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This study applied (1)H-MRS in the thalamus of schizophrenic patients and healthy subjects. There were no differences in the metabolite ratios (NAA/Cr, Cho/Cr or mI/Cr) between the two groups. Relationships were noted between NAA/Cr and age in patients with a trend toward this correlation in controls, suggesting an effect of age on the metabolism of the thalamus.
RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.
In the elderly diabetic patient, therapeutic decision making is not entirely based on evidence acquired from large-scale studies conducted in young adults. In this population autonomy, co-morbidity and prognosis are all objective parameters which must be taken into consideration. Frail patients run the risk of hypoglycaemia if the therapeutic goal is too strict. Frail patients can be distinguished from autonomous patients free of serious co-morbidity using evaluation scales validated for geriatric patients enabling the establishment of appropriate goals for the treatment of diabetes without compromising the patients' quality-of-life.
Diabetic hyperosmolarity is a serious acute metabolic disorder mainly occurring in the frail elderly subject presenting age-related favoring factors (reduced sensation of thirst, altered endocrine regulation), disease-related favoring factors (cognitive impairment, poor nutritional status and/or loss of autonomy), and a triggering factor, generally infection. Diabetic hyperosmolarity can occur in a previously non-diabetic patient. Intense dehydration dominants the clinical picture. The prognosis depends largely on the underlying chronic disease.
This paper presents a method for the detection, representation and visualisation of the cerebral vascular tree and its application to magnetic resonance angiography (MRA) images. The detection method is an iterative tracking of the vessel centreline with subvoxel accuracy and precise orientation estimation. This tracking algorithm deals with forks. Centrelines of the vessels are modelled by second-order B-spline. This method is used to obtain a high-level description of the whole vascular network. Applications to real angiographic data are presented. An MRA sequence has been designed, and a global segmentation of the whole vascular tree is realised in three steps. Applications of this work are accurate 3D representation of the vessel centreline and of the vascular tree, and visualisation. The tracking process is also successfully applied to 3D contrast enhanced MR digital subtracted angiography (3D-CE-MRA) of the inferior member vessels. In addition, detection of artery stenosis for routine clinical use is possible due to the high precision of the tracking algorithm.
BACKGROUND AND OBJECTIVES: Cerebral MRIs of normal aging and Alzheimer's disease (AD) frequently reveal corpus callosum (CC) atrophy, white matter hyperintensity (WMH), and hippocampal atrophy. However, their relationship or the relationship between these findings and cognitive function has not been fully studied. We investigated the relationship between CC atrophy, WMH, and hippocampal atrophy, together with frontal executive dysfunction in both normal aging and AD. METHOD: We examined 170 randomly selected residents from a designated community: 99 Clinical Dementia Rating (CDR) 0 (healthy, control group, HC) participants, 54 CDR 0.5 (very mild AD) patients, and 17 CDR 1 & 2 (probable AD) patients. By means of MRI, WMH and CC atrophy were visually rated. Four portions of the CC and the hippocampal width were measured. A Mini-Mental State Examination and Cognitive Abilities Screening Instrument (CASI) were performed to assess global function. For the frontal function, the CASI subitems of attention and word fluency, letter-based fluency, the Digit Symbol test of the WAIS-R, and Trail Making Tests were performed. RESULTS: Those patients with CDR 1 & 2 had both hippocampal and CC atrophy, whereas the CDR 0.5 patients had only hippocampal atrophy. Frontal executive dysfunction was associated with CC atrophy in both the HC and AD groups. Significant Spearman correlations were noted between CC atrophy and WMH in both groups. The combined effect of CC atrophy and WMH was noted only in the verbal fluency test in the HC group. CONCLUSION: In both groups, CC atrophy was associated with frontal executive dysfunction. The combined effect of CC atrophy and WMH in normal aging was probably due to subclinical ischemic conditions.
Several nonparametric regressors have been applied to modeling quantitative structure-activity relationship (QSAR) data. The simplest regressor, the Nadaraya-Watson, was assessed in a genuine multivariate setting. Other regressors, the local linear and the shifted Nadaraya-Watson, were implemented within additive models--a computationally more expedient approach, better suited for low-density designs. Performances were benchmarked against the nonlinear method of smoothing splines. A linear reference point was provided by multilinear regression (MLR). Variable selection was explored using systematic combinations of different variables and combinations of principal components. For the data set examined, 47 inhibitors of dopamine beta-hydroxylase, the additive nonparametric regressors have greater predictive accuracy (as measured by the mean absolute error of the predictions or the Pearson correlation in cross-validation trails) than MLR. The use of principal components did not improve the performance of the nonparametric regressors over use of the original descriptors, since the original descriptors are not strongly correlated. It remains to be seen if the nonparametric regressors can be successfully coupled with better variable selection and dimensionality reduction in the context of high-dimensional QSARs.
A set of disubstituted tetracyclic lactones has been synthesized and tested for potential antitumor activity. Several of them possess a noticeable cytotoxicity against L1210 and HT-29 colon cells in vitro. Relationships between chain nature and biological properties were sought. Lactones with a pentyl or hexyl substituent at C-11 are the most active ones. The introduction of a functional group at the side chain of C-11 modified the potency; carboxylic acid and primary amine decreased the cytotoxicity, whereas a cyano group increased the activity. An extensive structure-activity relationship study of these derivatives, including carbon homologues and bioisosteres has been performed. The synthesis and cytotoxicity of these compounds are discussed. Two lactones are recognized as potential lead compounds.
Although it is recognized that psychosocial variables influence the expression of psychopathology following trauma exposure, physiological variables have received less attention as potential mediators of psychological outcome in trauma victims. The purpose of this study was to examine the relationship of head injury to psychological outcome in 171 combat veterans seeking compensation for service-connected disabilities for mental disorders attributed to etiologies other than head injury. Veterans underwent structured psychiatric diagnostic interview and completed self-report measures of combat exposure, posttraumatic stress disorder (PTSD), depression, and occurrence of head injury. Comparisons between veterans with and without history of head injury indicated that head injury was associated with more severe depression. Regression analysis suggested that head injury predicted depression, but not PTSD, severity.
A Structured Clinical Interview for the DSM-IV (SCID) and psychological testing were administered to 260 combat veterans in order to investigate the relationship between symptoms of post-traumatic stress disorder (PTSD) and melancholic features of depression. Sixty-seven percent of PTSD patients experiencing comorbid major depression acknowledged symptoms indicative of a melancholic-depression subtype. Correlational and regression analyses show that the presence of melancholic features is related to severity of emotional-numbing experienced by the PTSD patients. These results suggest PTSD patients are likely to experience depressive episodes phenomenologically similar to melancholic-depression. It is likely that acknowledgment of melancholic symptoms is due to (a) the inclusion of guilt as a melancholic feature, and (b) the similarities between emotional numbing symptoms and other melancholic features.
We present a new approach to automatically define a quasi-optimal minimal set of pharmacophoric points mapping the interaction properties of a user-defined ligand binding site. The method is based on a fitting algorithm where a grid of sampled interaction energies of the target protein with small chemical fragments in the binding site is approximated by a linear expansion of Gaussian functions. A heuristic approximation selects from this expansion the smallest possible set of Gaussians required to describe the interaction properties of the binding site within a prespecified accuracy. We have evaluated the performance of the approach by comparing the computed Gaussians with the positions of aromatic sites found in experimental protein-ligand complexes. For a set of 53 complexes, good correspondence is found in general. At a 95% significance level, approximately 65% of the predicted interaction points have an aromatic binding site within 1.5 A. We then studied the utility of these points in docking using the program DOCK. Short docking times, with an average of approximately 0.18 s per conformer, are obtained, while retaining, both for rigid and flexible docking, the ability to sample native-like binding modes for the ligand. An average 4-5-fold speed-up in docking times and a similar success rate is estimated with respect to the standard DOCK protocol.
Attention and memory performances were studied in Persian Gulf War veterans with and without posttraumatic stress disorder (PTSD) diagnoses. Veterans diagnosed with PTSD showed relative performance deficiencies on tasks of sustained attention, mental manipulation, initial acquisition of information, and retroactive interference. Their performances were also characterized by errors of commission and intrusion. The tendency toward response disinhibition and intrusion on cognitive tasks was correlated positively with reexperiencing symptoms and negatively with avoidance-numbing symptoms. These cognitive deficit patterns are consistent with models of PTSD that emphasize the role of hyperarousal and implicate dysfunction of frontal-subcortical systems. Results suggest that intrusion of traumatic memories in PTSD may not be limited to trauma-related cognitions but instead reflects a more general pattern of disinhibition.
Attention, learning, memory, and estimated intellectual potential were examined in 26 Vietnam veterans diagnosed with posttraumatic stress disorder (PTSD) and in 21 Vietnam veterans without mental disorders. Results revealed PTSD-associated cognitive deficits on tasks of sustained attention, working memory, initial learning, and estimated premorbid intelligence but not on measures of focus of attention, shift of attention, or memory savings. Cognitive task performances adjusted for estimated native intelligence remained negatively correlated with PTSD severity. An intellectual measure adjusted for cognitive task performances was negatively correlated with PTSD severity, even after the authors statistically controlled the level of combat exposure. Results suggested that although intellectual resources may constitute a vulnerability-protective factor for PTSD development, PTSD was associated with cognitive impairment independent of intellectual functioning.
Sixty combat veterans with posttraumatic stress disorder performed an emotional Stroop task under 1 of 4 contextual conditions designed to test theoretical explanations for an attentional bias suppression effect. Results revealed that when the emotional Stroop task was performed under conditions involving a future threat of either watching a combat video or giving a speech, attentional bias was inhibited. There was limited support for the prediction that the suppression effect was strongest when stressor content matched word content on the Stroop. In contrast to participants in the threat conditions, veterans who believed that they would receive additional compensation for speeded color naming or who believed that they would have no other experimental demands were slower when color naming combat-threat words. Potential theoretical explanations of the findings are discussed.
UNLABELLED: Patients with systemic sclerosis commonly exhibit increased arterial stiffness, which may be predictive of the overall severity of the disease. The aim of the present study was to check the stability of parameters of arterial stiffness after 1 year in this population. ERAMS is a French multicentric prospective study designed to identify a link between arterial distensibility and outcome in 100 patients with systemic sclerosis. Arterial distensibility was evaluated by 24-h ambulatory monitoring of QKD interval along with blood pressure (BP) and heart rate (HR) (four measurements/hour). The index QKD(100-60), which is linked to aortic distensibility, was calculated automatically. QKD(100-60) is the value of QKD (which depends on pulse wave velocity) for 100 mm Hg sBP and 60 bpm HR. The reproducibility of QKD(100-60) was assessed on the first patients to be followed up for a complete year. So far the 100 patients have been recruited from 14 participating centres and 48 were re-evaluated after 1 year. QKD(100-60) was highly reproducible: 201 +/- 6 vs202 +/- 18 msec, standard deviation of difference = 13 msec. IN CONCLUSION: determination of QKD(100-60) to assess arterial stiffness gives stable results over 1 year in patients with systemic sclerosis.
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Hyperhomocysteinaemia is a risk factor for premature atherosclerosis and venous thromboembolic disease. Supplementation with folic acid and vitamin B6 has been shown to decrease plasma homocysteine but data fail to assess an effect on the progression of vascular disease. We measured plasma homocysteine and two markers of endothelial injury (plasma soluble thrombomodulin and von Willebrand factor) at baseline and after 3 months of treatment with folic acid and vitamin B6. After this treatment there was a significant decrease in fasting soluble thrombomodulin (-15 ng/ml, 95%CI 5-22.2). Von Willebrand factor was significantly raised after methionine load at baseline but did not significantly rise after supplementation.
BACKGROUND: We investigated the possible role of antiphospholipid (APA) and anti-human 2-glycoprotein I (beta2-GPI) antibodies (Ab) in thrombosis and atherosclerosis in human immunodeficiency (HIV)-positive patients, in whom they seem to be more frequent. METHODS: We measured APA and anti-beta2-GPI Ab in 58 HIV-positive patients together with markers of disease progression, circulating beta2-GPI, plasma lipids, biological markers of endothelial activation and integrity (plasma thrombomodulin, von Willebrand factor, vascular cell adhesion molecule 1) and with antimalonic dialdehyde antibodies (anti-MDA Ab). RESULTS: We found a 41% frequency of IgG APA in the HIV-positive patients. APA IgMs were rarely positive (7%), and anti-beta2-GPI IgGs were positive in 3-4% patients. There was no correlation between APA or anti-beta2-GPI Ab and the presence of opportunistic infections. Although plasma thrombomodulin, von Willebrand factor and vascular cell adhesion molecule 1 were significantly increased in the HIV-positive patients, APA was correlated only with vascular cell adhesion molecule 1, suggesting that APAs are correlated with endothelial activation but not with vascular endothelial lesions. A correlation between APA and anti-MDA IgG was demonstrated using multivariate analysis (r=0.542, P < 0.0001), suggesting a relationship between the targets of these antibodies. Finally, IgG APAs are frequent in HIV infection but are not correlated with biological markers of endothelial injury. CONCLUSION: Our results do not support a role for APA or anti-beta2-GPI in HIV-associated silent vascular endothelial damage. However, the role of these autoantibodies in clinically relevant thrombotic events should be investigated in HIV-positive patients.