A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.

BigWig and BigBed: enabling browsing of large distributed datasets.

SUMMARY: BigWig and BigBed files are compressed binary indexed files containing data at several resolutions that allow the high-performance display of next-generation sequencing experiment results in the UCSC Genome Browser. The visualization is implemented using a multi-layered software approach that takes advantage of specific capabilities of web-based protocols and Linux and UNIX operating systems files, R trees and various indexing and compression tricks. As a result, only the data needed to support the current browser view is transmitted rather than the entire file, enabling fast remote access to large distributed data sets. AVAILABILITY AND IMPLEMENTATION: Binaries for the BigWig and BigBed creation and parsing utilities may be downloaded at http://hgdownload.cse.ucsc.edu/admin/exe/linux.x86_64/. Source code for the creation and visualization software is freely available for non-commercial use at http://hgdownload.cse.ucsc.edu/admin/jksrc.zip, implemented in C and supported on Linux. The UCSC Genome Browser is available at http://genome.ucsc.edu.

The UCSC Genome Browser Database: update 2009.

The UCSC Genome Browser Database (GBD, http://genome.ucsc.edu) is a publicly available collection of genome assembly sequence data and integrated annotations for a large number of organisms, including extensive comparative-genomic resources. In the past year, 13 new genome assemblies have been added, including two important primate species, orangutan and marmoset, bringing the total to 46 assemblies for 24 different vertebrates and 39 assemblies for 22 different invertebrate animals. The GBD datasets may be viewed graphically with the UCSC Genome Browser, which uses a coordinate-based display system allowing users to juxtapose a wide variety of data. These data include all mRNAs from GenBank mapped to all organisms, RefSeq alignments, gene predictions, regulatory elements, gene expression data, repeats, SNPs and other variation data, as well as pairwise and multiple-genome alignments. A variety of other bioinformatics tools are also provided, including BLAT, the Table Browser, the Gene Sorter, the Proteome Browser, VisiGene and Genome Graphs.

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence.

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

The UCSC Genome Browser Database: 2008 update.

The University of California, Santa Cruz, Genome Browser Database (GBD) provides integrated sequence and annotation data for a large collection of vertebrate and model organism genomes. Seventeen new assemblies have been added to the database in the past year, for a total coverage of 19 vertebrate and 21 invertebrate species as of September 2007. For each assembly, the GBD contains a collection of annotation data aligned to the genomic sequence. Highlights of this year's additions include a 28-species human-based vertebrate conservation annotation, an enhanced UCSC Genes set, and more human variation, MGC, and ENCODE data. The database is optimized for fast interactive performance with a set of web-based tools that may be used to view, manipulate, filter and download the annotation data. New toolset features include the Genome Graphs tool for displaying genome-wide data sets, session saving and sharing, better custom track management, expanded Genome Browser configuration options and a Genome Browser wiki site. The downloadable GBD data, the companion Genome Browser toolset and links to documentation and related information can be found at: http://genome.ucsc.edu/.

Linkage between growth retardation and pituitary cell morphology in a dystrophin-deficient pig model of Duchenne muscular dystrophy.

OBJECTIVE: Human patients with Duchenne muscular dystrophy (DMD) commonly exhibit a short stature, but the pathogenesis of this growth retardation is not completely understood. Due to the suspected involvement of the growth hormone/insulin-like growth factor 1 (GH/IGF1) system, controversial therapeutic approaches have been developed, including both GH- administration, as well as GH-inhibition. In the present study, we examined relevant histomorphological and ultrastructural features of adenohypophyseal GH-producing somatotroph cells in a porcine DMD model. METHODS: The numbers and volumes of immunohistochemically labelled somatotroph cells were determined in consecutive semi-thin sections of plastic resin embedded adenohypophyseal tissue samples using unbiased state-of-the-art quantitative stereological analysis methods. RESULTS: DMD pigs displayed a significant growth retardation, accounting for a 55% reduction of body weight, accompanied by a significant 50% reduction of the number of somatotroph cells, as compared to controls. However, the mean volumes of somatotroph cells and the volume of GH-granules per cell were not altered. Western blot analyses of the adenohypophyseal protein samples showed no differences in the relative adenohypophyseal GH-abundance between DMD pigs and controls. CONCLUSION: The findings of this study do not provide evidence for involvement of somatotroph cells in the pathogenesis of growth retardation of DMD pigs. These results are in contrast with previous findings in other dystrophin-deficient animal models, such as the golden retriever model of Duchenne muscular dystrophy, where increased mean somatotroph cell volumes and elevated volumes of intracellular GH-granules were reported and associated with DMD-related growth retardation. Possible reasons for the differences of somatotroph morphology observed in different DMD models are discussed.

The UCSC genome browser database: update 2007.

The University of California, Santa Cruz Genome Browser Database contains, as of September 2006, sequence and annotation data for the genomes of 13 vertebrate and 19 invertebrate species. The Genome Browser displays a wide variety of annotations at all scales from the single nucleotide level up to a full chromosome and includes assembly data, genes and gene predictions, mRNA and EST alignments, and comparative genomics, regulation, expression and variation data. The database is optimized for fast interactive performance with web tools that provide powerful visualization and querying capabilities for mining the data. In the past year, 22 new assemblies and several new sets of human variation annotation have been released. New features include VisiGene, a fully integrated in situ hybridization image browser; phyloGif, for drawing evolutionary tree diagrams; a redesigned Custom Track feature; an expanded SNP annotation track; and many new display options. The Genome Browser, other tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

Effect of blood donation on well-being of blood donors.

The demand for blood products steadily increases. Concurrently, blood donor recruitment becomes more and more difficult. This study aimed to investigate effects of blood donation on blood donors, which could be helpful for blood donor recruitment and retention. In addition to cortisol measurements in saliva, three questionnaires quantifying mood (good/bad), vigilance (awake/tired), agitation (calm/nervous), actual strain and asking for donation-related effects perceived were distributed to 110 whole blood donors (DON). Results obtained were compared with 109 control subjects (CON) lacking the blood donation experience. Overall, 216 subjects completed the questionnaires. Sixty-eight percent of DON reported at least one effect perceived with blood donation. Exclusively, positive, negative or mixed effects were described by 26.5%, 23.5% and 17.6%, respectively. Among positive effects (i.e. physical/psychological well-being, feeling satisfied, happy, proud), no significant differences were observed between males and females (P = 0.07), whereas mixed or negative effects (i.e. vertigo, dizziness, tiredness, pain) were significantly (P = 0.03; P = 0.049) more associated with females. DON showed higher levels of well-being than CON as indicated by better mood (P = 0.004), higher vigilance (P = 0.015) and relaxation (P = 0.003). The latter even increased after donation with maximum values after 15 and 30 min. Despite significantly higher initial strain scores (P = 0.008), first-time donors maintained a better mood (P = 0.025) than repeat donors. DON showed a statistically better psychological well-being than CON, although the donation experience was perceived as stressful, especially for first-time donors. The results may facilitate donor recruitment and retention as blood donation may become less frightening and perhaps even attractive.

The UCSC Genome Browser Database: update 2006.

The University of California Santa Cruz Genome Browser Database (GBD) contains sequence and annotation data for the genomes of about a dozen vertebrate species and several major model organisms. Genome annotations typically include assembly data, sequence composition, genes and gene predictions, mRNA and expressed sequence tag evidence, comparative genomics, regulation, expression and variation data. The database is optimized to support fast interactive performance with web tools that provide powerful visualization and querying capabilities for mining the data. The Genome Browser displays a wide variety of annotations at all scales from single nucleotide level up to a full chromosome. The Table Browser provides direct access to the database tables and sequence data, enabling complex queries on genome-wide datasets. The Proteome Browser graphically displays protein properties. The Gene Sorter allows filtering and comparison of genes by several metrics including expression data and several gene properties. BLAT and In Silico PCR search for sequences in entire genomes in seconds. These tools are highly integrated and provide many hyperlinks to other databases and websites. The GBD, browsing tools, downloadable data files and links to documentation and other information can be found at http://genome.ucsc.edu/.

[Gender differences in vascular medicine]. / Geschlechtsunterschiede in der Gefässmedizin.

In vascular medicine only a few studies concerning gender differences in vascular diseases, course of the disease and therapy exist. Risk factors are allocated differently between men and women with different influences on cardiovascular diseases. Diabetic women do have a particular high risk. The proportion of women smokers with a risk for aggravation of the other risk factors is increased. In young female smokers the hypoplastic aortoiliac syndrome is a special course of peripheral arterial disease associated with a bad prognosis. The benefit of hormone replacement therapy in vascular diseases of postmenopausal women has not yet been demonstrated. On the other hand testosterone seems to have a favourable effect on vascular diameter and endothelium of coronaries. Women with peripheral arterial disease represent high risk patients with a particular risk for cardiovascular letality. Periprocedural complications of the analysed operations or interventions are found more frequent in women. Furthermore the disease is in an advanced stage when treated. Especially men with asymptomatic high grade carotid stenosis benefit more from an operation than women because of the higher risk for ischemic stroke. Unfortunately the benefit of the operation in women is neutralized by the higher rate of periprocedural complications. Some studies demonstrate the gender bias in treatment: women seldom receive revascularisation and guideline therapy as frequently as men. The same is true with thromboembolic prophylaxis concerning in hospital patients. In pharmacotherapy women have in result of metabolism more side effects. Additionally women are underrepresented in drug admission studies compared to their percentage of population and gender prevalence of diseases. Further studies concerning gender differences in vascular medicine are definitely needed.

The UCSC Genome Browser Database.

The University of California Santa Cruz (UCSC) Genome Browser Database is an up to date source for genome sequence data integrated with a large collection of related annotations. The database is optimized to support fast interactive performance with the web-based UCSC Genome Browser, a tool built on top of the database for rapid visualization and querying of the data at many levels. The annotations for a given genome are displayed in the browser as a series of tracks aligned with the genomic sequence. Sequence data and annotations may also be viewed in a text-based tabular format or downloaded as tab-delimited flat files. The Genome Browser Database, browsing tools and downloadable data files can all be found on the UCSC Genome Bioinformatics website (http://genome.ucsc.edu), which also contains links to documentation and related technical information.

Transesophageal two-dimensional echocardiography: comparison of ultrasonic and anatomic sections.

Conventional 2-dimensional echocardiography has become a well-established tool for evaluating cardiovascular diseases. Recent introduction of 2-dimensional transesophageal echocardiography has widened the ultrasonic examination possibilities of the heart and great arteries. The 6 standard transesophageal transducer positions that have proved representative and of diagnostic value are described. To facilitate structure identification and interpretation of anatomic relations, transesophageal recordings were compared with corresponding anatomic sections.

Locoregional/systemic chemotherapy of locally advanced/metastasized pancreatic cancer with a combination of mitomycin-C and gemcitabine and simultaneous follow-up by imaging methods and tumor markers.

Stimulated by surprising results in the first 7 patients treated with intraarterial/systemic chemotherapy with a combination of Mitomycin-C + Gemcitabine we now report on the data of 28 pancreatic cancer patients in comparison to 15 patients treated with gemcitabine alone(1000 mg/m2). Tumor response was evaluated on the basis of imaging methods, tumor markers and life quality parameters like body weight, pains and Karnofsky index etc. Tumor markers were monthly determined, imaging methods every 1-3 months. The locoregional/systemic approach included 3 week cycles with i.a. application of mitomycin-C + gemcitabine on day 1 and i.v. application of gemcitabine on days 8 and 15. The alltogether 125 cycles (mean 4 cycles per patient) resulted in 43% PR (n = 12), 1 CR (3%), 255 MR, 11% SD and 18% PD in the imaging methods and 20% CR, 60% PR, 4% MR and 12% SD in the course of the relevant tumor markers. Progression free survival amounted to a median of 7.5 (6) months defined by imaging methods (tumor markers). Second line treatments following new progress after effective locoregional approach with gemcitabine or a combination of gemcitabine + oxaliplatin did not result in a new tumor regression. However, third line therapy trials in 3 patients with high dose 5-FU or CPT 11 induced new antitumoral efficacy (survival of these tumors > 15, > 17 and > 28 months, n = 2 M1, n = 1 T3M0). About 75% of patients reported on a relevant benefit of life quality parameters. Side effects are on principle comparable to those of gemcitabine monotherapy, except for a tendency to a higher rate of pulmonary complications and 1 HUS observed. Even if not compared in a randomized study locoregional/systemic combined treatment modality seems to result in a higher rate of abjective tumor response defined by imaging methods as well as tumormarkers. Comparing tumor marker and imaging response to therapy CA 19-9 often showed a more rapid and subtle answer to therapy and an earlier new increase suggesting tumor markers as an essential part in the follow-up of these patients in order to optimize the patient's palliative treatment. Our results should stimulate the clinicians to rediscuss the chemosensitivity of exocrine pancreatic cancer and to perform prospective randomized studies focusing on combined gemcitabine approaches.

Extracorporeal shockwave lithotripsy of 2000 urinary calculi with the modulith SL-20: success and failure according to size and location of stones.

PURPOSE: We analyzed the successes and failures of SWL in the treatment of 2016 urinary calculi stratified according to size and position in the urinary tract. METHODS: All the patients were treated with a Modulith SL-20 (Storz Medical). RESULTS: The overall stone-free rate, regardless of the size and position of the stone, was 87.4%. The rate was different for kidney and ureteral stones. The stone-free rate observed for the different positions of the calculi within the kidney was upper calix 89.2%, middle calix 90.5% lower calix 84.8%, and renal pelvis 86.0%. For staghorn calculi, the stone-free rate was 60.0%. The stone-free rate for the different positions of calculi within the ureter was: upper ureter 84.3%, iliac ureter 82.4%, and pelvic ureter 91.0%. For calculi >24 mm, the retreatment rate increased, and the success rate dropped sharply. CONCLUSION: Extracorporal shockwave lithotripsy should be the first therapeutic option for urinary calculi of <24 mm regardless of their position in the urinary tract.

Patients with a malignant tumor have more extended thrombosis than patients without.

Changes in the coagulability or rheology of the blood are supposed to cause an increased frequency of thrombosis in patients with a malignant tumor. These procoagulopathic disorders may not only increase the frequency of thrombosis but may also enlarge the extent of the thrombosis. The authors retrospectively analyzed, therefore, the extension of thrombosis in patients with and without a malignant tumor. From 1991 to 1995 in the University Hospital Essen 489 consecutive cases of thrombosis were diagnosed. The diagnosis was made by color Doppler sonography or phlebography; 230 patients (47%) suffered from a malignant tumor (110 men, 120 women). To exclude the influence of the patient's age on the extension of the thrombosis the authors distinguished three different age groups. In the tumor group aged from 21 to 40 years they found 10 large (iliacal, femoral, and crural veins), six medium (femoral and crural veins), and four small thromboses (crural veins). In the tumor group aged from 41 to 60 years they found 38 large, 24 medium, and 27 small thromboses. In the group without a tumor aged from 21 to 40 years they found seven large, 13 medium, and 28 small thromboses, and in the group aged from 41 to 60 years, 12 large, 29 medium, and 41 small thromboses. The difference between the two groups supports the assumption that in patients suffering from a malignant tumor, thromboses tend to be more extended than in patients without a malignant tumor.

Association of subclavian and jugular vein thrombosis: color doppler sonographic evaluation.

In case of clinical symptoms of subclavian vein thrombosis a phlebographic or color Doppler sonographic investigation should be performed. Phlebography is a sensitive method to exclude the thrombosis in the subclavian vein but not in the jugular vein. Color Doppler sonography additionally gives information about the surrounding tissue and the jugular vein. The authors analyze their color Doppler sonographic data, first, to evaluate the association of internal jugular and subclavian vein thrombosis and, second, to demonstrate the necessity for a color Doppler investigation. Of 213 patients who suffered from a thrombosis, 93 had a subclavian vein thrombosis, 64 had a combined thrombosis in the internal jugular and subclavian vein, and 56 had an isolated internal jugular vein thrombosis. There is a high association between subclavian and internal jugular vein thrombosis, and a color Doppler investigation of both the subclavian and internal jugular veins is necessary.

[Duplex ultrasound imaging of vascularization in venous thrombosis]. / Duplexsonographische Darstellung der Vaskularisation venöser Thrombosen.

Vascularization of venous thrombosis. The degree of organisation of an intravenous thrombus is important for therapeutic interventions and the postthrombotic damage. Changes in echogenicity have already been described in B-mode sonography. We investigated 7 thrombosis in the jugular vein looking for intra-thrombotic vessels that occur during the organisation. In 3 thrombosis arterial vessels were found from the 12th to the 17th day. Such arterial vessels appeared only in a short range of time and only in circumscript areas of the thrombus. The intra-vitam documentation of arterial vessels in an organizating intravenous thrombus may give information about the mechanism of thrombogenesis and about the degree of organisation.

[Ischemia of the arm with finger necroses: differential carpal tunnel syndrome and thoracic outlet syndrome diagnosis]. / Ischämie des Arms mit Fingernekrosen: Differentialdiagnose Karpaltunnel-Syndrom und Thoracic-outlet-Syndrom.

Upper extremity ischemia with finger necrosis: carpal-tunnel syndrome or thoracic outlet syndrome? A 26-year-old male patient complained of pain paraesthesia in the right upper extremity while working with the arm elevated. After electrophysiological diagnosis of a carpal-tunnel-syndrome the patient received surgical treatment. Following this treatment he developed acral necrosis at the fingers. Additional diagnostic effort let to the diagnosis of a thoracic-outlet-syndrome due to a cervical rib. This case report and a review of the literature show that electrophysiological investigations alone can not differentiate the carpal-tunnel-syndrome from the thoracic-outlet-syndrome. Thus an operative release of a carpal-tunnel should not be performed until the arterial perfusion of the upper extremity has been judged.

[Diagnosis and therapy of hypothenar hammer syndrome]. / Diagnostik und Therapie des Hypothenar-Hammer-Syndroms.

Traumatic injuries of arteries lead to acute bleeding or ischemia. In the hand, which is perfused by two arteries, this symptom could be missed. The hypothenar hammer syndrome is a traumatic occlusion of the distal arteria ulnaris. Dependent on the mechanism of the trauma the clinical symptoms may appear late. A specific angiographic or duplex sonographic diagnostic investigation is necessary to show the arterial occlusion. There is no proven therapeutic procedure. Exact diagnosis of the occlusion as an effect of the trauma is important for the patient and is the basis of any therapeutic intervention.