bluuebunny/crossref_metadata_2025 huggingface dataset:
Locating disease genes using Bayesian variable selection with the Haseman-Elston method
Authors: Oh Cheongeun , Ye Kenny Q , He Qimei , Mendell Nancy R
Published: December 2003

Background

We applied stochastic search variable selection (SSVS), a Bayesian model selection method, to the simulated data of Genetic Analysis Workshop 13. We used SSVS with the revisited Haseman-Elston method to find the markers linked to the loci determining change in cholesterol over time. To study gene-gene interaction (epistasis) and gene-environment interaction, we adopted prior structures, which incorporate the relationship among the predictors. This allows SSVS to search in the model space more efficiently and avoid the less likely models.

Results

In applying SSVS, instead of looking at the posterior distribution of each of the candidate models, which is sensitive to the setting of the prior, we ranked the candidate variables (markers) according to their marginal posterior probability, which was shown to be more robust to the prior. Compared with traditional methods that consider one marker at a time, our method considers all markers simultaneously and obtains more favorable results.

Conclusions

We showed that SSVS is a powerful method for identifying linked markers using the Haseman-Elston method, even for weak effects. SSVS is very effective because it does a smart search over the entire model space.
Approaches to mapping genetically correlated complex traits
Authors: George Andrew W , Basu Saonli , Li Na , Rothstein Joseph H , Sieberts Solveig K , Stewart William , Wijsman Ellen M , Thompson Elizabeth A
Published: December 2003

Our Markov chain Monte Carlo (MCMC) methods were used in linkage analyses of the Framingham Heart Study data using all available pedigrees. Our goal was to detect and map loci associated with covariate-adjusted traits log triglyceride (lnTG) and high-density lipoprotein cholesterol (HDL) using multipoint LOD score analysis, Bayesian oligogenic linkage analysis and identity-by-descent (IBD) scoring methods. Each method used all marker data for all markers on a chromosome. Bayesian linkage analysis detected a linkage signal on chromosome 7 for lnTG and HDL, corroborating previously published results. However, these results were not replicated in a classical linkage analysis of the data or by using IBD scoring methods.

We conclude that Bayesian linkage analysis provides a powerful paradigm for mapping trait loci but interpretation of the Bayesian linkage signals is subjective. In the absence of a LOD score method accommodating genetically complex traits and linkage heterogeneity, validation of these signals remains elusive.
On different approximations to multilocus identity-by-descent calculations and the resulting power of variance component-based linkage analysis
Authors: Göring Harald HH , Williams Jeff T , Dyer Thomas D , Blangero John
Published: December 2003

An empirical comparison between three different methods for estimation of pair-wise identity-by-descent (IBD) sharing at marker loci was conducted in order to quantify the resulting differences in power and localization precision in variance components-based linkage analysis. On the examined simulated, error-free data set, it was found that an increase in accuracy of allele sharing calculation resulted in an increase in power to detect linkage. Linkage analysis based on approximate multi-marker IBD matrices computed by a Markov chain Monte Carlo approach was much more powerful than linkage analysis based on exact single-marker IBD probabilities. A "multiple two-point" approximation to true "multipoint" IBD computation was found to be roughly intermediate in power. Both multi-marker approaches were similar to each other in accuracy of localization of the quantitative trait locus and far superior to the single-marker approach. The overall conclusions of this study with respect to power are expected to also hold for different data structures and situations, even though the degree of superiority of one approach over another depends on the specific circumstances. It should be kept in mind, however, that an increase in computational accuracy is expected to go hand in hand with a decrease in robustness to various sources of errors.
Importance sampling method of correction for multiple testing in affected sib-pair linkage analysis
Authors: Klein Alison P , Kovac Ilija , Sorant Alexa JM , Baffoe-Bonnie Agnes , Doan Betty Q , Ibay Grace , Lockwood Erica , Mandal Diptasri , Santhosh Lekshmi , Weissbecker Karen , Woo Jessica , Zambelli-Weiner April , Zhang Jie , Naiman Daniel Q , Malley James , Bailey-Wilson Joan E
Published: December 2003

Using the Genetic Analysis Workshop 13 simulated data set, we compared the technique of importance sampling to several other methods designed to adjust p-values for multiple testing: the Bonferroni correction, the method proposed by Feingold et al., and naïve Monte Carlo simulation. We performed affected sib-pair linkage analysis for each of the 100 replicates for each of five binary traits and adjusted the derived p-values using each of the correction methods. The type I error rates for each correction method and the ability of each of the methods to detect loci known to influence trait values were compared. All of the methods considered were conservative with respect to type I error, especially the Bonferroni method. The ability of these methods to detect trait loci was also low. However, this may be partially due to a limitation inherent in our binary trait definitions.
An autosome-wide search using longitudinal data for loci linked to type 2 diabetes progression
Authors: Jun Gyungah , Song Yeunjoo , Stein Catherine M , Iyengar Sudha K
Published: December 2003

A genome-wide screen was conducted for type 2 diabetes progression genes using measures of elevated fasting glucose levels as quantitative traits from the offspring enrolled in the Framingham Heart Study. We analyzed young (20–34 years) and old (≥ 35 years) subjects separately, using single-point and multipoint sibpair analysis, because of the possible differential impact of progression on the groups of interest. We observed significant linkage with change in fasting glucose levels on 1q25-32 (p = 5.21 × 10-8), 3p26.3-21.31 (p = 1 × 10-11), 8q23.1-24.13 (p = 2.94 × 10-6), 9p24.1-21.3 (p = 7 × 10-7), and 18p11.31-q22.1 (p < 10-11). The evidence for linkage on chromosomes 8 and 18 was consistent for the subset of study participants aged 43 through 55 years.
Genome scan linkage results for longitudinal systolic blood pressure phenotypes in subjects from the Framingham Heart Study
Authors: James Katherine , Weitzel Lindsay-Rae B , Engelman Corinne D , Zerbe Gary , Norris Jill M
Published: December 2003

The relationship between elevated blood pressure and cardiovascular and cerebrovascular disease risk is well accepted. Both systolic and diastolic hypertension are associated with this risk increase, but systolic blood pressure appears to be a more important determinant of cardiovascular risk than diastolic blood pressure. Subjects for this study are derived from the Framingham Heart Study data set. Each subject had five records of clinical data of which systolic blood pressure, age, height, gender, weight, and hypertension treatment were selected to characterize the phenotype in this analysis.

We modeled systolic blood pressure as a function of age using a mixed modeling methodology that enabled us to characterize the phenotype for each individual as the individual's deviation from the population average rate of change in systolic blood pressure for each year of age while controlling for gender, body mass index, and hypertension treatment. Significant (p = 0.00002) evidence for linkage was found between this normalized phenotype and a region on chromosome 1. Similar linkage results were obtained when we estimated the phenotype while excluding values obtained during hypertension treatment. The use of linear mixed models to define phenotypes is a methodology that allows for the adjustment of the main factor by covariates. Future work should be done in the area of combining this phenotype estimation directly with the linkage analysis so that the error in estimating the phenotype can be properly incorporated into the genetic analysis, which, at present, assumes that the phenotype is measured (or estimated) without error.
Genome-wide linkage analysis of systolic blood pressure slope using the Genetic Analysis Workshop 13 data sets
Authors: Pinnaduwage Dushanthi , Beyene Joseph , Fallah Shafagh
Published: December 2003

Systolic blood pressure (SBP) is an age-dependent complex trait for which both environmental and genetic factors may play a role in explaining variability among individuals. We performed a genome-wide scan of the rate of change in SBP over time on the Framingham Heart Study data and one randomly selected replicate of the simulated data from the Genetic Analysis Workshop 13. We used a variance-component model to carry out linkage analysis and a Markov chain Monte Carlo-based multiple imputation approach to recover missing information. Furthermore, we adopted two selection strategies along with the multiple imputation to deal with subjects taking antihypertensive treatment. The simulated data were used to compare these two strategies, to explore the effectiveness of the multiple imputation in recovering varying degrees of missing information, and its impact on linkage analysis results. For the Framingham data, the marker with the highest LOD score for SBP slope was found on chromosome 7. Interestingly, we found that SBP slopes were not heritable in males but were for females; the marker with the highest LOD score was found on chromosome 18. Using the simulated data, we found that handling treated subjects using the multiple imputation improved the linkage results. We conclude that multiple imputation is a promising approach in recovering missing information in longitudinal genetic studies and hence in improving subsequent linkage analyses.
Genome scan for body mass index and height in the Framingham Heart Study
Authors: Geller Frank , Dempfle Astrid , Görg Tilman
Published: December 2003

Background

Body mass index (BMI) and adult height are moderately and highly heritable traits, respectively. To investigate the genetic background of these quantitative phenotypes, we performed a linkage genome scan in the extended pedigrees of the Framingham Heart Study. Two variance-components approaches (SOLAR and MERLIN-VC) and one regression method (MERLIN-REGRESS) were applied to the data.

Results

Evidence for linkage to BMI was found on chromosomes 16 and 6 with maximum LOD scores of 3.2 and 2.7, respectively. For height, all markers showing a LOD score greater than 1 in our analysis correspond to previously reported linkage regions, including chromosome 6q with a maximum LOD score of 2.45 and chromosomes 9, 12, 14, 18, and 22. Regarding the analysis, the three applied methods gave very similar results in this unselected sample with approximately normally distributed traits.

Conclusion

Our analysis resulted in the successful identification of linked regions. In particular, we consider the regions on chromosomes 6 and 16 for BMI and the regions on chromosomes 6, 9, and 12 for stature interesting for fine mapping and candidate gene studies.
Comparison of linkage analysis methods for genome-wide scanning of extended pedigrees, with application to the TG/HDL-C ratio in the Framingham Heart Study
Authors: Horne Benjamin D , Malhotra Alka , Camp Nicola J
Published: December 2003

Background

High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) jointly increase coronary disease risk. We performed linkage analysis for TG/HDL-C ratio in the Framingham Heart Study data as a quantitative trait, using methods implemented in LINKAGE, GENEHUNTER (GH), MCLINK, and SOLAR. Results were compared to each other and to those from a previous evaluation using SOLAR for TG/HDL-C ratio on this sample. We also investigated linked pedigrees in each region using by-pedigree analysis.

Results

Fourteen regions with at least suggestive linkage evidence were identified, including some that may increase and some that may decrease coronary risk. Ten of the 14 regions were identified by more than one analysis, and several of these regions were not previously detected. The best regions identified for each method were on chromosomes 2 (LOD = 2.29, MCLINK), 5 (LOD = 2.65, GH), 7 (LOD = 2.67, SOLAR), and 22 (LOD = 3.37, LINKAGE). By-pedigree multi-point LOD values in MCLINK showed linked pedigrees for all five regions, ranging from 3 linked pedigrees (chromosome 5) to 14 linked pedigrees (chromosome 7), and suggested localizations of between 9 cM and 27 cM in size.

Conclusion

Reasonable concordance was found across analysis methods. No single method identified all regions, either by full sample LOD or with by-pedigree analysis. Concordance across methods appeared better at the pedigree level, with many regions showing by-pedigree support in MCLINK when no evidence was observed in the full sample. Thus, investigating by-pedigree linkage evidence may provide a useful tool for evaluating linkage regions.
Phenotypic, genetic, and genome-wide structure in the metabolic syndrome
Authors: Martin Lisa J , North Kari E , Dyer Tom , Blangero John , Comuzzie Anthony G , Williams Jeff
Published: December 2003

Background

Insulin resistance, obesity, dyslipidemia, and high blood pressure characterize the metabolic syndrome. In an effort to explore the utility of different multivariate methods of data reduction to better understand the genetic influences on the aggregation of metabolic syndrome phenotypes, we calculated phenotypic, genetic, and genome-wide LOD score correlation matrices using five traits (total cholesterol, high density lipoprotein cholesterol, triglycerides, systolic blood pressure, and body mass index) from the Framingham Heart Study data set prepared for the Genetic Analysis Workshop 13, clinic visits 10 and 1 for the original and offspring cohorts, respectively. We next applied factor analysis to summarize the relationship between these phenotypes.

Results

Factors generated from the genetic correlation matrix explained the most variation. Factors extracted using the other matrices followed a different pattern and suggest distinct effects.

Conclusions

Given these results, different methods of multivariate data reduction may provide unique clues on the clustering of this complex syndrome.
A genome-wide linkage scan for body mass index on Framingham Heart Study families
Authors: Moslehi Roxana , Goldstein Alisa M , Beerman Michael , Goldin Lynn , Bergen Andrew W
Published: December 2003

Background

Genome-wide scan data from a community-based sample was used to identify the genetic factors that affect body mass index (BMI). BMI was defined as weight (kg) over the square of height (m), where weight and height were obtained from the first measurement available between the ages of 40 and 50 years.

Results

Significant familial correlations were observed in mother:father (spouse) relative pairs and in all relative pairs examined except parent:daughter pairs. Single-point sib-pair regression analysis provided nominal evidence for linkage (p < 0.05) of loci to BMI at 23 markers. Multi-point sib-pair regression analysis provided nominal evidence for linkage to BMI at 42 loci on 12 chromosomes. Empirical p-values showed results consistent with the multi-point results; all but three of the loci identified by multi-point analysis were also significant.

Conclusion

The largest regions of nominally significant linkage were found on chromosomes 2, 3, and 11. The most significant evidence for linkage was obtained with markers D2S1788, D2S1356, D2S1352, D3S1744, and D11S912 from multi-point sib-pair single-trait regression analysis. Our results are in agreement with some of the recently published reports on BMI using various data sets including the Framingham Heart Study data.
Structural equation model-based genome scan for the metabolic syndrome
Authors: Stein Catherine M , Song Yeunjoo , Elston Robert C , Jun Gyungah , Tiwari Hemant K , Iyengar Sudha K
Published: December 2003

Background

The metabolic syndrome is characterized by the clustering of several traits, including obesity, hypertension, decreased levels of HDL cholesterol, and increased levels of glucose and triglycerides. Because these traits cluster, there are likely common genetic factors involved.

Results

We used a multivariate structural equation model (SEM) approach to scan the genome for loci involved in the metabolic syndrome. We found moderate evidence for linkage on chromosomes 2, 3, 11, 13, and 15, and these loci appear to have different relative effects on the component traits of the metabolic syndrome.

Conclusion

Our results suggest that the metabolic syndrome components, diabetes, obesity, and hypertension, are under the pleiotropic control of several loci.
Depression in migrants and ethnic minorities
Authors: Bhugra Dinesh , Ayonrinde Oyedeji
Published: December 2003

Migration and its associated processes can produce considerable stress on those who are migrating as well as on those around them. Depression should be a common sequel of the process, but is not consistently found to be so. This paper reviews the literature and suggests that various vulnerability factors, including culture shock and changed cultural identity, can play a role in the genesis of depression. Clinicians must be aware of patterns of migration and resilience factors in order to plan any intervention strategies. Stresses due to political and economic factors will have differing influences on the mental state of individuals. One possible contribution may be a discrepancy between aspiration and achievement, which can result in poor self-esteem, leading to depression.
Depression in young adults
Authors: Smith Daniel J. , Blackwood Douglas H. R.
Published: December 2003

Depression, as a heterogeneous collection of disorders, is likely to include subgroups that are more genetic in origin. In common with other neuropsychiatric disorders such as schizophrenia, Alzheimer's disease and Huntington's disease, earlier age at onset in depression is associated with higher genetic loading and poorer long-term outcome. Adolescents and young adults with depression are also at high risk of developing a bipolar illness. This article reviews depressive illnesses that occur for the first time in adolescence and young adulthood. Case studies are used to discuss atypical presentations and the evolving concept of bipolar-spectrum disorders.
Risperidone long-acting injection: the first 50 patients
Authors: Paton Carol , Okocha Chike
Published: December 2003

Aims and Method

Risperidone long-acting injection (RLAI) is the first atypical antipsychotic drug to be available in a ‘depot’ formulation. The evidence base underpinning its use is small. We sought to evaluate its early use in clinical practice by a naturalistic follow-up study of the first 50 patients to be prescribed RLAI in one National Health Service Trust.

Results

At 6 months, 54% of patients had achieved at least minimal improvement, 4% were unchanged, 24% failed to comply, and 18% fared poorly and were switched to alternative antipsychotics. The attrition rate at 6 months was 42%. Supplementation with oral antipsychotics was often required for longer than 3 weeks. Only half of those who had a good clinical outcome at 6 months had achieved this by 3 months.

Clinical Implications

Some patients responded well to RLAI, but the overall attrition rate was high. Although RLAI provides additional choice in the range of treatments available for people with schizophrenia, we have much to learn about how to optimise its use in practice.
Accreditation of European training schemes in psychiatry
Authors: Strachan James G. , Schudel Willem J.
Published: December 2003

The Union Européenne des Médicins Spécialistes, through its sections and boards, has responsibility for European aspects of training, qualifications, continuing professional development and accreditation. Many specialties have recognised the necessity for a Europe-wide assessment of training schemes and examination of individual practitioner abilities. As a result, several specialties (notably those in surgery) have established accreditation and examination procedures that are recognised throughout the European Union. The processes will have wider influence as the number of countries in the Union expands.
Experience of prison psychiatry: a gap in psychiatrists' basic professional training
Authors: Reiss David , Famoroti Olumuyiwa John
Published: December 2003

Aims and Method

To survey the forensic psychiatry training and experience received by a sample of successful MRCPsych candidates. A questionnaire was sent to all 208 candidates who passed the Spring 2001 MRCPsych Part II examination.

Results

A total of 99 candidates replied. Of the 42 who had not trained in forensic psychiatry posts, two-thirds had never visited a prison.

Clinical Implications

More supervised visits to prisons should be provided for basic specialist trainees.
The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events
Authors: Thorne Rick F. , Legg James W. , Isacke Clare M.
Published: December 2003

CD44 is a widely distributed type I transmembrane glycoprotein and functions as the major hyaluronan receptor on most cell types. Although alternative splicing can produce a large number of different isoforms, they all retain the hyaluronan-binding Link-homology region and a common transmembrane and cytoplasmic domain, which are highly conserved between species. The past decade has seen an extensive investigation of this receptor owing to its importance in mediating cell-cell and cell-matrix interactions in both normal and disease states. Although roles for alternative splicing and variable glycosylation in determining ligand-binding interactions are now well established, the mechanisms by which CD44 integrates structural and signalling events to elicit cellular responses have been less well understood. However, there is now increasing evidence that CD44 is assembled in a regulated manner into membrane-cytoskeletal junctional complexes and, through both direct and indirect interactions, serves to focus downstream signal transduction events.
Impaired hypothalamus‐pituitary‐adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions
Authors: Huitinga Inge , Erkut Zeynel A. , van Beurden Denis , Swaab Dick F.
Published: December 2003

In this postmortem study, we investigated the relationship between multiple sclerosis (MS) lesions in the hypothalamus and the state of activity of corticotropin‐releasing hormone (CRH)–producing neurons that control the hypothalamus‐pituitary‐adrenal (HPA) axis. A high incidence (15/16) of MS lesions was found in the hypothalamus, of which more than 50% was active, that is, contained activated macrophages. MS patients have increased numbers of CRH‐immunoreactive neurons coexpressing vasopressin (CRH/VP neurons), a sign of chronic activation of CRH neurons and increased CRH mRNA expression. Active MS lesions correlated with a low number of hyperactive CRH/VP neurons. High human leukocyte antigen (HLA)‐DR, ‐DP, ‐DQ expression, a measure for macrophage and microglial activation, correlated with low CRH mRNA expression. The nearer the HLA expression was situated to the CRH neurons, the stronger the inhibiting effect, suggesting that activated microglial cells or macrophages suppress these neurons. The more active MS lesions were present in the hypothalamus, the shorter was the disease duration until the moment of death, indicating an unfavorable course of the disease. Thus, MS patients have a chronically activated CRH system, but, in the subgroup of patients with active MS lesions in the hypothalamus, this activation is impaired and the disease course is worse.
Early magnetic resonance imaging findings in patients receiving tissue plasminogen activator predict outcome: Insights into the pathophysiology of acute stroke in the thrombolysis era
Authors: Chalela Julio A. , Kang Dong‐Wha , Luby Marie , Ezzeddine Mustapha , Latour Lawrence L. , Todd Jason W. , Dunn Billy , Warach Steven
Published: December 2003

We measured ischemic brain changes with diffusion and perfusion MRI in 42 ischemic stroke patients before and 2 hours (range approximately 1.5 to 4.5 hours) after standard intravenous tissue plasminogen activator (tPA) therapy. The median time from stroke onset to tPA was 131 minutes. Clinical and MRI variables (change in perfusion and/or diffusion weighted lesion volume) were compared between those with excellent outcome defined as 3‐month modified Rankin score (mRS) of 0 to 1 and those with incomplete recovery (mRS >1). In multivariate logististic regression analysis, the most powerful independent predictor for excellent outcome was improved brain perfusion: hypoperfusion volume on mean transit time (MTT) map decrease >30% from baseline to 2‐hour post tPA scan (p=0.009; odds ratio [95% confidence interval], 20.7 [2.1‐203.9]). Except for age < 70 years, no other baseline clinical or imaging variable was an independent predictor of outcome. We propose MTT lesion volume decrease more than 30% 2 hours after tPA as an early marker of long‐term clinical benefit of thrombolytic therapy.
DJ‐1 colocalizes with tau inclusions: A link between parkinsonism and dementia
Authors: Rizzu Patrizia , Hinkle David A. , Zhukareva Victoria , Bonifati Vincenzo , Severijnen Lies‐Anne , Martinez Daniel , Ravid Rivka , Kamphorst Wouter , Eberwine James H. , Lee Virginia M.‐Y. , Trojanowski John Q. , Heutink Peter
Published: December 2003

Two novel mutations recently have been identified in the DJ‐1 gene that cause a new form of autosomal recessive, early‐onset parkinsonism. Because the pathological role of this protein is unknown, we examined the issue here and report the colocalization of DJ‐1 protein within a subset of pathological tau inclusions in a diverse group of neurodegenerative disorders known as tauopathies. Our study extends the view that different neurodegenerative diseases may have similar pathological mechanisms, and that these processes likely include DJ‐1.
Pathomechanisms of neurodegeneration in glutaryl‐CoA dehydrogenase deficiency
Authors: Kölker Stefan , Koeller David M. , Okun Jürgen G. , Hoffmann Georg F.
Published: December 2003

Glutaryl‐CoA dehydrogenase deficiency is an inherited organic aciduria with predominantly neurological presentation. Biochemically, it is characterized by an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3‐hydroxyglutaric acid. If untreated, acute striatal degeneration is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. The mechanism underlying these acute encephalopathic crises has been partially elucidated using in vitro and in vivo models. 3‐Hydroxyglutaric and glutaric acids share structural similarities with the main excitatory amino acid glutamate and are considered to play an important role in the pathophysiology of this disease. 3‐Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N‐methyl‐D‐aspartate receptors. Furthermore, glutaric and 3‐hydroxyglutaric acids indirectly modulate glutamatergic and GABAergic neurotransmission, resulting in an imbalance of excitatory and inhibitory neurotransmission. It also has been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine‐stimulated nitric oxide production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation‐dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability to 3‐hydroxyglutaric and glutaric acid toxicity.
Identification of amino‐terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration
Authors: Arai Tetsuaki , Ikeda Kenji , Akiyama Haruhiko , Nonaka Takashi , Hasegawa Masato , Ishiguro Koichi , Iritani Shuji , Tsuchiya Kuniaki , Iseki Eizo , Yagishita Saburo , Oda Tatsuro , Mochizuki Akihide
Published: December 2003

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated tau with four microtubule‐binding repeats. Although PSP and CBD have distinctive pathological features, no biochemical difference in aggregated tau has been identified. In this study, we examined the brains of eight patients with PSP, six patients with CBD, and one atypical case with pathological features of both CBD and PSP. On immunoblots of sarkosyl‐insoluble brain extracts, a 33kDa band predominated in the low molecular weight tau fragments in PSP, whereas two closely related bands of approximately 37kDa predominated in CBD. Immunoblots of the atypical case showed both the 33kDa band and the 37kDa doublet. Protein sequencing and immunochemical analyses showed that the 33kDa band and the 37kDa doublet consisted of the carboxyl half of tau with different amino termini. These results suggest that, despite the identical composition of tau isoforms, different proteolytic processing of abnormal tau takes place in these two diseases. Such a biochemical divergence may be related to the neuropathological features of these diseases.
Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p
Authors: Stevanin Giovanni , Bouslam Naima , Thobois Stéphane , Azzedine Hamid , Ravaux Lucas , Boland Anne , Schalling Martin , Broussolle Emmanuel , Dürr Alexandra , Brice Alexis
Published: December 2003

Autosomal dominant cerebellar ataxias constitute one of the most clinically, neuropathologically, and genetically heterogeneous groups of neurodegenerative disorders. Approximately 50 to 80% of the families carry mutations in genes known to be implicated in spinocerebellar ataxias (SCAs). Numerous loci (SCAn) also have been mapped, often in single families, but the responsible genes have not yet been identified. This suggests further genetic heterogeneity. We have ascertained 18 subjects from a large French family in which cerebellar ataxia and prominent sensory neuropathy segregated as a dominant trait. Intrafamilial variability was high regarding age at onset (17 months to 39 years), severity, and the clinical picture that ranged from pure sensory neuropathy with little cerebellar involvement to a Friedreich's ataxia‐like phenotype. After excluding known genes/loci responsible for SCA and hereditary sensory neuropathies, we detected linkage with chromosome 2p markers in a genomewide screen. We designated this new locus SCA25 after testing of 16 additional markers. Maximum two‐point logarithm of odds scores of 3.15 and 3.10 were obtained at D2S2378 and D2S2734, respectively. Haplotype analysis defined a critical 12.6cM region of 15Mb between D2S2174 and D2S2736. No linkage to this locus was found in four other families. This interval contains several genes that could be responsible for the disease. One of these genes, CRIPT, encodes a postsynaptic protein, but no mutations were found by direct sequencing, excluding its responsibility in the disease. CAG repeat expansions often are involved in SCA pathogenesis, but no pathological expansions were found at the protein or at the DNA level using the 1C2 antibody and the repeat expansion detection method, respectively. The gene responsible for SCA25 remains to be identified.
Chromosomal translocation t(18;21)(q23;q22.1) indicates novel susceptibility loci for frontotemporal dementia with ALS
Authors: Prudlo Johannes , Alber Burkhard , Kalscheuer Vera M. , Roemer Klaus , Martin Thomas , Dullinger Joern , Sittinger Helmut , Niemann Stephan , Heutink Peter , Ludolph Albert C. , Ropers Hilger H. , Zang Klaus , Meyer Thomas
Published: December 2003

A chromosomal translocation t(18;21)(q23;q22) is reported in a patient with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We exclude the physical involvement and silencing of the ALS‐linked gene for copper/zinc superoxide dismutase (SOD1) on chromosome 21q22.1. The breakpoints are assigned to sequences flanked by the markers ATA1H06, D18S462, D21S1915, and D21S1898. These critical regions may contain susceptibility loci for FTD associated with ALS.
The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: Two years' follow‐up of the randomized controlled trial
Authors: Kemler Marius A. , De Vet Henrica C. W. , Barendse Gerard A. M. , Van Den Wildenberg Frans A. J. M. , Van Kleef Maarten
Published: December 2003

Chronic reflex sympathetic dystrophy is a painful, disabling disorder for which no treatment with proven effect is available. We performed a randomized trial in a 2 to 1 ratio of patients, in which 36 patients were treated with spinal cord stimulation and physical therapy (SCS+PT), and 18 patients received solely PT. Twenty‐four SCS+PT patients were given a permanent spinal cord stimulation system after successful test stimulation; the remaining 12 patients received no permanent system. We assessed pain intensity, global perceived effect, functional status, and health‐related quality of life. Patients were examined before randomization, before implantation, and also at 1, 3, 6, 12, and 24 months thereafter. At 2 years, three patients were excluded from the analysis. The intention‐to‐treat analysis showed improvements in the SCS+PT group concerning pain intensity (−2.1 vs 0.0cm; p < 0.001) and global perceived effect (43% vs 6% “much improved”; p = 0.001). There was no clinically important improvement of functional status. Health‐related quality of life improved only in the group receiving spinal cord stimulation. After careful selection and successful test stimulation, spinal cord stimulation results in a long‐term pain reduction and health‐related quality of life improvement in chronic reflex sympathetic dystrophy.
Phosphorus Nuclear Magnetic Resonance Spectroscopy
Authors: Jones Richard A. Y. , Katritzky A. R.
Published: December 2003

Nuclear magnetic resonance of the 31P nucleus is suitable for the structural elucidation of phosphorus compounds, also for analytical and kinetic studies. In this paper, an attempt has been made towards the presentation of a comprehensive review of all 31P resonances so far determined.
Mixed‐Phase Pigments with Rutile Structures
Authors: Hund F.
Published: December 2003

Until the present time, new color pigments have been developed by isotypic and homotypic mixed‐phase formation. This paper deals primarily with heterotypic mixed‐phase formation for the preparation of new colored and white pigments with the rutile structure. Dioxides and difluorides crystallizing in the rutile lattice‐form were chosen as host‐lattices for the mixed‐phase formation. Hosts of the general formula AB2 can accommodate, as guests, in the form of solid solutions, oxides and/or fluorides with different structures. Characteristically, the mean statistical cation‐radius lies between 0.55 and 0.98 Å, with single radii between 0.46 and 0.98 Å. Relative quantities are so chosen that the cation to anion ratio of 1:2 prescribed by the host lattice, as well as electroneutrality, is maintained.
The Application of Mass Spectrometry in Organic Chemistry: Determination of the Structure of Natural Products
Authors: Biemann K.
Published: December 2003

Mass spectrometry is a very useful method for the determination of the structure of organic compounds although the technique has not yet been widely employed in this field. Of particular interest is the high sensitivity of the instrument, making possible the use of very small amounts of sample, and the information obtainable regarding the size of the molecule and position of the groups therein. A certain volatility is required and the choice of a suitable derivative is, therefore, sometimes of importance. The fragmentations of the molecules in the ion source may be considered as reactions of “carbonium ions without solvent.” The application of the method in the determination of the structure of some natural products is outlined, using lipids, amino acids, peptides and alkaloids as examples.
Inverse Polarography and Voltammetry: New Methods for Trace Analysis
Authors: Neeb Rolf
Published: December 2003

Inverse polarographic and voltammetric methods are surveyed. The electrochemical determination procedure is carried out by current reversal after electrolytic concentration on a working electrode. Analyses in the nanogram (ng) region (10−9 g.) are possible because the sensitivity is increased by a factor of 100 to 1000 in comparison with the usual polarographic and voltammetric methods. These methods are, therefore, of particular interestin trace analysis.
The Mechanism of Bimolecular β‐Elimination Reactions
Authors: Bunnett J. F.
Published: December 2003

In bimolecular β‐elimination (E 2 mechanism), several bonds are ruptured or formed in one concerted reaction step. However, the various aspects of bond‐making or ‐breaking need not be completely synchronous. In the E 2 transition state for elimination HX, rupture of the CX bond may be more advanced than that of the CH linkage, or vice versa. Factors influencing the relative extents of rupture of these two bonds at the transition state are discussed, and the consequences of non‐synchroneity in one sense or the other are developed from theory and illustrated from experiment. This treatment provides an understanding of the Hofmann‐vs.‐Saytzeff orientation problem.
Recent Developments in Non‐Mercurial Diuretics
Authors: Schlittler E. , Destevens G. , Werner L.
Published: December 2003

Mercurial diuretics today are still the drugs of choice when a prompt and full diuretic response is needed. However, most mercurial diuretics are effective only when given parenterally. This factor, plus the toxicity usually associated with organic mercurials; has prompted the search for non‐toxic, orally active, non‐mercurial diuretic drugs. The most important group of organic compounds found to date which fulfills these conditions is the sulfonamides. Among these, derivatives of chlorothiazide and hydrochlorothiazide are most effective. In the following report these compounds are described in detail. Aldosterone antagonists and blockers of aldosterone excretion play only a minor role.
Thin‐Layer Chromatography of Nucleotides
Authors: Randerath K.
Published: December 2003

Thin‐layer chromatography of nucleotides on DEAE‐ and ECTEOLA‐cellulose is superior to the methods of seperation in use up to the present. Using dilute hydrochloric acid, and without a gradient elution technique, it is possinle to acheive a group seperation of monodi‐, and tri‐phosphates as well as subfractionation within these groups depending on the basicity of the nucleobases. Thin‐layer chromatography is appreciably more sensitive than paper chromatography; 5×10−4 mole adenine neuclotides can be still be detected. The total quantity of material that can be chromatographed without tailing is greater in this procedure than that with paper chromatography; a mixture consisting of 1 μmole ATP and ADP per starting spot can be resolved with ease . Hence the procedure can also be applied for micro‐scale preparative seperations . A mixtures of 10−2 μmole ADP and ATP, respectively, can be seperated completely in four to ten minutes.
The Chemistry of Sulfur Tetraflouride
Authors: Smith William C.
Published: December 2003

Current knowledge regarding the chemical and physical properties of sulfur tetraflouride is reviewed. The structural features of the compound are discussed, and its toxicological properties are presented. Particular attention is given to its reaction as a flourinating agent in view of the widespread interest in this facet of its chemistry.
The Synthesis of Nucleosides
Authors: Ulbricht T. L. V.
Published: December 2003

The most important developments in nucleoside synthesis in the last few years have been the application of the mercury salt procedure to both purines and pyrimidines, and the isolation of relatively stable, crystalline 2‐deoxyribofurnosyl halides; as a result, almost any nucleoside may now be synthesized. Earlier syntheses, based on older methods or on the conversion of one nucleoside to another, played an essential part in establishing the structure of the nucleosides (and hence of the nucleic acids).
β‐Lactams, Their Polymerization and Use as Raw Materials for Fibers
Authors: Graf R. , Lohaus G. , Börner K. , Schmidt Erwin , Bestian H.
Published: December 2003

β‐Lactams can be prepared by cyclization of β‐aimno acid esters. Recently they have become available also from olefins by addition of N‐carbonysulfamyl chloride (isocyanatosulfonyl chloride) and from aldehydes by reaction with N‐carbonylsulfamyl chloride and ketene. Condensative or anionic polymerization results in polyamides the chains of which contain many more amide groups than the chains of polyamides of the nylon‐6 type. Hence the new polymers resemble silk moreclosely. Fibers and films can be prepared from solution.
The Isomerization of Aziridine Derivatives
Authors: Heine H. W.
Published: December 2003

Derivatives of aziridine or ethylenimine are isomerized by acids, nucleophilic reagents, or pyrolysis. All of the isomerizations reported so far are ring‐opening reactions, predominantly involving cleavage of the carbon‐nitrogen bond of the ring, although a few isomerizations are known in which the carbon‐carbon bond of the ring is broken. Isomerization of appropriate aziridine derivatives provides useful synthetic pathways leading to heterocyclic systems such as oxazolines, imidazolines (and related systems), imidazolidinoes, thiazolines, pyrazolines, and triazolines. Other isomerizations form N‐unsaturated amides, anils, and isocyanates.
The Preparation of Carbodiimides from Isocyantes
Authors: Neumann W. , Fisher Peter
Published: December 2003

Carbodiimides are formed with simultaneous evolution of CO2 by the reaction of basic catalyst with sterically hindered isocynates. Another generally applicable synthesis of carbodiimides involves intermediate formation of cyclic adducts of isocyanates and carbodiimides, which, upon cleavage, exchange the isocyanate and carbodiimide functions. Both processes are suitable for the preparation of polycarboiimides. Several commercial applications of mono‐ and polycarbodiimides are pointed out.
Syntheses Using the Michael Adddition of Phridinium Salts
Authors: Kröhnke F. , Zecher W. , Curtze J. , Drechsler D. , Pfleghar K. , Schnalke K. E. , Weis W.
Published: December 2003

By Michael addition of the active methylene groups in pyridinium salts onto suitable acceptor compounds, α‐pyridones, substituted pyridines, particularly pyridinecarboxylic acids and pyridylpyridines, including the minor alkaloid of tobacco nicotelline and annelized pyridines, can be prepared by a simple procedure and generally in good yields. From the Michael adducts, polycyclic aromatic hydrocarbons, e.g. substituted fluoranthenes and “bisfluoranthenes” can be prepared; internal Michael addition leads to pyrrolinopyrdinium salts. For example, Michael addition of pyridinium salts onto quinones gives phenacyl substituted quinones, from which benzofurans and cinnolines can be readily obtained.
Heterocyclic Azo Dyes by Oxidative Coupling
Authors: Hünig S. , Balli H. , Breither E. , Brühne F. , Geiger H. , Grigat E. , Müller F. , Quast H.
Published: December 2003

New findings in the field of oxidative coupling reactions are reported. These involve: extension of this type of reaction to amidrazone system displaying (vinylogous) tautomerism and to unsymmetrical diarylhydrazines; elucidation of the coupling mechanism for these arylhydrazines and for the amidrazone systems previously described; the properties of some dyes, complexed with heavy metals, and the synthesis of tetraazapentamethine and penta‐azapentamethine dyes.
β‐Chloroethylphosphonic Dichloride: Its Synthesis and Use
Authors: Rochlitz F. , Vilcsek H.
Published: December 2003

Ethylene, phosphorus trichloride, and oxygen react together to give β‐chloroethylphosphonic dichloride in good yields. Being a bifunctional acid chloride, this compound undergoes polycondensation reactions with other, at least bifunctional, compounds affording polyesters, polyamides, epoxy resins, etc. β‐Chloroethylphosphonic dichloride also may be converted into vinylphosphonic dichloride, thus serving as a starting material for the preparation of vinylphosphonic acid and its derivatives. These undergo both homopolymerization and copolymerization with compounds containing olefinic double bonds. The products are used in the field of synthetic resins, for dressing textiles, and as protective surface coatings.
Polycondensation Dyes. A New Principle for the Preparation of Wash‐Fast Cotton Dyeings
Authors: Schimmelschmidt K. , Hoffmann Hermann , Baier E.
Published: December 2003

Dyes which contain only thiosulfate residues as water‐solubilizing groups are readily polycondensed on cellulose under mild conditions in the presence of condensing agents such as sodium sulfide to give insoluble, high molecular‐weight dyes. This type of fixation leads to wash‐fast dyeings and, in contrast to reactive dyes, involves no reaction with the fiber. The preparation and application of the dyes are described.
Conductivity and Surface Chemistry of Crystals
Authors: Schwab G.‐M.
Published: December 2003

Doping of metals and semiconductors can change both their electrical conductivity and catalytic activity. The change in conductivity gives information about the number of occupied and vacant electron levels. If the rate‐determining step of a catalytic reaction involving a doped solid can be identified, then a relationship between the conductivity and chemical behavior of the solid may be established.
Reactions of Graphite with Metal Chlorides
Authors: Rüdorff W. , Stumpp E. , Spriessler W. , Siecke F. W.
Published: December 2003

Graphite reacts with numerous anhydrous metal chlorides to form inclusion compounds. Recent results on the composition and structure of these compounds and on their magnetic and catalytic properties are reported in this review.
The Silicate Bond from the Standpoint of Electronic Theory
Authors: Noll W.
Published: December 2003

Starting from a consideration of the “undisturbed” SiOSi bond in the modification of silicic acid, the types of bonds present in silicates with polymeric SiOSi groups are discussed, taking into consideration the inductive effect of the metal cations. Experimental data on the influence of various substituents in organopolysiloxanes form the basis for this discussion. The bonds in silicates differ by direction and character and are determined by the relative ability of the metal atoms to act as donors and by the degree of condensation of the SiOSi bond. It is shown that on this basis, it is possible to explain, for example, why silicates differ in their atomic distances, susceptibility to cleavage by acids, stability relationships, and other properties.
Thermal Rearrangements
Authors: von E. Doering W. , Roth W. R.
Published: December 2003

The effect of conjugation with double bonds and (in cyclopropane) the effect of ring strain on the cleavage of carbon‐carbon bonds during thermal rearrangements is discussed. In particular, the Cope rearrangement and the geometry of its transition state are described. The structurally degenerate Cope rearrangement of bicyclo[5. 1. 0]octa‐2,5‐diene is discussed, and this compound is used to illustrate the concept of “fluctional structure”, which finds its extreme expression in the hypothetical compound, tricyclo[3. 3. 2. 04,6]‐deca‐2,7,9‐triene.