The docking of chiral analytes on proline-based chiral stationary phases: A molecular dynamics study of selectivity.

Molecular dynamics simulations are employed to examine the selectivity of four proline-based chiral stationary phases in two solvent environments, a relatively apolar n-hexane/2-propanol solvent and a polar water/methanol solvent. The four chiral surfaces are based on a BOC-terminated diproline, a TMA-terminated diproline, a TMA-terminated triproline and a TMA-terminated hexaproline. This range of chiral selectors allows an analysis of the impact of oligomer length and terminal group on selectivity while the two solvent environments indicate the impact of solvent hydrogen bonding and polarity. The selector-analyte interactions are examined for six closely related analytes that each have an aromatic moiety, a hydrogen, and an alcohol group directly bonded to the stereocenter. The analytes differ in the nature of the aromatic group (phenyl or anthracyl), in the attachment point (to the central ring or a side ring in the anthracyl), and in the fourth group bonded to the carbon (CH3, CF3, or C2H5). For each of the 48 solvent+selector+analyte systems, selectivity factors are calculated and, when possible, compared to experiment. The docking mode for these proline-based selectors is analyzed.

Poly-proline-based chiral stationary phases: a molecular dynamics study of triproline, tetraproline, pentaproline and hexaproline interfaces.

Poly-proline chains and derivatives have been recently examined as the basis for new chiral stationary phases in high performance liquid chromatography. The selectivity of poly-proline has been measured for peptides with up to ten proline units. In this article, we employ molecular dynamics simulations to examine the interfacial structure and solvation of surface-bound poly-proline chiral selectors. Specifically, we study the interfacial structure of trimethylacetyl-terminated poly-proline chains with three-to-six prolines. The surface includes silanol groups and end-caps, to better capture the characteristics of the stationary phase, and the solvent is either a polar water/methanol or a relatively apolar n-hexane/2-propanol mixture. We begin with a comprehensive ab initio study of the conformers, their energies, and an assessment of conformer flexibility. Force fields have been developed for each poly-proline selector. Molecular dynamics simulations are employed to study the preferred backbone conformations and solvent hydrogen bonding for different poly-proline/solvent interfaces. For triproline, the effect of two different terminal groups, trimethylacetyl and t-butyl carbamate are compared.

Intelligent data analysis to model and understand live cell time-lapse sequences.

BACKGROUND: One important aspect of cellular function, which is at the basis of tissue homeostasis, is the delivery of proteins to their correct destinations. Significant advances in live cell microscopy have allowed tracking of these pathways by following the dynamics of fluorescently labelled proteins in living cells. OBJECTIVES: This paper explores intelligent data analysis techniques to model the dynamic behavior of proteins in living cells as well as to classify different experimental conditions. METHODS: We use a combination of decision tree classification and hidden Markov models. In particular, we introduce a novel approach to "align" hidden Markov models so that hidden states from different models can be cross-compared. RESULTS: Our models capture the dynamics of two experimental conditions accurately with a stable hidden state for control data and multiple (less stable) states for the experimental data recapitulating the behaviour of particle trajectories within live cell time-lapse data. CONCLUSIONS: In addition to having successfully developed an automated framework for the classification of protein transport dynamics from live cell time-lapse data our model allows us to understand the dynamics of a complex trafficking pathway in living cells in culture.

On simulations of complex interfaces: molecular dynamics simulations of stationary phases.

Methodological considerations for molecular dynamics simulations of complex interfaces are presented in this article. A slab geometry is examined in the context of stationary phases where selectivity occurs predominantly in pores within silica beads. Specifically, we examine the Whelk-O1 interface with n-hexane/2-propanol, the TMA-(Pro)(2)-N(CH(3))-tether interface with n-hexane/2-propanol, and the C(18)H(37)Si interface with water/methanol. The following methodological issues are considered in detail: The assessment of solvent density within the confined region and excluded volume of the interface; the structural equilibration of surface-bound moieties; solvent equilibration for binary mixtures; surface size effects, and periodic boundary conditions; the treatment of electrostatic interactions; and the impact of pore size.

Proline-based chiral stationary phases: a molecular dynamics study of the interfacial structure.

Proline chains have generated considerable interest as a possible basis for new selectors in chiral chromatography. In this article, we employ molecular dynamics simulations to examine the interfacial structure of two diproline chiral selectors, one with a terminal trimethylacetyl group and one with a terminal t-butyl carbamate group. The solvents consist of a relatively apolar n-hexane/2-propanol and a polar water/methanol mixture. We begin with electronic structure calculations for the two chiral selectors to assess the energetics of conformational changes, particularly along the backbone where the amide bonds can alternate between cis and trans conformations. Force fields have been developed for the two selectors, based on these ab initio calculations. Molecular dynamics simulations of the selective interfaces are performed to examine the preferred backbone conformations, as a function of end-group and solvent. The full chiral surface includes the diproline selectors, trimethylsilyl end-caps, and silanol groups. Connection is made with selectivity measurements on these interfaces, where significant differences are observed between these two very similar selectors.

Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation.

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness=1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N=27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N=17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers.

A controlled study of MRI signal hyperintensities in older depressed patients with and without hypertension.

OBJECTIVES: To compare the frequency/severity of signal hyperintensities--likely markers of cerebrovascular disease--in the subcortical gray and deep white matter on magnetic resonance imaging (MRI) scans of brains of hypertensive and normotensive older depressed and nondepressed comparison subjects. DESIGN: Between-groups comparison of cross-sectional MRI data employing analyses of covariance controlling for the effects of age, gender, and height. SETTING: A comprehensive inpatient-outpatient geriatric psychiatry service in a university hospital. PARTICIPANTS: Nondemented older depressed (n = 81) and nondepressed comparison (n = 70) subjects divided into four groups (hypertensive depressed (n = 40), hypertensive normals (n = 21), normotensive depressed (n = 41), normotensive normals (n = 49)). MEASUREMENTS: Signal hyperintensities were rated on T-2 weighted MRI scans blind to patient diagnoses employing two standardized hyperintensity rating systems (Fazekas, Boyko). RESULTS: Hypertensive depressives had significantly more- severe hyperintensity ratings in both subcortical gray and deep white matter than did normotensive depressives and controls (P < .05) and significantly more-severe hyperintensity ratings only in subcortical gray matter (P < .05) than did hypertensive controls. Hypertensive controls had significantly more-severe ratings in deep white matter than either normotensive group (P < .05). CONCLUSIONS: Findings suggest a relationship between deep white matter hyperintensities and hypertension (regardless of depressive state), and a particular role of subcortical gray matter hyperintensities (possibly interacting with more-severe deep white matter lesions) in older depressed hypertensives, as compared with older depressed normotensives of similar ages and severity of depression. These data support possible heterogeneous pathogenic contributions in late-life depression subgroups, one of which appears to be influenced by cerebrovascular disease.

Magnetic resonance imaging of the fetus in congenital intrathoracic disorders: preliminary observations.

BACKGROUND AND OBJECTIVE: Advances in magnetic resonance imaging (MRI) provide high-quality images of the intrathoracic organs. We studied the ability of MRI to define spatial relationships of the fetal lungs and measured lung volume in two cases of congenital diaphragmatic hernia (CDH), one of severe oligohydramnios secondary to bilateral cystic renal dysplasia and one case of prenatal chylothorax. PATIENTS AND METHODS: We performed pelvic MRI using single-shot fast spin echo (SSFSE) pulse sequence in four pregnant women referred because of abnormal prenatal ultrasound (US) findings associated with pulmonary hypoplasia. RESULTS: The exact anatomic position of the contents of the hernia in CDH, including the position of the liver, was better defined with MRI. Pleural effusions were identified as well as the renal abnormality in the case of oligohydramnios. Lung volume was measured and the degree of pulmonary hypoplasia was quantified in every case. Lung-to-thorax ratio was calculated in the case of fetal chylothorax. CONCLUSION: Ongoing work suggests that MRI can provide additional detailed quantitative information in prenatal disorders associated with fetal lung compression and resulting hypoplasia. Correlation of fetal lung volume with postnatal management and outcome may affect prognosis in these cases.

Reduced anterior cingulate gyrus volume correlates with executive dysfunction in men with first-episode schizophrenia.

Although frontal lobe structural and functional abnormalities have been identified in schizophrenia, their relationship remains elusive. Because the frontal lobes are both structurally and functionally heterogeneous, it is possible that some measures of frontal lobe structure may not have accurately identified relevant frontal lobe subregions. The authors hypothesized that the volumes of two dorsal, 'archicortical' subregions (i.e. superior frontal gyrus and anterior cingulate gyrus), but not a ventral, 'paleocortical' subregion (i.e. orbital frontal region) would be significantly and selectively correlated with executive and motor dysfunction in patients with schizophrenia as previously reported for the anterior hippocampal region. Volumes of these frontal lobe subregions were measured from magnetic resonance images based on sulcal anatomy in 20 men and 15 women with first-episode schizophrenia. All patients completed a comprehensive neuropsychological test battery while clinically stabilized that encompassed six domains of functioning: attention, executive, motor, visuospatial, memory and language. Findings indicated that reduced anterior cingulate gyrus volume was significantly correlated with worse executive functioning in men; among women, there were no significant correlations. Among men, anterior cingulate gyrus volume was significantly more strongly correlated with executive functioning than with attention, visuospatial, memory, language and general intellectual functioning. Neither executive nor motor functioning was significantly more strongly correlated with the dorsal 'archicortical' volumes than with orbital frontal volume. These findings suggest a link between executive deficits and dysfunction of the dorsal 'archicortical' system and implicate sex differences in their relationship in first-episode schizophrenia.

Cerebral volume asymmetries in schizophrenia and mood disorders: a quantitative magnetic resonance imaging study.

Multiple abnormalities of brain structure have been identified in schizophrenia using in vivo neuroimaging methods, but little is known about the diagnostic specificity of these abnormalities. In a prior study of first-episode schizophrenia we found that this group lacked the normal pattern of cerebral volume asymmetries. Data from that study were combined with data from groups of patients with more chronic schizophrenia, and with bipolar and unipolar mood disorders, to determine the specificity of this abnormality to diagnostic subgroups defined by syndromal status or chronicity. The total sample comprised 235 patients (67 healthy volunteers, 81 patients with mood disorders or schizoaffective disorders, and 87 with schizophrenia or schizophreniform disorders). Asymmetries of regional cerebral volumes were measured on coronal magnetic resonance images with 3.1-mm contiguous slices and nominal in-plane resolution of 1 mm x 1 mm. Asymmetries differed significantly across groups in the occipitoparietal, prefrontal, and temporal regions. These asymmetries, and a composite index of asymmetry across regions ('torque'), all showed the same diagnostic group effect, with the schizophrenia group showing the least normal asymmetry, the mood disorder group intermediate asymmetry, and the control group the most marked asymmetry. No other diagnostic subgroup or chronicity effects were apparent. The findings support a 'continuum' rather than a 'diagnostic specificity' hypothesis, and suggest that the reduction of normal hemispheric asymmetries may mark a neurodevelopmental risk factor for major mental illnesses, and that some syndromal characteristics may be correlated with the degree of deviation from the normal anatomic pattern.

Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder.

BACKGROUND: Functional neuroimaging studies have implicated the frontal lobes and the hippocampus-amygdala complex in the pathophysiology of obsessive-compulsive disorder (OCD). These brain regions have not been well investigated in patients with OCD, however, using magnetic resonance imaging. METHODS: Volumes of the superior frontal gyrus, anterior cingulate gyrus, orbital frontal region, hippocampus, and amygdala were computed from contiguous magnetic resonance images in a sample of 26 patients with OCD and 26 healthy comparison subjects. RESULTS: Patients with OCD had significantly reduced bilateral orbital frontal and amygdala volumes compared with healthy comparison subjects and lacked the normal hemispheric asymmetry of the hippocampus-amygdala complex. Neither brain structure volumes nor asymmetry indices were significantly correlated with total illness duration or length of current OCD episode. CONCLUSIONS: Findings of reduced orbital frontal and amygdala volumes in patients implicate a structural abnormality of these brain regions in the pathophysiology of OCD. Absence of the normal hemispheric asymmetry of the hippocampus-amygdala complex in patients is consistent with an anomalous neurodevelopmental process.

Hippocampal/amygdala volumes in geriatric depression.

BACKGROUND: The hippocampus, amygdala and related functional circuits have been implicated in the regulation of emotional expression and memory processes, which are affected in major depression. Several recent investigations have reported abnormalities in these structures in adult and elderly depressives. METHODS: Elderly DSM-III-R unipolar depressives (N = 40) and normal controls (N = 46) participated in a magnetic resonance imaging study (1.0T). Brain images were obtained in the coronal plane. Using established anatomical guidelines for structure delineation, volumetric measurements of left and right hippocampus and anterior hippocampus/amygdala complex were completed under blinded conditions using a semi-automated computer mensuration system, with patients and controls in random order. RESULTS: Medial temporal volumes did not significantly distinguish either elderly depressed and age-similar normal control subjects, or late onset and early onset depressed patients (ANCOVA). Major overlap of measured volumes existed between patient and control groups. In depressives, hippocampal volumes significantly correlated with age, and cognitive and depression ratings, but not with number of prior depressive episodes or age-at-onset of first depression. CONCLUSIONS: Hippocampal volumes do not discriminate a typical clinical population of elderly depressed patients from age-similar normal control subjects. If hippocampal dysfunction contributes to a diagnosis of syndromal depression in the elderly, such dysfunction does not appear to be regularly reflected in structural abnormalities captured by volumetric measurement as conducted. On the other hand, relationships between hippocampal volumes and clinical phenomena in depressives, but not controls, suggest potentially meaningful interactions between hippocampal structure and the expression of major depression in the elderly.

Investigation of frontal lobe subregions in first-episode schizophrenia.

The evidence for frontal lobe structural abnormalities in schizophrenia using magnetic resonance (MR) imaging has been mixed, but most studies used either single slice measures or total volumes of a single frontal region, neither of which is sensitive to potential volume differences in more specific subregions. This study employed reliable methods for parcellation of the frontal lobes from MR images based on the sulcal anatomy. Following a cytoarchitectonic theory that distinguishes dorsomedial (archicortically derived) from ventrolateral (paleocortically derived) frontal subregions, we measured the superior frontal gyrus, anterior cingulate gyrus, and orbital frontal region in 19 first-episode schizophrenia patients and 26 healthy comparison subjects. Results indicated that male patients had significantly larger right orbital frontal volume compared to their left orbital frontal volume and compared to healthy men. Among male patients larger right orbital frontal volume was significantly correlated with smaller right 'archicortical' (i.e. anterior cingulate and superior frontal gyri) volume. Furthermore, the ratio of right orbital frontal to right 'archicortical' volume was significantly and positively correlated with level of delusions among male patients. These findings suggest that there may be reciprocal controls on 'archicortical' and 'paleocortical' neurodevelopment among men with schizophrenia, and that larger paleocortical relative to archicortical volumes may be associated with increased delusions.

Neuropsychological functioning and MRI signal hyperintensities in geriatric depression.

OBJECTIVE: The purpose of this study was to examine the relationship between signal hyperintensities--a probable marker of underlying pathology--on T2-weighted magnetic resonance brain scans and neuropsychological test findings in elderly depressed and normal subjects. METHOD: Elderly subjects with a DSM-III-R diagnosis of major depression (N=41) and normal elderly comparison subjects (N=38) participated in a magnetic resonance imaging study (1.0-T) of signal hyperintensities in periventricular, deep white matter, and subcortical gray matter. Hard copies of scans were rated in random order by research psychiatrists blind to diagnosis; the modified Fazekas hyperintensity rating scale was used. Cognitive performance was independently assessed with a comprehensive neuropsychological battery. Clinical and demographic differences between groups were assessed by t tests and chi-square analysis. Relationships between neuropsychological performance and diagnosis and hyperintensities and their interaction were analyzed by using analysis of covariance, with adjustment for age and education. RESULTS: Elderly depressed subjects manifested poorer cognitive performance on several tests than normal comparison subjects. A significant interaction between hyperintensity location/severity and presence/absence of depression on cognitive performance was found: depressed patients with moderate-to-severe deep white matter hyperintensities demonstrated worse performance on general and delayed recall memory indices, executive functioning and language testing than depressed patients without such lesions and normal elderly subjects with or without deep white matter changes. CONCLUSIONS: Findings validate cognitive performance decrements in geriatric depression and suggest possible neuroanatomic vulnerabilities to developing particular neuropsychological dysfunction in depressed subjects.

Low-dose spiral computed tomography of the thorax: comparison with the standard-dose technique.

RATIONALE AND OBJECTIVES: This study was conducted to determine whether significant reduction in radiation dose (250 mAs-->50 mAs), in chest computed tomography (CT) using volume acquisition affects image quality or the detectability of pathologic findings in the lung and mediastinum. METHODS: Phantom studies were conducted to evaluate resolution and noise level, then a patient study was then done. Fifty consecutive patients (10 normal and 40 abnormal) cases were examined. After a scan (250 mAs, 120OkVp) of the entire thorax, five additional slices (50 mAs, 120kVp) at the level of the abnormality were obtained. Three independent observers evaluated the visibility of normal lung and mediastinal structures, as well as image noise. The mean score was compared between the standard and low doses. In a second study, an independent evaluation of the presence or absence of pathologic findings was made by four observers. RESULTS: Lucite phantom studies demonstrated diminished low-contrast resolution and increased noise level for the low-dose technique. Observers assessed more noise in the low-dose images (P < 0.001). The normal structures were judged to be more visible with standard dose (P < 0.01), but the magnitude of the judged differences was small especially in the lung. No differences were found in the detection of lung and mediastinal abnormalities (P > 0.10). CONCLUSIONS: The low-dose technique was effective in demonstrating pathologic findings for the lung and mediastinum. Low-dose spiral CT should be considered as a viable alternative to standard-dose spiral CT.

Neuroanatomic localization of magnetic resonance imaging signal hyperintensities in geriatric depression.

BACKGROUND AND PURPOSE: Increased frequency and severity of signal hyperintensities have been regularly reported in elderly depressed patients compared with normal subjects, however, greater neuroanatomic localization of lesions has been limited. METHODS: T2-weighted MRI scans in elderly depressed patients (n = 35) and normal comparison subjects (n = 31) were assessed for signal hyperintensities in lateralized discrete brain regions. RESULTS: Logistic regression revealed that left frontal deep white matter (P<.005) and left putaminal (P<.04) hyperintensities significantly predicted depressive group assignment. CONCLUSIONS: Findings suggest that greater neuroanatomic localization of hyperintensities than heretofore appreciated may relate to late-life depression.

Bilateral reductions in hippocampal volume in adults with epilepsy and a history of febrile seizures.

OBJECTIVES: To examine the degree and frequency of reductions in hippocampal volume in patients with temporal lobe epilepsy with and without a history of febrile seizures. METHODS: In vivo measures of hippocampal volume were computed from three dimensional gradient echo (FLASH) images in 44 patients undergoing comprehensive evaluations for epilepsy surgery. Twenty one patients (48%) reported a history of febrile seizures. The volumes from these patients were compared with those from 23 patients without a history of febrile seizures and 34 healthy controls. RESULTS: The febrile seizure group had significant reductions in volume, both ipsilateral (30% decrease) and contralateral (15% decrease), to the EEG seizure focus. Twelve of 18 patients with febrile seizures exhibited clinically significant ipsilateral volume reductions, defined as volumes falling 2 SD below the mean obtained from the control sample. Only four of 19 patients without febrile seizures exhibited this degree of reduction. No significant correlations were found between seizure variables (for example, duration of epilepsy, seizure frequency) and ipsilateral reductions in volume. However, a significant inverse correlation (r=-0.45, P<0.05) between seizure frequency and the volume of the hippocampus contralateral to the seizure focus was found in the febrile seizure group. CONCLUSION: These results suggest that a history of febrile seizures is associated with the finding of a smaller hippocampus on the side ipsilateral to the subsequent temporal lobe focus whereas chronic factors seem to be be related to pathology contralateral to the seizure focus.

Brain morphometric comparison of first-episode schizophrenia and temporal lobe epilepsy.

BACKGROUND: Converging evidence has suggested that the abnormalities in brain morphology observed in schizophrenia are similar to those seen in temporal lobe epilepsy (TLE). The purpose of this study was to compare the features of these groups directly with measures of the brain using magnetic resonance (MR) morphometry. METHOD: Morphometric measures of ventricular and hippocampal volumes obtained from FLASH MR images were studied in 32 patients with first-episode schizophrenia (FES), 39 patients with TLE (21 left, 18 right), and 42 healthy controls. RESULTS: Ventricular volumes in the FES and TLE groups were both significantly larger that those seen in controls and did not differ from each other. The FES group showed significantly larger temporal horns, while the TLE group had relatively larger frontal horns. Analyses of hippocampal volumes revealed a significant group by hemisphere effect. The FES group showed relative reductions in left hippocampal volume that were comparable only to TLE patients with seizures originating from the left hemisphere. CONCLUSION: The results indicate that FES and TLE groups both show evidence of ventricular enlargement. Lateralised morphological abnormalities of the hippocampal formation in FES and left TLE are comparable, and may be specific to temporolimbic regions.

Carotid artery stenosis: optimization of CT angiography with a combination of shaded surface display and source images.

PURPOSE: To evaluate the accuracy of CT angiography of occlusive disease of the carotid arteries using three-dimensional surface-rendered images alone and in conjunction with display of axial source images. METHODS: Forty-eight symptomatic patients had conventional angiography followed by CT angiography within 24 hours. Images of 96 carotid arteries were acquired using contrast-enhanced spiral CT. Image postprocessing was performed on a free-standing workstation to produce 3-D shaded surface display (SSD) images. Two readers independently evaluated the CT angiographic (SSD) images and then reevaluated each case while simultaneously reviewing the SSD and axial source images. Digital subtraction angiograms were evaluated in a separate session and eventually compared with CT angiograms. All evaluations were performed under blinded conditions to control for reader bias. RESULTS: SSD images alone underestimated stenosis relative to angiograms whereas combined SSD and axial images did not. CONCLUSION: SSD angiograms in conjunction with the source images are better than SSD images alone in estimating the degree of stenosis in carotid artery disease.