is needed to allow successful identification of spectral patterns associated with relevant biological variability. HiRes is a unique stand-alone software tool that combines standard NMR spectral processing functionalities with techniques for multi-spectral dataset analysis, such as principal component analysis and non-negative matrix factorization. In addition, HiRes contains extensive abilities for data cleansing, such as baseline correction, solvent peak suppression, removal of frequency shifts owing to experimental conditions as well as auxiliary information management. Integration of these components together with multivariate analytical procedures makes HiRes very capable of addressing the challenges for assessment and interpretation of large metabolomic datasets, greatly simplifying this otherwise lengthy and difficult process and assuring optimal information retrieval., Availability: HiRes is freely available for research purposes at http://hatch.cpmc.columbia.edu/highresmrs.html

The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients., (Copyright 2006 John Wiley & Sons, Ltd.)

Background and Purpose: Ensuring the translatability of primate stroke models is critical for preclinical testing of cerebroprotective strategies, and such models would benefit from further characterization of the experimental ischemic tissue. Our purpose was to examine the cerebral metabolic response to stroke in baboons with MR spectroscopy and to correlate metabolite levels with functional neurologic outcomes., Methods: Seven baboons underwent 1 hour of middle cerebral artery occlusion. At 3 and 10 days, each animal was imaged with traditional MR imaging and multivoxel proton (1)H-MR spectroscopy, and a neurologic examination was performed. Spectra obtained from the infarcted hemisphere of each animal were compared with the contralateral hemisphere, and metabolite levels were correlated with neurologic outcome scores., Results: Spectra obtained at 3 days postischemia revealed prominent lactate (LAC) resonances and attenuated N-acetylaspartate (NAA) peaks in infarcted hemispheres. Ten-day spectra showed persistence of these findings in animals with large strokes (>30% of the hemisphere), with partial normalization of the spectra in animals with small strokes (<30% of the hemisphere). Mean area under the curve from LAC spectra had a negative correlation with functional outcome by 2 different scoring systems (r(2) = 0.72 and 0.73), whereas NAA showed a positive correlation (r(2) = 0.79 and 0.62)., Conclusions: The metabolic alterations observed in our primate model of reperfused ischemia by (1)H-MR spectroscopy recapitulate those seen in clinical stroke. Furthermore, correlations between LAC and NAA peaks with functional outcome further suggest that MR spectroscopy may play a role in outcome prediction following cerebral infarction in higher primates.

Background: Spontaneous age-dependent epithelial cell hyperplasia occurs in the lateral and dorsal, but not the ventral, lobes of aging Brown Norway (BN) rats. Diminished antioxidant enzyme activities and increased formation of reactive oxygen species (ROS) promote the pathology of many aging disorders. We investigated the hypothesis that prostatic epithelial cell hyperplasia in the BN rat was related to age-dependent and/or lobe-specific changes in superoxide dismutase (SOD)., Materials and Methods: Using Western blots, immunohistochemistry and enzyme activity assays we determined the levels of protein expression, subcellular localization, and activities, respectively, of the three SOD isoforms, cytoplasmic SOD1, mitochondrial SOD2, and extracellular SOD3 in the ventral, lateral, and dorsal prostate lobes of 4-month-old rats with normal prostate morphology, in 24-month-old rats with lobe-specific hyperplasia and in older 30-month-old rats., Results: We observed little change in SOD activities as a function of age, although expression of SOD3 increased in the prostatic lobes of older rats. SOD2 levels were higher in the lateral lobe of 4- and 24-month-old rats, but declined by 30 months of age to levels in the ventral and dorsal lobes. SOD1 was localized by immunohistochemistry to the nuclei of epithelial cells in all lobes, but the number of immunopositive nuclei increased in the lateral and dorsal lobes of 24-month-old animals. The concentration of zinc was highest in the prostate lobes of 24-month-old animals., Conclusion: Based upon our data, superoxide dismutase is not significantly altered in the rat prostate during aging and thus is unlikely to be an important factor in the evolution of epithelial cell hyperplasia., ((c) 2005 Wiley-Liss, Inc.)

Purpose: Four-corner arthrodesis with scaphoid excision has been used to reduce pain and preserve functional range of motion for patients with radioscaphoid arthritis. Early results of 4-corner arthrodesis with scaphoid excision using dorsal circular plate fixation are compared with reported results in the literature., Methods: We reviewed retrospectively the first 18 four-corner arthrodeses performed with this system by 4 hand surgeons. Two patients had revision surgery for nonunions before the study that were considered failures. Eight patients returned for final radiographs, objective examination, and functional questionnaire. The average follow-up period was 20 months (range, 13-33 mo). These results were compared with reported results in the literature using alternate fixation methods., Results: Radiographic union was achieved in only 3 wrists. Range of motion was 46% that of the opposite normal wrist and grip strength compared with the opposite wrist was 56%. Five patients would have the procedure again and 6 of 8 have returned to their original employment., Conclusions: Four-corner arthrodesis with scaphoid excision using a circular internal fixation plate produced a high number of nonunions. Grip strength and range of motion results also were inferior to those reported in the literature.

Background: Total homocysteine (tHcy) has been implicated as a risk factor for stroke and dementia, but the mechanism is unclear. White matter hyperintensities may be a risk factor for both, but studies of the relationship between tHcy and quantitative measures of white matter hyperintensity volume (WMHV) are lacking, especially in minority populations., Methods: A community-based sample of 259 subjects with baseline tHcy levels underwent pixel-based quantitative measurement of WMHV. We examined the relationship between tHcy and WMHV adjusting for age, sociodemographics, vascular risk factors, and B12 deficiency., Results: Higher levels of tHcy were associated with WMHV adjusting for sociodemographics and vascular risk factors., Conclusions: These cross-sectional data provide evidence that tHcy is a risk factor for white matter damage.

In previous studies of testicular biopsy tissue from healthy men, intratesticular testosterone (ITT) has been shown to be much higher than serum testosterone (T), suggesting that high ITT is needed relative to serum T for normal spermatogenesis in men. However, the quantitative relationship between ITT and spermatogenesis is not known. To begin to address this issue experimentally, we determined the dose-response relationship between human chorionic gonadotropin (hCG) and ITT to ascertain the minimum dose needed to maintain ITT in the normal range. Twenty-nine men with normal reproductive physiology were randomized to receive 200 mg T enanthate weekly in combination with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 wk. ITT was assessed in testicular fluid obtained by percutaneous fine needle aspiration at baseline and at the end of treatment. Baseline serum T (14.1 nmol/liter) was 1.2% of ITT (1174 nmol/liter). LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group, and 26% greater than baseline in the 500 IU hCG group. These results demonstrate that relatively low dose hCG maintains ITT within the normal range in healthy men with gonadotropin suppression. Extensions of this study will allow determination of the ITT concentration threshold required to maintain spermatogenesis in man.

Little is known about how human spermatogenesis is regulated, so it is not surprising that there have been few breakthroughs in the treatment of male infertility resulting from abnormalities of spermatogenesis. Testosterone is the predominant intratesticular steroid in both the rat and man. Previous studies have shown that the testosterone concentration within the rat testis that is required for the quantitative maintenance of spermatogenesis is far higher than the total testosterone concentration in rat blood, indicating that much of the testosterone within the testis might be biologically inactive. In contrast to the rat, little is known about the androgen requirements for human spermatogenesis, in part because, until recently, a minimally invasive method suitable for obtaining intratesticular fluids from the human testis has not been available. Percutaneous aspiration now makes it feasible to do so. A major objective of the present study was to assay the bioactive androgen concentration within the testes of normal, fertile men. Percutaneous aspiration was used to obtain intratesticular fluid from such men, and we adapted a highly sensitive recombinant protein mammalian cell-based bioassay to measure androgen bioactivity. Total intratesticular testosterone concentration, which we define as immunoreactive testosterone as measured by radioimmunoassay, was well in excess of that in serum (1236 +/- 86 nM vs 11.7 +/- 0.7 nM). The concentration of bioactive androgens within the normal human testis was found to be about two thirds that of the total testosterone concentration. Interestingly, the concentration of the major, known binding proteins for testosterone within the testis, serum hormone-binding globulin (SHBG)/ABP (52.4 +/- 9.7 nM), was insufficient to account for the difference between total testosterone and bioactive androgens. This indicates that, in addition to its binding to SHBG/ABP, androgens may also be bound by unknown molecules, and that this contributes to reducing androgen bioactivity. These observations could have relevance for understanding the relationship between spermatogenesis and intratesticular androgens in normal men and in men diagnosed with infertility.

It is the coexistence of physical and cognitive impairments, together with emotional and social issues in a disease with an uncertain course, that makes MS rehabilitation unique and challenging. Inpatient rehabilitation improves functional independence but has only limited success improving the level of neurologic impairment. Benefits are usually not long lasting. Severely disabled people derive equal or more benefit than those who are less disabled, but cognitive problems and ataxia tend to be refractory. There is now good evidence that exercise can improve fitness and function for those with mild MS and helps to maintain function for those with moderate to severe disability. Therapy can be performed over 6 to 15 weeks in outpatient or home-based settings or as a weekly day program lasting several months. Several different forms of exercise have been investigated. For most individuals, aerobic exercise that incorporates a degree of balance training and socialization is recommended. Time constraints, access, impairment level, personal preferences, motivations, and funding sources influence the prescription for exercise and other components of rehabilitation. Just as immunomodulatory drugs must be taken on a continual basis and be adjusted as the disease progresses, so should rehabilitation be viewed as an ongoing process to maintain and restore maximum function and QOL.