Photon-Modulated Bond Covalency of [Sm(II)(η9-C9H9)2].

Lanthanides are widely assumed not to form covalent bonds due to the localized nature of their 4f valence electrons. This work demonstrates that the ionic bond of Sm(II) with cyclononatetraenyl (η9-C9H9-) in [Sm(η9-C9H9)2] can be modulated and becomes more covalent by photon-induced transfer of Sm 4f electrons to Sm 5d orbitals. This photon-induced change in bonding properties facilitates a subsequent reconfiguration of [Sm(η9-C9H9)2]. As a result, Sm-C bond length contraction is detected and the local Sm coordination environment exhibits more extensive disorder. Both Sm 4f and 5d electrons have increased participation in covalent Sm-ligand interactions. The Sm L3-edge valence band resonant inelastic X-ray scattering (VB-RIXS), high-resolution X-ray absorption near-edge structure (HR-XANES), and quantum chemical computations showcase a spectroscopic methodology for in-depth studies of bond covalency of lanthanide atoms.

Use of "omics" technologies to dissect neurologic disease.

Over the past 5 years, the advent of massively parallel technologies for understanding disease at the molecular level accompanied by simultaneous rapid development of the computational tools needed to analyze and filter such data has revolutionized medical science. These "next-generation" "omics" technologies include next-generation sequencing technology for detection of disease-associated DNA sequence variants, RNA sequencing for transcriptome and noncoding RNA analysis, quantitative detection of epigenomic dynamics, and chromatin immunoprecipitation sequencing analysis for DNA-protein interactions, interactome analysis for networks formed by protein-protein interactions, and metabolome analysis for metabolic systems. The analysis and integration of data derived from massively parallel technologies will significantly deepen our understanding of human disease, will inform functional studies, in vitro and in vivo model generation, and will advance the development of improved, personalized diagnostic tools and more effective therapeutic targets. In this chapter we review the classic genomic approaches for identifying mechanisms underlying human disease, and summarize the emerging "omics" technologies allowing massively parallel interrogation of biologic systems.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP).

Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P≤0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease.

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aß plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aß42/Aß40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Subclinical cerebrovascular disease in mild cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample. METHODS: A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI. RESULTS: WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-epsilon4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains. CONCLUSION: White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.

Endophenotypes in normal brain morphology and Alzheimer's disease: a review.

Late-onset Alzheimer's disease is a common complex disorder of old age. Though these types of disorders can be highly heritable, they differ from single-gene (Mendelian) diseases in that their causes are often multifactorial with both genetic and environmental components. Genetic risk factors that have been firmly implicated in the cause are mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes, which are found in large multi-generational families with an autosomal dominant pattern of disease inheritance, the apolipoprotein E (APOE)epsilon4 allele and the sortilin-related receptor (SORL1) gene. Environmental factors that have been associated with late-onset Alzheimer's disease include depressive illness, various vascular risk factors, level of education, head trauma and estrogen replacement therapy. This complexity may help explain their high prevalence from an evolutionary perspective, but the etiologic complexity makes identification of disease-related genes much more difficult. The "endophenotype" approach is an alternative method for measuring phenotypic variation that may facilitate the identification of susceptibility genes for complexly inherited traits. The usefulness of endophenotypes in genetic analyses of normal brain morphology and, in particular for Alzheimer's disease will be reviewed as will the implications of these findings for models of disease causation. Given that the pathways from genotypes to end-stage phenotypes are circuitous at best, identifying endophenotypes more proximal to the effects of genetic variation may expedite the attempts to link genetic variants to disorders.

Memory performance is related to amyloid and tau pathology in the hippocampus.

OBJECTIVE: To determine the relation of amyloid and tau pathology in the hippocampal formation to decline in memory and other cognitive functions in Alzheimer's disease (AD). METHODS: Regression models were used to relate semiquantitative measurements of amyloid plaques, neurofibrillary tangles (NFTs) and neuropil threads (NTs) at autopsy with antemortem performance in memory, abstract/visuospatial and language domains in two independent samples (n = 41, n = 66) that had repeated neuropsychological measurements before death. RESULTS: In both groups, the number of NFTs in the entorhinal cortex, subiculum and CA1 region was inversely associated with memory performance at the last visit before death. However, the number of amyloid plaques and NTs in the entorhinal cortex was also inversely related to poor memory function. Moreover, as the number of plaques or NTs increased in any region of the hippocampal formation, there was a more rapid decline in memory performance over time; a similar decline was associated with increasing numbers of NFTs in the CA1 or subiculum. In contrast, there was no association between amyloid plaques, NFTs or NTs in the frontal or parietal lobe and performance in memory, nor was there an association between plaques, NFTs or NTs in the hippocampal formation and cognitive functions unrelated to memory. DISCUSSION: This study implicates both amyloid deposition and tau pathology in the hippocampus as an early and late cause of decline in memory function over time in AD. Memory performance appears to be specifically related to the amount of amyloid plaques, NFTs and NTs in the entorhinal cortex and hippocampus.

Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study.

BACKGROUND AND OBJECTIVE: Previous studies relating smoking with the risk of dementia have been inconsistent and limited in their validity by short follow-up times, large intervals between baseline and follow-up assessments, and unspecific determination of dementia diagnosis. We re-assessed after longer follow-up time in the large population-based cohort of the Rotterdam Study whether smoking habits and pack-years of smoking are associated with the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: Prospective population-based cohort study in 6,868 participants, 55 years or older and free of dementia at baseline. First, Cox proportional hazard models were used to relate smoking status at baseline with the risks of incident dementia, VaD, and AD, using never smokers as the reference category in all analyses. Then Cox proportional hazard models were used to relate pack-years of smoking with the risks of incident dementia, VaD, and AD. To explore the impact of the APOEepsilon4 allele, sex, and age on the association between smoking status and dementia, we repeated all analyses stratifying, in separate models, by APOEepsilon4 genotype, sex, and median of age. RESULTS: After a mean follow-up time of 7.1 years, current smoking at baseline was associated with an increased risk of dementia (HR 1.47, 95% CI 1.18 to 1.86) and AD (HR 1.56, 95% CI 1.21 to 2.02). This increase in disease risk was restricted to persons without the APOEepsilon4 allele. There was no association between current smoking and risk of VaD, and there was no association between past smoking and risk of dementia, AD, or VaD. CONCLUSION: Current smoking increases the risk of dementia. This effect is more pronounced in persons without the APOEepsilon4 allele than APOEepsilon4 carriers.

Aggregation of vascular risk factors and risk of incident Alzheimer disease.

BACKGROUND: The prevalence of Alzheimer disease (AD) is increasing in the elderly, and vascular risk factors may increase its risk. OBJECTIVE: To explore the association of the aggregation of vascular risk factors with AD. METHODS: The authors followed 1,138 individuals without dementia at baseline (mean age 76.2) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD. RESULTS: Four risk factors (diabetes, hypertension, heart disease, and current smoking) were associated with a higher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of risk factors (diabetes + hypertension + heart disease + current smoking). The adjusted hazards ratio of probable AD for the presence of three or more risk factors was 3.4 (95% CI: 1.8, 6.3; p for trend < 0.0001) compared with no risk factors. Diabetes and current smoking were the strongest risk factors in isolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD when clustered with diabetes, smoking, or each other. CONCLUSIONS: The risk of Alzheimer disease (AD) increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome, given strong associations when only probable AD is considered.

Impact of plasma lipids and time on memory performance in healthy elderly without dementia.

OBJECTIVE: To examine the association of plasma lipid levels to changes in cognitive function in elderly subjects without dementia. METHODS: The authors examined changes in performance in tests of memory, visuospatial/cognitive, and language abilities in 1,147 elderly individuals without dementia or cognitive impairment at baseline followed for 7 years using generalized estimating equations. RESULTS: Performance in all cognitive domains declined significantly over time, while there was no association between levels of any plasma lipid or lipid lowering treatment and memory, cognitive/visuospatial, or language performance at any interval. Higher age at baseline was related to lower scores in all three domains at each interval, while higher education and white ethnicity were associated with higher scores in all domains. Analyses relating plasma lipids to performance in color trails tests using proportional hazards regression showed no association. In subsequent analyses excluding subjects with incident dementia, memory performance declined over time, while cognitive/visuospatial and language performance did not. Higher plasma high density lipoprotein and total cholesterol were associated with higher scores in language performance at baseline; this domain declined faster among individuals with higher total cholesterol, but this result was not significant after taking multiple comparisons into account. Plasma triglycerides, low density lipoprotein, or treatment with lipid lowering agents were not associated with changes in cognitive performance. CONCLUSIONS: Plasma lipid levels or treatment with lipid lowering agents in the elderly were not associated with changes in cognitive function.

[Evaluation of discomfort and complications in a population of 18,102 patients overweight or obese patients]. / Evaluation de la gêne et des complications chez 18,102 patients en surpoids ou obèses.

AIMS: The burden of disorders associated with overweight and obesity is a major public health problem. It is therefore important to better identify these concomitant disorders and how their frequencies vary with sex and age. METHODS: A survey was carried out during a 5 month-period from September 2001 to January 2002) among 4 727 general practitioners distributed throughout France in 18 102 patients with a body mass index (BMI)>25 kg/m2. The practitioners evaluated the presence of concomitant disorders using a closed questionnaire. The patients assessed global discomfort linked to overweight using an analog visual scale. Univariate and multivariate analyses of the concomitant disorders and self-reported discomfort depending on age, gender and BMI were performed. RESULTS: The survey population comprised 66.8% of women (W) and 33.2% of men (M). Mean age was 48.0 +/- 13.2 years and mean BMI was 34.6 +/- 6.1, with no differences between the two sexes. The most frequent concomitant disorders were back pain (44.6%), hypertension (44.2%), dyslipidemia (39.9%), knee osteoarthritis (30.8%), lower limb edema (24.3%), hypersudation (23.8%), skin fold mycosis (22.8%) and type 2 diabetes (21.6%). In multivariate analyses, the distribution of these disorders varied with sex: hypertension, type 2 diabetes, dyslipidemia, and hypersudation were more frequent in men, whereas knee osteoarthritis, back pain, and skin fold mycosis were more frequent in women. The prevalence (odd ratio, OR) of back pain and dyslipidemia did not increase with higher BMI and the prevalence of back pain did not increase with age. Overall discomfort related to overweight was rated as 61.3 +/- 19.9 mm on a 0 to 100-mm scale. Discomfort was less marked in men, decreased with age and increased with BMI (and with the consultations in the Paris area). CONCLUSIONS: This study shows the complexity of relationships between concomitant diseases, overall discomfort, BMI, age and sex (in the population of overweight and obese patients) and should improve the management of such patients and their complications.

Genetic and phenotypic characterization of macrolide resistance in group A streptococci isolated from adults with pharyngo-tonsillitis in France.

Three hundred and three strains of group A streptococci (GAS) isolated from adults with pharyngitis were tested to evaluate their phenotype of resistance to macrolides-lincosamides and to search for macrolide resistance genes. MICs of clarithromycin were determined. The overall rate of resistance to both erythromycin and clarithromycin was 9.6%. Constitutive, inducible and M phenotypes of resistance were detected in 4.3, 2 and 3.3% of strains, respectively. All constitutive phenotypes harboured ermB genes, whereas inducible phenotypes had the ermTR gene and M phenotypes had the mefA gene. In France, the current resistance rate of GAS to erythromycin and clarithromycin remains low.

[Patterns of use of terazosine in current medical practice in ambulatory patients with obstructive and irritative obstructive disorders of urination]. / Modalités d'utilisation de la térazosine en pratique médicale courante chez des patients ambulatoires présentant des troubles mictionnels obstructifs et irritatifs.

OBJECTIVES: To evaluate the efficacy and to describe the modalities of use of terazosin hydrochloride dihydrate, prescribed under conditions of routine clinical practice to a vast population of patients with benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: 1,624 patients suffering from BPH and requiring medical treatment were included in this multicentre open clinical trial performed by 983 general practitioners. After a one-week titration phase, terazosin was administered for 4 weeks at the dosage of 5 mg per day as a single dose in the evening at bedtime. The efficacy of treatment was assessed by the variation of the IPSS score between inclusion and the end of treatment, the treatment response rate (at least 3 point reduction of the IPSS score) and the course of the quality of life score. The safety of treatment was evaluated by clinical interview and physical examination at each visit and by analysis of all adverse events occurring during the trial. RESULTS: A mean 45.8% improvement of the IPSS score (corresponding to a mean decrease of 8.81 points) was demonstrated between D0 and D35 (p < 0.001). The treatment response rate was 91.8%. A mean improvement of 2.11 points (p < 0.001) of the quality of life score was obtained. Complementary subgroup analysis (moderate dysuria n = 775 and severe BPH n = 702) showed that the efficacy of treatment was independent of the initial severity of the voiding disorders. The clinical safety of treatment was considered to be good in 92.5% of cases by the investigators. The incidence of adverse events attributable to treatment and related to a fall in blood pressure was 2.6%. Less than half (20/43, i.e. 1.25% of the population) of the patients experiencing this type of adverse event had to discontinue treatment. The ease of use of treatment was considered to be good in 85.2% of cases. CONCLUSION: Terazosin constitutes an effective symptomatic treatment for BPH when surgery is not indicated, whether the initial disorders are moderate or severe. The safety of treatment appears to be perfectly satisfactory, in a patient series representative of the general practice outpatient population concerned by BPH (age, state of health, concomitant treatments). The one-week progressive dose regimen allows cautious introduction of treatment and generally does not raise any problems of acceptability.

[Acute rhinosinusitis in the adult: national survey of general practice management]. / Rhinosinusites aiguës de l'adulte: enquête nationale sur les pratiques en médecine générale.

Between the 17/1/2000 and the 31/3/2000 a study was carried out in 5000 general practitioners in the management of patients with acute maxillary sinusitis. The general practitioners filled out a questionnaire in 2 parts: the first part about their management (diagnosis-treatment) and the second part included 1 case study. According to the results of the first part, acute maxillary sinusitis occurred frequently during the winter months adding further complications. The second part of the study confirmed the finding of the first part. Analysis of case study demonstrates that this pathology affected men at the median age 37.6. The incidence of bilateral sinusitis is (61.4%) maxillary (61.1%), frontal (31.7%), ethmoidomaxillary (9.4%) or sphenoidal (1.7%). One quarter of patients participated in further medical investigations that included regular X rays of sinus and 14% patients in anterior rhinoscopy. In the older patients, on the patients with unilateral sinusitis, or sphenoidal sinusitis, the investigations were more frequent and these patients appealed for the specialist frequently (Ear Nose and Throat specialist mainly). The first line of treatment included 3.2 products of which antibiotics 98.5%, vasoconstrictors 55%, anti-inflammatory 55% (corticosteroids 46.8%, non corticosteroids 8.7%), mucolytics 41.6%. In total, general practitioners confirmed their pragmatic management in the treatment of acute sinusitis based on clinical diagnosis.

Analysis of tear proteins by one- and two-dimensional thin-layer iosoelectric focusing, sodium dodecyl sulfate electrophoresis and lectin blotting. Detection of a new component: cystatin C.

BACKGROUND: Isoelectric focusing (IEF) of tear proteins has not yet been carried out in a satisfactory way. Two-dimensional (2D) electrophoresis, especially in the combination of IEF with SDS, is able to differentiate between proteins in detail. The purpose of this study was therefore to analyze tear proteins by 1D IEF alone and in combination with a 2D pattern, and by IEF followed by lectin staining. METHODS: Ampholines, covering a broad range from pH 3 to pH 10, were applied. After IEF, semi-dry blotting and incubation with a group II lectin and two group V lectins was performed. RESULTS: Tear proteins could be separated into 31 single bands. Tear-specific pre-albumin (TSPA), lactoferrin, sIgA, IgG and lysozyme were found to be main components. Isoelectric points (IEPs, pls) of all proteins separated were determined by comparison with IEF standards. 2D patterns of IEF and SDS electrophoresis were obtained for the main subunit components of lactoferrin, sIgA, TSPA, and lysozyme. An additional new component of considerable concentration was focused at pI 8.6 with a subunit MW of 14 kDa. With s-WGA a component at an IEP of 5.2 was visualized, representing transferrin. With SNA, lactoferrin stained as a sharp main band at pI 5.1 with three additional weaker bands at IEPs from 4.8 to 4.9. At IEPs between 4.4 and 6.1, multiple components of sIgA were stained with MAA. The sugar specificity of transferrin at pI 5.2 was beta-GlcNAc. Lactoferrin showed glycation with NANA-alpha-2-6-Gal or NANA-alpha-2-6-GalNAc, whereas the sugar specificity of sIgA was NANA-alpha-2-3-Gal. CONCLUSIONS: The investigative strategy applied here, including IEF alone, in combination with SDS-electrophoresis, and SDS-electrophoresis followed by lectin staining proved to be a reproducible method for tear protein analysis of hitherto unexperienced capacity. Lectin-stained bands of native tear proteins are not uniformly glycated by one sugar residue, but show various sugar specificities. IgA as a whole molecule is specifically glycated with NANA-alpha-2-3-Gal.

[Discrete motor and sensory disorders (neurologic soft signs) in the acute course of endogenous psychoses]. / Diskrete motorische und sensorische Störungen (neurologische soft signs) im Akutverlauf endogener Psychosen.

Neurological soft signs (NSS) were investigated in 67 patients with DSM-III schizophrenia (remitting course, n = 23, chronic course, n = 27) and affective psychosis (n = 17). Patients were examined on admission, 7 days later and before discharge when being in a stable condition. In all diagnostic groups the NSS scores varied in the clinical course with a significant decline towards discharge. The variation of the NSS in the clinical course was further investigated with respect to psychopathological and clinical variables. Significant correlations between NSS, thought disorders, negative symptoms and a worse premorbid adaptation were found. To characterize NSS more precisely, all subjects executed a battery of standard neuropsychological tests on discharge. This step revealed significant correlations between NSS, graphomotoric and mnestic performance, the subscale "thought processes" of the Tübinger Luria Christiansen Scale and--to a lower extent--attentional performance. Our study provides two major findings: first, NSS vary in the clinical course and second, NSS are associated with other neuropsychological, such as mnestic and attentional, disorders. Thus, one may hypothesize, that NSS do not only reflect a primary motoric and sensoric deficiency but may be characterized as heterogeneous phenomena which occur frequently in the clinical course of endogenous psychosis.

Subsyndromes in chronic schizophrenia: do their psychopathological characteristics correspond to cerebral alterations?

This article examines the relationship between psychopathological subsyndromes in schizophrenia and cerebral alterations. A factor analysis of the psychopathological characteristics of 50 DSM-III schizophrenic patients revealed four subsyndromes. On the basis of these subsyndromes, four corresponding clusters of patients--remitted, chronic delusional, chronic asthenic, and chronic disorganized--were identified. These clusters were then compared with respect to negative symptoms, treatment response, neurological soft signs (NSS), and computed tomographic findings, such as the ventricle-brain ratio (VBR), using a discriminant analysis. The first discriminant function consisted of negative symptoms and significantly differentiated the remitted cluster from the three chronic clusters. Within the chronic clusters, the disorganized cluster was clearly identified by the second discriminant function (VBR and NSS). The third function (width of the interhemispheric fissure) provided only a tentative differentiation between the chronic delusional cluster and the chronic asthenic cluster. Although the subsyndromes of chronic schizophrenia share negative symptoms as a common feature, they appear to differ somewhat with regard to their morphological sites. These findings indicate that negative symptoms may arise from different psychopathological states and corroborate the existence of three subsyndromes in chronic schizophrenia.

Neurological soft signs in schizophrenia.

A new scale for neurological soft signs (NSS) was constructed and consists of 17 items compiled from the literature. The scale was found to have a high internal reliability (Cronbach's alpha 0.83) and a high interrater reliability (0.88). According to the results of a factor analysis, NSS are covered by five factors: 'motor coordination', 'integrative functions', 'complex motor tasks', 'righ/left and spatial orientation' and 'hard signs'. Using this scale, the associations of NSS with clinical course and brain alterations were investigated. NSS varied with the clinical course and were significantly correlated with some BPRS subscales, in particular 'thought disorder'. In addition, the 'motor coordination' soft signs were found to correlate with morphological alterations in the basal ganglia.