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.

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.

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.

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.

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.

High-dose combination alkylating agent therapy with autologous bone marrow rescue for refractory solid tumors.

Twenty-six adults, ages 27 to 60, with refractory metastatic solid tumors were treated with high-dose cyclophosphamide (Cy) + carmustine (BCNU) at one of three escalating dose schedules followed by autologous bone marrow transplantation (ABMT). Toxicity was severe and dose-related, with the maximum tolerated dose for the combination determined to be Cy 160 mg/kg and BCNU 900 mg/m2. Median time to WBC recovery (greater than or equal to 1,000/microL) was 13 days post-ABMT (range, nine to 22 days) and to a platelet count of greater than or equal to 50,000/microL, 22 days (range, 13 to 83 days). Sixteen of 20 evaluable patients (80%) responded to therapy with at least 50% reduction in measurable tumor, and three patients achieved complete remission (CR). Responders included eight of nine evaluable patients with breast carcinoma, two of five with melanoma, two of two with sarcoma, and four of four with colon carcinoma. Response durations were short (median, 4 months), even for complete responders, and relapses generally occurred at sites of previous metastases. In order for this approach to have a more significant impact on overall survival, it may need to be applied earlier in the natural history of the malignancy.

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.

Vitamin E and benign breast disease.

Vitamin E has been used in the treatment of benign breast disease for 25 years. To evaluate the efficacy of treatment by means of mammography as the objective and sensitive parameter, 105 women were randomly selected and entered into a double-blind, placebo-controlled crossover trial. All patients had mammographic evidence of benign breast disease. They received 600 mg of placebo and alpha-tocopherol acetate in 3-month treatment phases. Breast examinations and mammography were done, after each treatment, at approximately the same phase of the patients menstrual cycle. No significant subjective or objective effects after treatment were observed. We conclude that alpha-tocopherol is not beneficial in the treatment of benign breast disease. We would warn against the use of alpha-tocopherol for misdirected treatment of undiagnosed overt disease because such treatment may delay the diagnosis of breast cancer.

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.

Pure red cell aplasia associated with fenoprofen.

A 69-year-old man developed pure red cell aplasia after taking fenoprofen for ten months. The erythroid defect fully reversed after the drug was discontinued and could not be attributed to the patient's previously treated lung carcinoma. This case represents the third example of erythroid aplasia associated with an anti-inflammatory agent and the first instance due to fenoprofen.

The setting of vinyl polysiloxane and condensation silicone putties when mixed with gloved hands.

Neither the vinyl nor the latex gloves tested affected any of the condensation silicone putties tested. The vinyl gloves tested had no effect on any of the vinyl polysiloxane putties. Some brands of latex gloves as received from the distributor caused severe retardation or complete inhibition of setting in most vinyl polysiloxane putties; other brands of latex gloves affected the setting in the vinyl polysiloxane putties to varying degrees. Washing the latex gloves decreased the effect of inhibition of setting on the putty but did not eliminate it. Thus, latex gloves should not be worn while mixing or handling vinyl polysiloxane putties. Putties should not be dispensed while wearing latex gloves as the entire jar can become contaminated. If gloves are removed to mix the putty, hands should be washed thoroughly; however, this violates the barrier technique and is not recommended. Vinyl gloves may be worn over latex gloves (or by themselves), for dispensing and mixing the putty; but the vinyl gloves should not be contaminated with powder from the latex gloves. To assure compatibility, the putty/glove combination should always be checked.

[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.

[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.

[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.

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.

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.