Mutation screening of patients with Alzheimer disease identifies APP locus duplication in a Swedish patient.

BACKGROUND: Missense mutations in three different genes encoding amyloid-β precursor protein, presenilin 1 and presenilin 2 are recognized to cause familial early-onset Alzheimer disease. Also duplications of the amyloid precursor protein gene have been shown to cause the disease. At the Dept. of Geriatric Medicine, Karolinska University Hospital, Sweden, patients are referred for mutation screening for the identification of nucleotide variations and for determining copy-number of the APP locus. METHODS: We combined the method of microsatellite marker genotyping with a quantitative real-time PCR analysis to detect duplications in patients with Alzheimer disease. RESULTS: In 22 DNA samples from individuals diagnosed with clinical Alzheimer disease, we identified one patient carrying a duplication on chromosome 21 which included the APP locus. Further mapping of the chromosomal region by array-comparative genome hybridization showed that the duplication spanned a maximal region of 1.09 Mb. CONCLUSIONS: This is the first report of an APP duplication in a Swedish Alzheimer patient and describes the use of quantitative real-time PCR as a tool for determining copy-number of the APP locus.

Jeunes filles scoliotiques et orthopédie a la Belle Epoque: l'essor urbain de la mécanothérapie a Lausanne et Genève [Scoliotic young girls and orthopaedics in Belle Epoque: the urban surge of mecanotherapy in Lausanne and Geneva].

In Belle Epoque towns marked by the industrial and medical surge, a new technical therapy, called mechanotherapy, emerged, stemming from Swedish medical gymnastics and auxiliary to orthopaedics. Aiming mostly at treating scoliosis, this therapy by movement attracted a sizeable female clientele to these towns, because of the hygienic and social conceptions feeding collective imagination linked to the bodies of scoliotic young girls. Taking the French-speaking Swiss towns of Lausanne and Geneva as examples, the article first seeks to describe the emergence of mechanotherapy as a medical and urban phenomenon. It then addresses the role played by scoliosis in this orthopaedic practice, and examines the clientele attracted to the towns, among which well-born young girls seem to be predominant.

Reflux vésico-­‐urétéral et atteinte rénale: rôle de l'albuminurie

Introduction :¦Le reflux vésico-urétéral (RVU) touche environs 1% des nouveau-nés et est retrouvé chez 25 à 30 % des enfants ayant une pyélonéphrite. Le RVU peut être associé à une hypoplasie/dysplasie rénale ou/et à des cicatrices rénales causées par les pyélonéphrites. Ces changements morphologiques sont plus ou moins importants selon le grade du reflux et peuvent conduire à une insuffisance rénale chronique et potentiellement évoluer en une insuffisance rénale terminale.¦La microalbuminurie (MA) reflète une augmentation anormale de la perméabilité capillaire glomérulaire et est un indicateur prédictif de la péjoration de la fonction rénale vers l'insuffisance chronique. La MA est également un facteur de risque cardiovasculaire.¦Objectif :¦Le but de cette recherche transversale est d'évaluer la présence de MA chez des patients atteints de RVU et de voir s'il est possible de corréler la MA avec le degré de reflux, la présence d'une hyperfiltration et le degré de l'insuffisance rénale.¦Patients et méthode :¦Une base de données de 160 dossiers médicaux du service de pédiatrie du CHUV, portant sur les années 2007, 2008, 2009 et 2010, va être investiguée. Ces dossiers regroupent tous les patients atteints de RVU ayant eu une exploration fonctionnelle rénale, dont l'âge varie du nouveau-né au jeune adulte âgé de 21 ans. Les variables suivantes seront considérées et analysées en détail: âge, sexe, taille, type de RVU, taux de filtration glomérulaire (TFG), flux plasmatique rénal (FPR), fraction de filtration (FF), albuminurie, rapport albumine/créatinine.¦- Les RVU sont classés en cinq grades (I, II, III, IV, V) et peuvent être uni- ou bilatéraux¦- Le TFG est calculé avec la clairance à l'inuline, un polymère de glucose filtré, non réabsorbé, ni sécrété, qu'on perfuse au patient. TFG = Uin V/Pin (ml/min)¦- Le FPR est calculé avec la clairance au PAH (acide para-amino-hippurique), une substance entièrement filtrée et sécrétée au premier passage et qu'on injecte au patient. FPR = UPAHV / PPAH (ml/min)¦- La FF est la proportion du FPR qui est filtrée.¦FF= TGF / FPR ou FF = Cl in / Cl PAH¦- La MA a été mesurée par la méthode Immulite (Siemens) jusqu'en fin août 2010 et par la méthode ALBT2 (Roche Diagnostics) à partir d'octobre 2010. Le taux normal d'albuminurie est de moins de 20 mg/l sur un échantillon d'urine.¦- Le rapport albumine urinaire / créatinine urinaire permet d'éviter les problèmes de variation de volume urinaire lors de l'analyse d'échantillon urinaire d'une seule miction. Le rapport normal est de moins de 2,5 g/mol de créatinine.¦Un questionnaire sera envoyé aux patients pour obtenir des précisions sur la fréquence et la sévérité des infections urinaires éventuellement survenues depuis.¦Les dossiers seront revus pour connaître l'évolution du RVU.¦Résultats attendus et discussion: Les résultats nous permettront :¦1) De savoir si les patients avec un RVU ont une MA¦2) De savoir si la MA varie en fonction du grade de leur reflux¦3) De savoir si la MA varie en fonction de l'hyperfiltration mesurée par la FF.¦Interprétation :¦Si la MA varie en fonction de la FF cela indiquera que la MA est la conséquence directe de l'hyperfiltration compensatrice de la perte de la masse néphronique et qu'elle est ainsi le reflet d'une cause principalement mécanique. Si la MA ne varie pas en fonction de la FF cela indiquera qu'elle est liée à l'hypoplasie/dysplasie ou/et aux cicatrices dues aux pyélonéphrites. Elle pourra alors être par exemple la conséquence d'une néphropathie glomérulotubulointerstitielle.¦Du point de vue pratique, cette étude permettra de déterminer si la simple mesure da la MA peut aider à prédire le degré de l'atteinte rénale et/ou le degré de l'hyperfiltration dans ce groupe de patients atteints de RVU.¦Bibliographie¦1. Silbernagl S, Despopoulos A. Atlas de poche de physiologie. Paris : Flammarion médecine-sciences; 2004.¦2. Brenner BM, Rector FC. The Kidney . Philadelphia : WB Saunders Company; 1996.¦3. Brandström P, Esbjörner E, Herthelius M, Holmdahl G, Läckgren G, Nevéus T, et al. The Swedish Reflux Trial in Children: I. Study Design and Study Population Characteristics. The Journal of Urology. 2010;184:274-279.¦4. Holmdahl G, Brandström P, Läckgren G, Sillén U, Stokland E, Jodal U, et al. The Swedish Reflux Trial in Children: II. Vesicoureteral Reflux Outcome. The Journal of Urology. 2010;184:280-285.¦5. Brandström P, Esbjörner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish Reflux Trial in Children: III. Urinary Tract Infection Pattern. The Journal of Urology. 2010;184:286-291.¦6. Brandström P, Nevéus T, Sixt R, Stokland E, Jodal U, Hansson S. The Swedish Reflux Trial in Children: IV. Renal Damage. The Journal of Urology. 2010;184:292-297.¦7. Ruggenenti P, Remuzzi G. Time to abandon microalbuminuria? Kidney Int. 2006;70:1214-1222.¦8. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J. Am. Soc. Nephrol. 2001;12:1315-1325.¦9. Basic J, Golubovic E, Miljkovic P, Bjelakovic G, Cvetkovic T, Milosevic V. Microalbuminuria in children with vesicoureteral reflux. Ren Fail. 2008:639-643.¦10. González E, Papazyan JP, Girardin E. Impact of vesicoureteral reflux on the size of renal lesions after an episode of acute pyelonephritis. The Journal of Urology. 2005;173:571-575.

Climate change, anthropogenic disturbance and the northward range expansion of Lactuca serriola (Asteraceae)

The distribution range of Lactuca serriola, a species native to the summer-dry mediterranean climate, has expanded northwards during the last 250 years. This paper assesses the influence of climate on the range expansion of this species and highlights the importance of anthropogenic disturbance to its spread. Location Central and Northern Europe. Methods Data on the geographic distribution of L. serriola were assembled through a literature search as well as through floristic and herbarium surveys. Maps of the spread of L. serriola in Central and Northern Europe were prepared based on herbarium data. The spread was assessed more precisely in Germany, Austria and Great Britain by pooling herbarium and literature data. We modelled the bioclimatic niche of the species using occurrence and climatic data covering the last century to generate projections of suitable habitats under the climatic conditions of five time periods. We tested whether the observed distribution of L. serriola could be explained for each time period, assuming that the climatic niche of the species was conserved across time. Results The species has spread northwards since the beginning of the 19th century. We show that climate warming in Europe increased the number of sites suitable for the species at northern latitudes. Until the late 1970s, the distribution of the species corresponded to the climatically suitable sites available. For the last two decades, however, we could not show any significant relationship between the increase in suitable sites and the distributional range change of L. serriola. However, we highlight potential areas the species could spread to in the future (Great Britain, southern Scandinavia and the Swedish coast). It is predominantly non-climatic influences of global change that have contributed to its rapid spread. Main conclusions The observation that colonizing species are not filling their climatically suitable range might imply that, potentially, other ruderal species could expand far beyond their current range. Our work highlights the importance of historical floristic and herbarium data for understanding the expansion of a species. Such historical distributional data can provide valuable information for those planning the management of contemporary environmental problems, such as species responses to environmental change.

Laparoscopic gastric banding: a prospective, randomized study comparing the Lapband and the SAGB: early results.

OBJECTIVE: The objective of this study was to evaluate the results of laparoscopic gastric banding using 2 different bands (the Lapband [Bioenterics, Carpinteria, CA] and the SAGB [Swedish Adjustable Gastric Band; Obtech Medical, 6310 Zug, Switzerland]) in terms of weight loss and correction of comorbidities, short-and long-term complications, and improvement of quality of life in morbidly obese patients SUMMARY BACKGROUND DATA: During the past 10 years, gastric banding has become 1 of the most common bariatric procedures, at least in Europe and Australia. Weight loss can be excellent, but it is not sufficient in a significant proportion of patients, and a number of long-term complications can develop. We hypothesized that the type of band could be of importance in the outcome. METHODS: One hundred eighty morbidly obese patients were randomly assigned to receive the Lapband or the SAGB. All the procedures were performed by the same surgeon. The primary end point was weight loss, and secondary end points were correction of comorbidities, early- and long-term complications, importance of food restriction, and improvement of quality of life. RESULTS: Initial weight loss was faster in the Lapband group, but weight loss was eventually identical in the 2 groups. There was a trend toward more early band-related complications and more band infections with the SAGB, but the study had limited power in that respect. Correction of comorbidities, food restriction, long-term complications, and improvement of quality of life were identical. Only 55% to 60% of the patients achieved an excess weight loss of at least 50% in both groups. There was no difference in the incidence of long-term complications. CONCLUSIONS: Gastric banding can be performed safely with the Lapband or the SAGB with similar short- and midterm results with respect to weight loss and morbidity. Only 50% to 60% of the patients will achieve sufficient weight loss, and close to 10% at least will develop severe long-term complications.

Variants : The Journal of the European Society for Textual Scholarship

This volume is the 10th issue of Variants . In keeping with the mission of the European Society for Textual Scholarship, the articles are richly interdisciplinary and transnational. They bring to bear a wide range of topics and disciplines on the field of textual scholarship: historical linguistics, digital scholarly editing, classical philology, Dutch, English, Finnish and Swedish Literature, publishing traditions in Japan, book history, cultural history and folklore. The questions that are explored - what texts are worth editing? what is the nature of the relationship between text, work, document and book? what is a critical digital edition? - all return to fundamental issues that have been at the heart of the editorial discipline for decades. With refreshing insight they assess the increasingly hybrid nature of the theoretical considerations and practical methodologies employed by textual scholars, while reasserting the relevance and need for producing scholarly editions, whether in print or digital, and continuing advanced research in bibliographical codes, textual transmissions, genetic dossiers, the fluidity of texts and other such subjects that connect textual scholarship with broader investigations into our nations' literary culture and written heritage.

Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial.

BACKGROUND: Most patients with glioblastoma are older than 60 years, but treatment guidelines are based on trials in patients aged only up to 70 years. We did a randomised trial to assess the optimum palliative treatment in patients aged 60 years and older with glioblastoma. METHODS: Patients with newly diagnosed glioblastoma were recruited from Austria, Denmark, France, Norway, Sweden, Switzerland, and Turkey. They were assigned by a computer-generated randomisation schedule, stratified by centre, to receive temozolomide (200 mg/m(2) on days 1-5 of every 28 days for up to six cycles), hypofractionated radiotherapy (34·0 Gy administered in 3·4 Gy fractions over 2 weeks), or standard radiotherapy (60·0 Gy administered in 2·0 Gy fractions over 6 weeks). Patients and study staff were aware of treatment assignment. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered, number ISRCTN81470623. FINDINGS: 342 patients were enrolled, of whom 291 were randomised across three treatment groups (temozolomide n=93, hypofractionated radiotherapy n=98, standard radiotherapy n=100) and 51 of whom were randomised across only two groups (temozolomide n=26, hypofractionated radiotherapy n=25). In the three-group randomisation, in comparison with standard radiotherapy, median overall survival was significantly longer with temozolomide (8·3 months [95% CI 7·1-9·5; n=93] vs 6·0 months [95% CI 5·1-6·8; n=100], hazard ratio [HR] 0·70; 95% CI 0·52-0·93, p=0·01), but not with hypofractionated radiotherapy (7·5 months [6·5-8·6; n=98], HR 0·85 [0·64-1·12], p=0·24). For all patients who received temozolomide or hypofractionated radiotherapy (n=242) overall survival was similar (8·4 months [7·3-9·4; n=119] vs 7·4 months [6·4-8·4; n=123]; HR 0·82, 95% CI 0·63-1·06; p=0·12). For age older than 70 years, survival was better with temozolomide and with hypofractionated radiotherapy than with standard radiotherapy (HR for temozolomide vs standard radiotherapy 0·35 [0·21-0·56], p<0·0001; HR for hypofractionated vs standard radiotherapy 0·59 [95% CI 0·37-0·93], p=0·02). Patients treated with temozolomide who had tumour MGMT promoter methylation had significantly longer survival than those without MGMT promoter methylation (9·7 months [95% CI 8·0-11·4] vs 6·8 months [5·9-7·7]; HR 0·56 [95% CI 0·34-0·93], p=0·02), but no difference was noted between those with methylated and unmethylated MGMT promoter treated with radiotherapy (HR 0·97 [95% CI 0·69-1·38]; p=0·81). As expected, the most common grade 3-4 adverse events in the temozolomide group were neutropenia (n=12) and thrombocytopenia (n=18). Grade 3-5 infections in all randomisation groups were reported in 18 patients. Two patients had fatal infections (one in the temozolomide group and one in the standard radiotherapy group) and one in the temozolomide group with grade 2 thrombocytopenia died from complications after surgery for a gastrointestinal bleed. INTERPRETATION: Standard radiotherapy was associated with poor outcomes, especially in patients older than 70 years. Both temozolomide and hypofractionated radiotherapy should be considered as standard treatment options in elderly patients with glioblastoma. MGMT promoter methylation status might be a useful predictive marker for benefit from temozolomide. FUNDING: Merck, Lion's Cancer Research Foundation, University of Umeå, and the Swedish Cancer Society.

Impact of soluble CD26 on treatment outcome and hepatitis C virus-specific T cells in chronic hepatitis C virus genotype 1 infection.

BACKGROUND: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50-80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells. METHODS: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8(+) T cells. RESULTS: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8(+) T cells (P = 0.02). CONCLUSIONS: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8(+) T cells.

Protective behavioral strategies and future drinking behaviors: Effect of drinking intentions.

Alcohol use is common among United States and Swedish high school students and is related to negative consequences. Whereas drinking intentions are associated with future drinking behaviors, the use of protective behavioral strategies (PBS) is associated with decreased alcohol-related harm among young adults. The interactive effect of PBS and drinking intentions in predicting alcohol outcomes has not been examined. Further, because most PBS studies have been conducted among U.S. college students, PBS research among other populations is needed. The aims of this study were to evaluate longitudinally (a) the relationships between drinking intentions, PBS and alcohol outcomes, and (b) the moderating roles of drinking intentions and country in these relationships among United States and Swedish high school drinkers. Data were collected at baseline, 6- and 12-month follow-ups on 901 Swedish and 288 U.S. high school drinkers. Drinking intentions were associated with more alcohol use and consequences, and use of certain PBS was related to fewer alcohol-related consequences over time. Additionally, the negative prospective relationship between use of PBS and alcohol use, but not alcohol-related consequences, was moderated by intentions, such that the relationship was stronger among participants endorsing high drinking intentions. Country did not moderate these relationships. These results provide initial support for the generalizability of PBS college research to United States and Swedish high school students and suggest that interventions targeting the use of PBS may be most effective among high school drinkers endorsing high drinking intentions. (PsycINFO Database Record

La radiochirurgie dans le traitement de la douleur [Radiosurgery in Pain Treatment]

Le traitement de radiochirurgie par Gamma Knife (GK) est utilisé de plus en plus souvent comme une alternative à la microchirurgie conventionnelle pour le traitement des pathologies neurochirurgicales intracrâniennes. Il s'agit d'irradier en dose unique et à haute énergie, en condition stéréotaxique et à l'aide d'une imagerie multimodale (imagerie par résonance magnétique [IRM], tomodensitométrie et éventuellement artériographie). Le GK a été inventé par le neurochirurgien suédois Lars Leksell, qui a réalisé le premier ciblage du nerf trijumeau en 1951, sur la base d'une radiographie standard. Depuis, les progrès de l'informatique et de la robotique ont permis d'améliorer la technique de radiochirurgie qui s'effectue actuellement soit par accélérateur linéaire de particules monté sur un bras robotisé (Novalis®, Cyberknife®), soit par collimation de près de 192 sources fixes (GK). La principale indication radiochirurgicale dans le traitement de la douleur est la névralgie du nerf trijumeau. Les autres indications, plus rares, sont la névralgie du nerf glossopharyngien, l'algie vasculaire de la face, ainsi qu'un traitement de la douleur d'origine cancéreuse par hypophysiolyse. Gamma Knife surgery (GKS) is widely used as an alternative to open microsurgical procedures as noninvasive treatment of many intracranial conditions. It consists of delivering a single dose of high energy in stereotactic conditions, and with the help of a multimodal imaging (e.g., magnetic resonance imaging [MRI], computer tomography, and eventually angiography). The Gamma Knife (GK) was invented by the Swedish neurosurgeon Lars Leksell who was the first to treat a trigeminal neuralgia sufferer in 1951 using an orthogonal X-ray tube. Since then, the progresses made both in the field of informatics and robotics have allowed to improve the radiosurgical technique, which is currently performed either by a linear accelerator of particles mounted on a robotized arm (Novalis®, Cyberknife®), or by collimation of 192 fixed Co-60 sources (GK). The main indication of GKS in the treatment of pain is trigeminal neuralgia. The other indications, less frequent, are: glossopharyngeal neuralgia, cluster headache, and hypophysiolyse for cancer pain.

Impact of a cis-associated gene expression SNP on chromosome 20q11.22 on bipolar disorder susceptibility, hippocampal structure and cognitive performance.

BackgroundBipolar disorder is a highly heritable polygenic disorder. Recent enrichment analyses suggest that there may be true risk variants for bipolar disorder in the expression quantitative trait loci (eQTL) in the brain.AimsWe sought to assess the impact of eQTL variants on bipolar disorder risk by combining data from both bipolar disorder genome-wide association studies (GWAS) and brain eQTL.MethodTo detect single nucleotide polymorphisms (SNPs) that influence expression levels of genes associated with bipolar disorder, we jointly analysed data from a bipolar disorder GWAS (7481 cases and 9250 controls) and a genome-wide brain (cortical) eQTL (193 healthy controls) using a Bayesian statistical method, with independent follow-up replications. The identified risk SNP was then further tested for association with hippocampal volume (n = 5775) and cognitive performance (n = 342) among healthy individuals.ResultsIntegrative analysis revealed a significant association between a brain eQTL rs6088662 on chromosome 20q11.22 and bipolar disorder (log Bayes factor = 5.48; bipolar disorder P = 5.85×10(-5)). Follow-up studies across multiple independent samples confirmed the association of the risk SNP (rs6088662) with gene expression and bipolar disorder susceptibility (P = 3.54×10(-8)). Further exploratory analysis revealed that rs6088662 is also associated with hippocampal volume and cognitive performance in healthy individuals.ConclusionsOur findings suggest that 20q11.22 is likely a risk region for bipolar disorder; they also highlight the informative value of integrating functional annotation of genetic variants for gene expression in advancing our understanding of the biological basis underlying complex disorders, such as bipolar disorder.