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Objective. To evaluate the impact of left renal vein entrapment on outcome after surgical varicocele repair using color Doppler sonography. Methods. Eighty-four men had varicoceles on color Doppler sonography (2 right sided, 74 left sided, and 8 bilateral), which were diagnosed on the basis of a venous diameter of 3 mm or greater and venous retrograde flow in the pampiniform plexus of veins during the Valsalva maneuver or when changing from a supine to an upright position. Diagnosis of the left renal vein entrapment was based on the following criteria: anteroposterior diameter of greater than 1 cm and peak velocity of less than 15 cm/s for the left renal vein at the mid portion and anteroposterior diameter of less than 0.2 cm and peak velocity of greater than 110 cm/s (or, alternatively, a diameter ratio and peak velocity ratio of >5) for the left renal vein between the aorta and superior mesenteric artery. All patients underwent surgical varicocele repair. In postoperative follow-up, we compared the presence of left renal vein entrapment with the frequency of varicocele recurrence. Results. Sixteen (19%) of 84 patients had left renal vein entrapment with a left-sided varicocele. Postoperatively (mean follow-up ± SD, 19.3 ± 11.7 months), 27 (32.2%) of 84 had varicocele recurrence, including all 16 patients with left renal vein entrapment and 11 (20.1%) of 68 patients without left renal vein entrapment. The varicocele recurrence rate was significantly greater in patients with left renal vein entrapment (P < .001, Fisher exact test). Conclusions. The presence of left renal vein entrapment resulted in a significantly higher varicocele recurrence rate. Patients with varicoceles should routinely be evaluated for the presence of left renal vein entrapment before surgical repair.

This study was designed to evaluate power Doppler imaging for assessment of urinary bladder neck blood flow in comparison with laser Doppler flowmetry (LDF) in an animal model. Transrectal power Doppler ultrasound (US) and LDF of the urinary bladder neck were performed in three anesthetized pigs during comparative cystometry. Normal saline (NaCl) was used for the first run, followed by a second run with 0.2 mol/L potassium chloride (KCl). Standardized sonographic equipment settings (Acuson Sequoia 512®; MountainView, CA) were used for power Doppler imaging. Computer-assisted calculation of color pixel density (CPD) of power Doppler images was performed using Scion Image® software image analysis. Tissue perfusion units (TPU) were measured using a BLF21 laser Doppler flowmeter (Transonic Systems® Inc., Ithaca, NY, USA). The power Doppler results were compared with the findings obtained by LDF. NaCl filling resulted in a mean CPD increase at the bladder neck from 18.65 (± 1.78) at empty bladder to 37.8 (± 1.84) at 100 mL and to 88.32 (± 1.35) at full bladder capacity (Cmax) of 270 mL, respectively. With KCl filling, a mean CPD increase from 18.65 (± 1.78) to 59.63 (± 0.5) at 100 mL and 110.82 (± 2.98) at full bladder capacity (270 mL) was observed. The CPD increase was significantly higher for KCl than with NaCl (p < 0.001). With NaCl filling, bladder neck blood flow increased from 22 TPU (empty) to 46 TPU (100 mL) and 62.5 TPU at Cmax, compared to 22 TPU, 50 TPU and 102.5 TPU with KCl. CPD and TPU measurements showed a strong correlation at p = 0.01. In conclusion, transrectal power Doppler US image quantification is a feasible and accurate method for assessing blood flow changes in the urinary bladder neck. (E-mail: antonius.schuster@lkhf.at)

We report a case of bilateral synchronous malignant mesothelioma of the testis. A 21-year-old man presented with an acute scrotum after 3 months of recurrent pain on the right side. Ultrasonography demonstrated an irregular thickening of the tunica vaginalis testis, scrotolyths, and an increased blood flow to the right epididymis testis. Bilateral exploration revealed torsion of the hydatid and a bilateral malignant mesothelioma of the tunica vaginalis. One year later, elective bilateral exploration showed one minute area on the parietal tunica vaginalis of malignant mesothelioma. After 2 years of follow-up, the patient had no signs of distant disease.

Many cellular signaling pathways induce gene expression by activating specific transcription factor complexes. Conventional approaches to the prediction of transcription factor binding sites lead to a notoriously high number of false discoveries. To alleviate this problem, we consider only binding sites that are conserved in man-mouse genomic sequence comparisons. We employ two alternative methods for predicting binding sites: exact matches to validated binding site sequences and weight matrix scans. We then ask the question whether there is a characteristic association between a transcription factor or set thereof to a particular group of genes. Our approach is tested on genes, which are induced in dendritic cells in response to the cells’ exposure to LPS. We chose this example because the underlying signaling pathways are well understood. We demonstrate the benefit of conserved predicted binding sites in interpreting the LPS experiment. Additionally, we find that both methods for the prediction of conserved binding sites complement one another. Finally, our results suggest a distinct role for SRF in the context of LPS-induced gene expression. Contact: christoph.dieterich@molgen.mpg.de *To whom correspondence should be addressed.

Bladder cancer is the fourth most common cancer among men and the sixth most common non-cutaneous cancer overall, with 54,200 new cases and 12,000 deaths in 1999 (NCI website). Local treatment may be successful, but tumors commonly reoccur. Tumor invasion into the muscle layer of the bladder wall usually requires total bladder removal. Without metastasis, cystectomy with urinary diversion is the only possible cure for these patients, although the risk for postoperative metastasis development is considerably high.

The DNA sequence of human chromosome 21 (HSA21) has opened the route for a systematic molecular characterization of all of its genes. Trisomy 21 is associated with Down's syndrome, the most common genetic cause of mental retardation in humans. The phenotype includes various organ dysmorphies, stereotypic craniofacial anomalies and brain malformations. Molecular analysis of congenital aneuploidies poses a particular challenge because the aneuploid region contains many protein-coding genes whose function is unknown. One essential step towards understanding their function is to analyse mRNA expression patterns at key stages of organism development. Seminal works in flies, frogs and mice showed that genes whose expression is restricted spatially and/or temporally are often linked with specific ontogenic processes. Here we describe expression profiles of mouse orthologues to HSA21 genes by a combination of large-scale mRNA in situ hybridization at critical stages of embryonic and brain development and in silico (computed) mining of expressed sequence tags. This chromosome-scale expression annotation associates many of the genes tested with a potential biological role and suggests candidates for the pathogenesis of Down's syndrome.

We report the case of a 42-year-old male who was admitted to our hospital after an acute hypertensive crisis despite four-way anti-hypertensive therapy. The renal scintigraphy, the excretory urogram and the biochemical profile performed two years before were unremarkable, except for slightly elevated serum creatinine and plasma aldosterone, in presence of normal aldosterone/ renin ratio. The renal arterial angiography that was performed despite a second unremarkable scintigraphy revealed high-grade bilateral arterial stenosis in the presence of multiple renal arteries. Following dilatation of the left stenosis, the aldosterone/renin ratio was pathologic. Recumbent and orthostatic aldosterone values were 830 pg/ml and 1824 pg/ml, respectively, and recumbent and orthostatic renin values were 0.82 and 1.21 ng angiotensin I/ml/h, respectively. The abdominal computed tomography performed to investigate a possible concomitant Conn’s syndrome resulted in the detection of a left adrenal tumor. After resection of the lesion, plasma-aldosterone levels normalized and a pronounced rise in serum potassium levels was observed. Following angioplasty of the right renal artery stenosis, blood pressure could easily be managed with combined gB and calcium channel blocker therapy. Particularly in cases of bilateral (but also in the presence of unilateral) renal artery stenosis in association with Conn’s syndrome, all the available screening methods for these disorders can fail. In cases of poor response to combination hypertensive therapies, renal arteriography and a fludrocortisone- suppression test should be performed in order to rule out both renal arterial stenosis and Conn’s syndrome, even in the absence of clinical and biochemical findings suspicious for either disorder.

Choriocarcinoma was diagnosed in a 77-year-old woman with an acute massive, painless hematuria. One year after anterior pelvic exenteration and ileal conduit, the beta-human chorionic gonadotropin level increased to 934 mIU/mL without any sign of tumor progression. After six courses of chemotherapy (vincristine, actinomycin, and cyclophosphamide), the beta-human chorionic gonadotropin levels returned to normal. To our knowledge, this is the fourth case of pure choriocarcinoma in the bladder, with the longest survival time of 33 months so far.

Background Leishmania are obligated intracellular pathogens that replicate almost exclusively in macrophages. The outcome of infection depends largely on parasite pathogenicity and virulence but also on the activation status and genetic background of macrophages. Animal models are essential for a better understanding of pathogenesis of different microbes including Leishmania. Results Here we compared the transcriptional signatures of resistant (C57BL/6) and susceptible (BALB/c) mouse bone marrow-derived macrophages in response to Leishmania major (L. major) promastigotes infection. Microarray results were first analyzed for significant pathways using the Kyoto Encylopedia of Genes and Genomes (KEGG) database. The analysis revealed that a large set of the shared genes is involved in the immune response and that difference in the expression level of some chemokines and chemokine receptors could partially explain differences in resistance. We next focused on up-regulated genes unique to either BALB/c or C57BL/6 derived macrophages and identified, using KEGG database, signal transduction pathways among the most relevant pathways unique to both susceptible and resistant derived macrophages. Indeed, genes unique to C57BL/6 BMdMs were associated with target of rapamycin (mTOR) signaling pathway while a range of genes unique to BALB/c BMdMs, belong to p53 signaling pathway. We next investigated whether, in a given mice strain derived macrophages, the different up-regulated unique genes could be coordinately regulated. Using GeneMapp Cytoscape, we showed that the induced genes unique to BALB/c or C57BL/6 BMdMs are interconnected. Finally, we examined whether the induced pathways unique to BALB/c derived macrophages interfere with the ones unique to C57BL/6 derived macrophages. Protein-protein interaction analysis using String database highlights the existence of a cross-talk between p53 and mTOR signaling pathways respectively specific to susceptible and resistant BMdMs. Conclusions Taken together our results suggest that strains specific pathogenesis may be due to a difference in the magnitude of the same pathways and/or to differentially expressed pathways in the two mouse strains derived macrophages. We identify signal transduction pathways among the most relevant pathways modulated by L. major infection, unique to BALB/c and C57BL/6 BMdM and postulate that the interplay between these potentially interconnected pathways could direct the macrophage response toward a given phenotype.

SeqAhead is a COST Action created by a group of researchers involved in the development of Next Generation Sequencing (NGS) data-analysis software and pipelines. The primary objective of SeqAhead is to develop a coordinated action plan to help the scientific community to handle the flood of NGS data in an efficient and coherent manner, using state-of-the-art bioinformatics. Establishment of a strong European network of NGS, data-analysis and informatics centres will facilitate and stimulate the exchange of data, protocols, software, experiences and ideas.

At present, most non-small cell lung cancer (NSCLC) treatments are not adapted to the individual response of a patient. The stratification of patients for the most efficient response to conventional chemotherapeutics and targeted therapies will improve established therapy schemes and patient's perspectives. Our project aims at unraveling the influence of specific signaling molecules on the response to common NSCLC drugs. We searched for predictive markers for the response of NSCLC tumors to certain drugs and novel combinations of treatments, which may be useful for therapy decisions towards a more efficient personalized treatment. Expression of 77 proteins described to be involved in EGFR signaling (e.g. MAPK, JAK/STAT, PI3K/AKT pathways) and NSCLC disease in general were quantified in 53 patient derived NSCLC xenograft models using the reverse-phase protein array technology (RPPA). The tumor models are characterized by different response rates upon treatment with different chemotherapeutics and EGFR-targeted therapies. The response rates were obtained directly in the xenograft models. After RPPA analysis we associated the protein expression with the response to established chemotherapeutics (e.g. Vinorelbine, Paclitaxel, Carboplatin) and EGFR-targeted therapies (Cetuximab, Erlotinib). Another goal is to analyze the protein expression changes after treatment in dependence on the response rate. Therefore, protein profiles were raised in NSCLC xenograft models before and after treatment with Cetuximab, a chimeric (mouse/human) monoclonal antibody that inhibits EGFR. The major goal in this experimental subset is to find links between the activities of specific proteins and the response to Cetuximab treatment. A similar experiment with Erlotinib (an EGFR inhibitor) treated samples is ongoing. Statistical analysis indicated significant associations between the expression of distinct proteins and the response rate to certain drugs. Proteins of the ErbB signaling pathway were differentially expressed in Carboplatin responders and non-responders. MEK1 upregulation was observed upon Cetuximab treatment in responders. We revealed an association between higher P-SRC expression and increased Gemcitabine response rates. This result fits to observations that describe coherence between SRC inhibition and reduced suppression of cell growth and survival in the presence of Gemcitabine in cancer cell lines. We are now strengthening our results in various validation experiments. First, we selected seven target proteins based on RPPA analysis. Predictive targets for drug sensitivity are being analyzed to investigate the dependency between target protein activity, downstream signaling and response to distinct drugs in tumor cell lines in a pharmacogenomic approach. Therefore, we knocked down target genes in several NSCLC cell lines and unraveled changes in the drug sensitivity. Microarray and protein analyzes were carried out to study the mechanisms of target-drug association by investigating the downstream signaling upon target knockdown. In summary, our study suggests predictive markers for the response of NSCLC tumors to certain drugs, which may be useful for therapy decisions towards a more efficient personalized treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A185.

Endourologische Operationstechniken (transurethrale Resektion und Koagulation, Nd-YAG-Laser) zur Behandlung der interstitiellen Zystitis (IC) wurden nur in wenigen Studien wissenschaftlich untersucht. Nach Ausschopfen konservativer Behandlungsstrategien stellen sie theoretisch den nachsten Schritt im Therapiekonzept dar, bevor offen chirurgische Behandlungsansatze als Ultima ratio zum Einsatz kommen. Diese Ubersicht zeigt, dass nach Anwendung strenger Kriterien aus dem Bereich der evidenzbasierten Medizin, wissenschaftliche Grundlagen fur die Empfehlung endourologischer Techniken zur Behandlung der IC noch weitgehend fehlen.

Background Multiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches. Results Here we report on a meta-analysis approach that integrates data of heterogeneous origin in the domain of type-2 diabetes mellitus (T2DM). Different data sources such as DNA microarrays and, complementing, qualitative data covering several human and mouse tissues are integrated and analyzed with a Bootstrap scoring approach in order to extract disease relevance of the genes. The purpose of the meta-analysis is two-fold: on the one hand it identifies a group of genes with overall disease relevance indicating common, tissue-independent processes related to the disease; on the other hand it identifies genes showing specific alterations with respect to a single study. Using a random sampling approach we computed a core set of 213 T2DM genes across multiple tissues in human and mouse, including well-known genes such as Pdk4, Adipoq, Scd, Pik3r1, Socs2 that monitor important hallmarks of T2DM, for example the strong relationship between obesity and insulin resistance, as well as a large fraction (128) of yet barely characterized novel candidate genes. Furthermore, we explored functional information and identified cellular networks associated with this core set of genes such as pathway information, protein-protein interactions and gene regulatory networks. Additionally, we set up a web interface in order to allow users to screen T2DM relevance for any – yet non-associated – gene. Conclusion In our paper we have identified a core set of 213 T2DM candidate genes by a meta-analysis of existing data sources. We have explored the relation of these genes to disease relevant information and – using enrichment analysis – we have identified biological networks on different layers of cellular information such as signaling and metabolic pathways, gene regulatory networks and protein-protein interactions. The web interface is accessible via http://t2dm-geneminer.molgen.mpg.de.

Diabetes is a complex trait, reflecting interactions of a network of genes with environmental factors, such as obesity, age and nutrition [1]. The polygenic nature of type 2 diabetes is now well established. The individual contributions of each individual gene to the phenotype is likely to be small. The primary objective of our work is to provide identification and data integration for obesity and type 2 diabetes mellitus. Microarrays have become a standard technology platform for genome screening. This technique fails in the integration of other data sources relevant for diagnostic purposes. For these tasks, data integration methods are indispensable. In our poster we present strategies to incorporate these sources within the framework of R/BioConductor [2, 3]. To elucidate the most important genes for diabetes we employ scoring to gain new knowledge on the pathways and marker genes relevant. Pathway information from databases like KEGG [4] is comprised to map the genes into their function/framework. Ultimately, the proposed marker genes will enable us to develop models for the disease. Medical researcher can combine molecular biological data with clinically relevant parameters to predict quantitatively individual predispositions to type 2 diabetes and include physiological data.

The lower transverse abdominal incision, as described by Hermann Johannes Pfannenstiel, cutting both skin and fascia in a transverse fashion was popularized in 1900. Nerve pain syndromes included invalidating pain involving neuroma formation or scar encasement of the ilioinguinal or iliohypogastric nerves. We report a case of a female patient who developed severe pain at the lateral wound edges of a Pfannenstiel incision. The diagnosis of pain of nerve origin was made by infiltration of local anesthetic, after which the pain immediately vanished temporarily. Only complete excision of the scar and involved part of the nerve stopped the pain.