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The Hippocratic Collection, including the most of ancient Greek medicine, remains still interesting, despite the recent advances that transformed definitely the urological healing methods. Considering the patient as a unique psycho-somatic entity and avoiding high risk surgical manipulations were the leading principles dictating the everyday practice. Contemporary physicians can still learn from the clinical observations in times of complete absence of laboratory or imaging aid, from the prognostic thoughts, the ethics, and the philosophical concepts, represented by the Hippocratic writings, tracing into them the roots of Rational Medicine in general and Urology in particular.

Abstract Background Expression quantitative trait loci (eQTL) studies provide insights into regulatory mechanisms underlying disease risk. Expanding studies of gene regulation to underexplored populations and to medically relevant tissues offers potential to reveal yet unknown regulatory variants and to better understand disease mechanisms. Here, we performed eQTL mapping in subcutaneous (S) and visceral (V) adipose tissue from 106 Greek individuals (Greek Metabolic study, GM) and compared our findings to those from the Genotype-Tissue Expression (GTEx) resource. Results We identified 1,930 and 1,515 eGenes in S and V respectively, over 13% of which are not observed in GTEx adipose tissue, and that do not arise due to different ancestry. We report additional context-specific regulatory effects in genes of clinical interest (e.g. oncogene ST7) and in genes regulating responses to environmental stimuli (e.g. MIR21, SNX33). We suggest that a fraction of the reported differences across populations is due to environmental effects on gene expression, driving context-specific eQTLs, and suggest that environmental effects can determine the penetrance of disease variants thus shaping disease risk. We report that over half of GM eQTLs colocalize with GWAS SNPs and of these colocalizations 41% are not detected in GTEx. We also highlight the clinical relevance of S adipose tissue by revealing that inflammatory processes are upregulated in individuals with obesity, not only in V, but also in S tissue. Conclusions By focusing on an understudied population, our results provide further candidate genes for investigation regarding their role in adipose tissue biology and their contribution to disease risk and pathogenesis.

Everything we do today is becoming more and more reliant on the use of computers. The field of biology is no exception; but most biologists receive little or no formal preparation for the increasingly computational aspects of their discipline. In consequence, informal training courses are often needed to plug the gaps; and the demand for such training is growing worldwide. To meet this demand, some training programs are being expanded, and new ones are being developed. Key to both scenarios is the creation of new course materials. Rather than starting from scratch, however, it's sometimes possible to repurpose materials that already exist. Yet finding suitable materials online can be difficult: They're often widely scattered across the internet or hidden in their home institutions, with no systematic way to find them. This is a common problem for all digital objects. The scientific community has attempted to address this issue by developing a set of rules (which have been called the Findable, Accessible, Interoperable and Reusable [FAIR] principles) to make such objects more findable and reusable. Here, we show how to apply these rules to help make training materials easier to find, (re)use, and adapt, for the benefit of all.

RNA sequencing has become the standard technique for high resolution genome-wide monitoring of gene expression. As such, it often comprises the first step towards understanding complex molecular mechanisms driving various phenotypes, spanning organ development to disease genesis, monitoring and progression. An advantage of RNA sequencing is its ability to capture complex transcriptomic events such as alternative splicing which results in alternate isoform abundance. At the same time, this advantage remains algorithmically and computationally challenging, especially with the emergence of even higher resolution technologies such as single-cell RNA sequencing. Although several algorithms have been proposed for the effective detection of differential isoform expression from RNA-Seq data, no widely accepted golden standards have been established. This fact is further compounded by the significant differences in the output of different algorithms when applied on the same data. In addition, many of the proposed algorithms remain scarce and poorly maintained. Driven by these challenges, we developed a novel integrative approach that effectively combines the most widely used algorithms for differential transcript and isoform analysis using state-of-the-art machine learning techniques. We demonstrate its usability by applying it on simulated data based on several organisms, and using several performance metrics; we conclude that our strategy outperforms the application of the individual algorithms. Finally, our approach is implemented as an R Shiny application, with the underlying data analysis pipelines also available as docker containers.

Approximately 10% of breast cancer (BC) cases are hereditary BC (HBC), with HBC most commonly encountered in the context of hereditary breast and ovarian cancer (HBOC) syndrome. Although thousands of loss-of-function (LoF) alleles in over 20 genes have been associated with HBC susceptibility, the genetic etiology of approximately 50% of cases remains unexplained, even when polygenic risk models are considered. We focused on one of the least-studied European populations and applied whole-exome sequencing (WES) to 52 individuals from 17 Greek HBOC families, in which at least one patient was negative for known HBC risk variants. Initial screening revealed pathogenic variants in known cancer genes, including BARD1:p.Trp91* detected in a cancer-free individual, and MEN1:p.Glu260Lys detected in a BC patient. Gene- and variant-based approaches were applied to exome data to identify candidate risk variants outside of known risk genes. Findings were verified in a collection of Canadian HBOC patients of European ancestry (FBRCAX), in an independent group of Canadian BC patients (CHUM-BC) and controls (CARTaGENE), as well as in individuals from The Cancer Genome Atlas (TCGA) and the UK Biobank (UKB). Rare LoF variants were uncovered in MDM1 and NBEAL1 in Greek and Canadian HBOC patients. We also report prioritized missense variants SETBP1:c.4129G > C and C7orf34:c.248C > T. These variants comprise promising candidates whose role in cancer pathogenicity needs to be explored further.

Abstract Background The use of Cardiovascular Disease (CVD) risk estimation scores in primary prevention has long been established. However, their performance still remains a matter of concern. The aim of this study was to explore the potential of using ML methodologies on CVD prediction, especially compared to established risk tool, the HellenicSCORE. Methods Data from the ATTICA prospective study (n = 2020 adults), enrolled during 2001–02 and followed-up in 2011–12 were used. Three different machine-learning classifiers (k-NN, random forest, and decision tree) were trained and evaluated against 10-year CVD incidence, in comparison with the HellenicSCORE tool (a calibration of the ESC SCORE). Training datasets, consisting from 16 variables to only 5 variables, were chosen, with or without bootstrapping, in an attempt to achieve the best overall performance for the machine learning classifiers. Results Depending on the classifier and the training dataset the outcome varied in efficiency but was comparable between the two methodological approaches. In particular, the HellenicSCORE showed accuracy 85%, specificity 20%, sensitivity 97%, positive predictive value 87%, and negative predictive value 58%, whereas for the machine learning methodologies, accuracy ranged from 65 to 84%, specificity from 46 to 56%, sensitivity from 67 to 89%, positive predictive value from 89 to 91%, and negative predictive value from 24 to 45%; random forest gave the best results, while the k-NN gave the poorest results. Conclusions The alternative approach of machine learning classification produced results comparable to that of risk prediction scores and, thus, it can be used as a method of CVD prediction, taking into consideration the advantages that machine learning methodologies may offer.

Arteriovenous fistulas (AVFs) of the lower extremity are uncommon. The main causes are traumatic or iatrogenic, with 15% of traumatic AVFs occurring in the popliteal vessels. Herein, we present a 60-year-old female with a traumatic AVF caused after a car accident 40 years ago. The patient presented with right leg venous claudication and symptoms of congestive heart failure. Duplex ultrasound of lower limb vessels revealed an AVF at the distal part of the tibiofibular trunk. The patient was successfully managed with an endovascular approach using a coil-assisted covered endovascular repair technique of the tibiofibular bifurcation (CERTIFIB) with excellent results and distal vessels patency. At 3 months follow-up, patient presented with an impressive regression of 3 cm of the lower extremity oedema and improvement of both claudication and heart failure., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The effect of thiamine (TA), ascorbic acid (AA), citric acid, and gallic acid (GA) on bacterial cellulose (BC) production by Komagataeibacter sucrofermentans, in synthetic (Hestrin and Schramm, HS) and natural substrates (industrial raisins finishing side stream extract, FSSE; orange juice, OJ; green tea extract, GTE), was investigated. The Response Surface Methodology was found reliable for BC yield prediction and optimization. Higher yields were achieved in the FSSE substrates, especially those supplemented with AA, TA, and GA (up to 19.4 g BC/L). The yield in the non-fortified substrates was 1.1-5.4 and 11.6-15.7 g/L, in HS and FSSE, respectively. The best yield in the natural non-fortified substrate FSSE-OJ-GTE (50-20-30 %), was 5.9 g/L. The porosity, crystallinity, and antioxidant properties of the produced BC films were affected by both the substrate and the drying method (freeze- or oven-drying). The natural substrates and the process wastewaters can be further exploited towards added value and sustainability. Take Home Message Sentence: Raisin and citrus side-streams can be efficiently combined for bacterial cellulose production, enhanced by other vitamin- and phenolic-rich substrates such as green tea., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To analyze the early performance and efficacy of the first commercially available off-the-shelf precannulated multibranched endograft in the endovascular repair of pararenal abdominal aortic aneurysms (PAAAs). The device received European marketing approval in late 2020., Materials and Methods: Between January 2021 and June 2023, a retrospective analysis of prospectively collected data from all consecutive patients with pAAAs undergoing implantation of the E-nside precannulated inner-branched endograft was conducted in 2 centers. The primary outcome measure was technical success defined as the composite endpoint of successful (1) delivery of the 24F endograft, (2) use of the precannulation tubes, and (3) implantation of the bridging stent-grafts (BSGs) to the target vessels. Main secondary endpoints were mortality, target vessel instability (TVI), absence of type I or III endoleak, reintervention, spinal cord ischemia, and supra-celiac aortic coverage., Results: Twenty-one patients (20 men, mean age: 71 years) were included in this study with a mean follow-up of 14±7.7 months. Nine patients had a symptomatic aneurysm (43%). Technical success amounted to 95% (in one patient, an iliofemoral conduit was necessary to advance the device). One out of 112 BSGs (1%, right renal artery) occluded at 30 days, resulting in freedom from TVI and reintervention rate at 12 months of 95%. No type I or III endoleaks were identified during follow-up. One patient (5%) died at 13 months due to non-aneurysm-related death, and 1 patient (5%) developed spinal cord ischemia. No other major perioperative complications were observed. Mean supra-celiac aortic coverage reached 52±8%., Conclusions: Given the imperative need for an off-the-shelf endograft tailored to address PAAAs, the E-nside stent-graft demonstrated encouraging outcomes in this study. Nevertheless, it is essential to emphasize that the extent of aortic coverage mandates the production of a truncated variant., Clinical Impact: The endovascular repair of urgent pararenal aortic aneurysms remains still an unsolved problem in the endovascular era since there are no available off-the-shelf dedicated fenestrated or branched endografts. This paper confirms the safety and efficacy of the off-the-shelf precannulated inner branched endograft for this specific indication., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TB received fee for consulting from Artivion, COOK Medical, Medtronic, W.L. Gore and Bentley.

The safety and efficacy of tofacitinib in Crohn's disease (CD) has been studied in 2 phase II trials in patients with moderate-to-severe CD with no new safety signals observed, but no significant difference from placebo in the primary efficacy endpoint of clinical response. 1-3 However, post hoc analyses and smaller studies have observed clinical and biologic response to tofacitinib in patients with CD. 2 , 4 , 5 There is a paucity of real-world effectiveness and safety data for tofacitinib in non-Food and Drug Administration label usage in patients with CD and patients with inflammatory bowel disease-unclassified (IBD-U)., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Adverse events (AEs) including reactivation of herpes zoster (HZ) and venous thromboembolism (VTE) have been reported from clinical trials of tofacitinib in ulcerative colitis (UC). We investigated the incidence rates of AEs in a real-world study of UC patients given tofacitinib., Methods: We collected data from 260 patients with UC in the Tofacitinib Real-world Outcomes in Patients with ulceratIve colitis and Crohn's disease consortium study, performed at 6 medical centers in the United States. Patients were followed up for a median of 6 months (interquartile range, 2.7-11.5 mo). AEs were captured using a standardized data collection instrument before study initiation and at weeks 8, 16, 26, 39, and 52. Serious AEs were defined as life-threatening or resulting in a hospitalization, disability, or discontinuation of therapy. Logistic regression was performed to examine risk factors for AEs., Results: AEs occurred in 41 patients (15.7%); most were infections (N = 13; 5.0%). The incidence rate of any AE was 27.2 (95% CI, 24.4-30.7 per 100 patient-years of follow-up evaluation). Fifteen were serious AEs (36.6% of AEs), and tofacitinib was discontinued for 12 patients (4.6% of cohort). The incidence rates of serious AEs was 10.0 (95% CI, 8.9-11.2 per 100 patient-years of follow-up evaluation). Five patients developed HZ infection and 2 developed VTE (all receiving 10 mg tofacitinib, twice per day)., Conclusions: Real-world safety signals for tofacitinib are similar to those for clinical trials, with AEs reported from almost 16% of patients. HZ infection and VTE occurred in patients receiving 10 mg tofacitinib twice per day. These results support dose de-escalation after induction therapy, to reduce the risk of AEs., (Copyright © 2021 AGA Institute. All rights reserved.)

Background: There are limited data on how vedolizumab (VDZ) impacts extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD). The aim of this study was to determine the clinical outcomes of EIMs after initiation of VDZ for patients with IBD., Methods: A multicenter retrospective study of patients with IBD who received at least 1 dose of VDZ between January 1, 2014 and August 1, 2019 was conducted. The primary outcome was the rate of worsening EIMs after VDZ. Secondary outcomes were factors associated with worsening EIMs and peripheral arthritis (PA) specifically after VDZ., Results: A total of 201 patients with IBD (72.6% with Crohn disease; median age 38.4 years (interquartile range, 29-52.4 years); 62.2% female) with EIMs before VDZ treatment were included. The most common type of EIM before VDZ was peripheral arthritis (PA) (68.2%). Worsening of EIMs after VDZ occurred in 34.8% of patients. There were no statistically significant differences between the worsened EIM (n = 70) and the stable EIM (n = 131) groups in term of age, IBD subtype, or previous and current medical therapy. We found that PA was significantly more common in the worsening EIM group (84.3% vs 59.6%; P < 0.01). Worsening of EIMs was associated with a higher rate of discontinuation of VDZ during study follow-up when compared with the stable EIM group (61.4% vs 44%; P = 0.02). Treatment using VDZ was discontinued specifically because of EIMs in 9.5% of patients., Conclusions: Almost one-third of patients had worsening EIMs after VDZ, which resulted in VDZ discontinuation in approximately 10% of patients. Previous biologic use or concurrent immunosuppressant or corticosteroid therapy did not predict EIM course after VDZ., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The graft-versus-leukemia (GVL) effect after allogeneic hematopoietic cell transplant (HCT) can prevent relapse but the risk of severe graft-versus-host disease (GVHD) leads to prolonged intensive immunosuppression and possible blunting of the GVL effect. Strategies to reduce immunosuppression in order to prevent relapse have been offset by increases in severe GVHD and nonrelapse mortality (NRM). We recently validated the MAGIC algorithm probability (MAP) that predicts the risk for severe GVHD and NRM in asymptomatic patients using serum biomarkers. In this study we tested whether the MAP could identify patients whose risk for relapse is higher than their risk for severe GVHD and NRM. The multicenter study population (n = 1604) was divided into two cohorts: historical (2006-2015, n = 702) and current (2015-2017, n = 902) with similar NRM, relapse, and survival. On day 28 post-HCT, patients who had not developed GVHD (75% of the population) and who possessed a low MAP were at much higher risk for relapse (24%) than severe GVHD and NRM (16 and 9%); this difference was even more pronounced in patients with a high disease risk index (relapse 33%, NRM 9%). Such patients are good candidates to test relapse prevention strategies that might enhance GVL.

Critical infrastructures and associated real time Informational systems need some security protection mechanisms that will be able to detect and respond to possible attacks. For this reason, Anomaly Detection Systems (ADS), as part of a Security Information and Event Management (SIEM) system, are needed for constantly monitoring and identifying potential threats inside an Information Technology (IT) system. Typically, ADS collect information from various sources within a CI system using security sensors or agents and correlate that information so as to identify anomaly events. Such sensors though in a CI setting (factories, power plants, remote locations) may be placed in open areas and left unattended, thus becoming targets themselves of security attacks. They can be tampering and malicious manipulated so that they provide false data that may lead an ADS or SIEM system to falsely comprehend the CI current security status. In this paper, we describe existing approaches on security monitoring in critical infrastructures and focus on how to collect security sensor-agent information in a secure and trusted way. We then introduce the concept of hardware assisted security sensor information collection that improves the level of trust (by hardware means) and also increases the responsiveness of the sensor. Thus, we propose a Hardware Security Token (HST) that when connected to a CI host, it acts as a secure anchor for security agent information collection. We describe the HST functionality, its association with a host device, its expected role and its log monitoring mechanism. We also provide information on how security can be established between the host device and the HST. Then, we introduce and describe the necessary host components that need to be established in order to guarantee a high security level and correct HST functionality. We also provide a realization-implementation of the HST overall concept in a FPGA SoC evaluation board and describe how the HST implementation can be controlled. In addition, in the paper, two case studies where the HST has been used in practice and its functionality have been validated (one case study on a real critical infrastructure test site and another where a critical industrial infrastructure was emulated in our lab) are described. Finally, results taken from these two case studies are presented, showing actual measurements for the in-field HST usage.

Introduction: Oxidized regenerated cellulose-based (ORC - TABOTAMP), oxidized non-regenerated cellulose-based (ONRC - RESORBA CELL), and gelatin-based (GELA - GELITA TUFT-IT) hemostats are commonly used in surgery. However, their impact on the wound healing process remains largely unexplored. We here assess time-dependent effects of exposure to these hemostats on fibroblast-related wound healing processes., Material and Methods: Hemostats were applied to fibroblast cell cultures for 5-10 (short-), 30 and 60 min (intermediate-) and 24 h (long-term). Representative images of the hemostat degradation process were obtained, and the pH value was measured. Cell viability, apoptosis and migration were analyzed after the above exposure times at 3, 6 and 24 h follow-up. Protein levels for tumor necrosis factor α (TNF-α) and transforming-growth factor β (TGF-β) were assessed., Results: ORC and ONRC reduced pH values during degradation, while GELA proved to be pH-neutral. Hemostat structural integrity was prolonged for GELA (vs. ORC and ONRC). TGF-β and TNF-α levels were reduced for ORC and ONRC (vs. GELA and control) ( p < 0.05). Further, exposure of ORC and ONRC for longer than 5-10 min reduced cell viability vs. GELA and control at 3 h post-exposure ( p < 0.05). Similarly, cell migration was impaired with ORC and ONRC exposure longer than 60 min at 24 h follow-up ( p < 0.05)., Conclusions: Short-term exposure to ORC and ONRC impairs relevant wound healing-related processes in fibroblasts, and alters protein levels of key mediating cytokines. GELA does not show similar effects. We conclude that GELA may be preferred over ORC and ONRC over short-, intermediate- and long-term exposures. Future validation of the clinical relevance is warranted., Competing Interests: All authors who are affiliated with the Department of Vascular and Endovascular Surgery, Heinrich-Heine University Düsseldorf, Germany and Alexander Oberhuber participated in the “GELITA Medical Gelatin Hemostat Postmarket Registry” (Registry-ID: 2016116001)., (Copyright: © 2020 Termedia & Banach.)

Introduction: Recent studies have indicated that the damaging effects of stroke are not only limited to the brain. We sought to examine the changes of liver and renal enzymes in the acute phase of ischemic stroke and to investigate possible explanations and therapeutic options, concerning in particular the functional alterations of peripheral organs after administration of an anti-inflammatory agent., Material/methods: Twelve-week-old Wistar male rats were randomly divided into control and Cyclosporine groups (n = 10 each). Cyclosporine was given orally by gavage for 5 days prior to cerebral ischemia at a total volume of 15 mg/kg/day. All animals were subjected to 60 minutes focal ischemia by filament occlusion of the middle cerebral artery. Serum concentrations of Creatinine, Urea, SGOT, SGPT, and γGT were determined at the time before surgery and after 60 minutes brain ischemia., Results: Comparing data of 2 time-points, in both groups the serum liver enzyme levels increased progressively during the ischemic period. The liver enzymes and Urea were significantly lower in the Cyclosporine group than in the control group and the levels of Creatinine were slightly higher in the Cyclosporine group, in both time-points., Conclusions: The detection of high liver enzyme serum levels in the acute phase of ischemic stroke implies the secondary effect of cerebral infraction on the peripheral organs and particularly on the liver function. Cyclosporine seems to exhibit a protective activity and to affect both liver and renal function after ischemic stroke., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Microsatellite unstable colorectal cancers (MSI+ CRCs) expressing PD-L1, respond to anti-PD-1 or anti-PD-L1 checkpoint blockade, whereas microsatellite-stable tumors do not respond the same. Our aim was to examine how the immune landscape relates to different aspects of the CRC's biology, including neoepitope burden., Methods: We used TCGA data to stratify patients based on a cytolytic T-cell activity expression index and correlated immune cytolytic activity (CYT) with mutational, structural, and neoepitope features of each tumor sample. The expression of several immune checkpoints was verified in an independent cohort of 72 CRC patients, relative to their MSI status, using immunohistochemistry and RT-qPCR., Results: CRC exhibits a range of intertumoral cytolytic T-cell activity, with lower cytolytic levels in the tumor, compared to the normal tissue. We separated CRC patients into CYT-high and CYT-low subgroups. High cytolytic activity correlated with increased mutational load in colon tumors, the count of MHC-I/-II classically defined and alternatively defined neoepitopes, high microsatellite instability and deregulated expression of several inhibitory immune checkpoints (VISTA, TIGIT, PD-1, IDO1, CTLA-4, and PD-L1, among others). Many immune checkpoint molecules (IDO1, LAG3, TIGIT, VISTA, PD-1, PD-L1 and CTLA-4) expressed significantly higher in MSI+ CRCs compared to MSS tumors. The expression of Treg markers was also significantly higher in CYT-high tumors. Both individual and simultaneous high levels of CTLA-4 and PD-L1 had a positive effect on the patients' overall survival. On the reverse, simultaneous low expression of both genes led to a significant shift towards negative effect. Assessed globally, CYT-low CRCs contained more recurrent somatic copy number alterations. PD-L1 protein was absent in most samples in the independent cohort and stained lowly in 33% of MSI CRCs. PD-L1+ CRCs stained moderately for CD8 and weakly for FOXP3. CYT-high colon tumors had higher TIL load, whereas CYT-high rectum tumors had higher TAN load compared to their CYT-low counterparts., Conclusions: Overall, we highlight the link between different genetic events and the immune microenvironment in CRC, taking into consideration the status of microsatellite instability. Our data provide further evidence that MSI+ and CYT-high tumors are better candidates for combinatorial checkpoint inhibition.

Objective: Inferior vena cava thrombosis is rare, but patients are at high risk for development of a post-thrombotic syndrome (PTS) in the long term. Surgical approaches include indirect transfemoral venous thrombectomy (iTFVT) and direct open venous thrombectomy (dOVT). This study reports patient outcomes after iTFVT and dOVT for inferior vena cava thrombosis covering a 25-year follow-up period., Methods: The study period was from January 1, 1982, to December 31, 2013. Data were retrieved from archived medical records, and patients were invited for a detailed phlebologic follow-up examination (DPFE). Health-related quality of life was assessed with the 36-Item Short Form Health Survey questionnaire. Patient survival, patency rates, and freedom from PTS were calculated using Kaplan-Meier estimation with log-rank testing. The χ 2 test with Yates continuity correction and logistic regression analysis were applied to identify associations between risk factors or coagulation disorders, mortality, and PTS., Results: Complete medical records were available for 152 patients. Patients' 5-year survival was 91% ± 3%, and 5-year primary and secondary patency rates were 80% ± 3% and 94% ± 2%. Freedom from PTS after 25 years was 84% ± 6%. No differences for patient survival, patency rates, or freedom from PTS were identified between iTFVT, dOVT, and a combination of both procedures. Antithrombin III deficiency was the most common coagulation disorder, and patients' physical function and social function were impaired compared with those found in German normative data (P < .05). No risk factor or coagulation disorder was associated with survival or PTS., Conclusions: Open surgical venous thrombectomy is safe and delivers satisfying short- and long-term outcomes compared with endovascular approaches. It remains valuable for patients who are not eligible for other interventional therapies., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

BACKGROUND Accumulating evidence has indicated that S100B protein may be involved in the pathophysiology of ischemia-reperfusion brain injury. Cyclosporine has been shown to have neuroprotective functions. This study investigated the effect of cyclosporine on S100B serum levels and the severity of brain tissue damage in a rat model of cerebral ischemia-reperfusion (I/R). MATERIAL AND METHODS Twelve-week-old Wistar male rats were randomly divided into Control I/R and Cyclosporine I/R groups (n=10 each). Cyclosporine was given orally by gavage for 5 days prior to cerebral I/R, at a total volume of 15 mg/kg/day. The Control group received an equal volume of saline. Body weight was measured and all animals were subjected to 60-min focal ischemia by filament occlusion of the middle cerebral artery. ELISA was used to assess the concentrations of serum S100B and development of brain infarct size and neurological outcomes were determined at 2 and 24 h after occlusion withdrawal. RESULTS Cyclosporine improved the neurological deficit score and decreased the cerebral infarct size and body weight. S100B serum levels were significantly elevated in Cyclosporine-treated rats compared with untreated Control rats during the reperfusion phase. Total infarct size was positively associated with S100B serum levels in the Control I/R group, but no significant correlation was observed in the Cyclosporine I/R group. CONCLUSIONS Cyclosporine seems to affect both ischemia-reperfusion brain tissue damage and S100B protein serum levels. S100B serum level appears to be a state marker for the severity of the cerebral ischemia-reperfusion, rather than a trait marker for Cyclosporine responsiveness.

Background: Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies. Still, it is not completely understood how different tumors induce and adapt to immune responses., Methods: Here, we calculated the CYT across different cancer types and focused on differences between primary and metastatic tumors. Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types. We correlated the cytolytic levels in each cancer type with the corresponding patient group's overall survival, the expression of several immune-checkpoint molecules, as well as with the load of tumor-infiltrating lymphocytes (TILs), and tumor-associated neutrophils (TANs) in these tumors., Results: We found diverse levels of CYT across different cancer types, with highest levels in kidney, lung, and cervical cancers, and lowest levels in glioma, adrenocortical carcinoma (ACC), and uveal melanoma. GZMA protein was either lowly expressed or absent in at least half of these tumors; whereas PRF1 protein was not detected in almost any of the different tumor types, analyzing tissue microarrays from 20 different tumor types. CYT was significantly higher in metastatic skin melanoma and correlated significantly to the TIL load. In TCGA-ACC, skin melanoma, and bladder cancer, CYT was associated with an improved patient outcome and high levels of both GZMA and PRF1 synergistically affected patient survival in these cancers. In bladder, breast, colon, esophageal, kidney, ovarian, pancreatic, testicular, and thyroid cancers, high CYT was accompanied by upregulation of at least one immune-checkpoint molecule, indicating that similar to melanoma and prostate cancer, immune responses in cytolytic-high tumors elicit immune suppression in the tumor microenvironment., Conclusion: Overall, our data highlight the existence of diverse levels of CYT across different cancer types and suggest that along with the existence of complicated associations among various tumor-infiltrated immune cells, it is capable to promote or inhibit the establishment of a permissive tumor microenvironment, depending on the cancer type. High levels of immunosuppression seem to exist in several tumor types.

This paper discusses the concept of ageing as this applies to the operation of Evolutionary Algorithms, and examines its relationship to the concept of ageing as this is understood for human beings. Evolutionary Algorithms constitute a family of search algorithms which base their operation on an analogy from the evolution of species in nature. The paper initially provides the necessary knowledge on the operation of Evolutionary Algorithms, focusing on the use of ageing strategies during the implementation of the evolutionary process. Background knowledge on the concept of ageing, as this is defined scientifically for biological systems, is subsequently presented. Based on this information, the paper provides a comparison between the two ageing concepts, and discusses the philosophical inspirations which can be drawn for human ageing based on the operation of Evolutionary Algorithms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This paper presents a novel robotic system, which aims to enhance children's motivation through the gamification of the CIMT process. The system offers adjustability of the required movement skills, ensuring children will put increasingly more effort to achieve the rehabilitation goal, while keeping the task fun and engaging.

We compare the performance of an alternative method based on portable Fourier-transform infrared (FTIR) spectroscopy described in TGN M22, "Measuring Stack Gas Emissions Using FTIR Instruments," to the Standard Reference Methods (SRMs) for CO (EN 15058), NOx (EN 14792), SO₂(EN 14791), HCl (EN 1911), and H₂O (EN 14790). Testing was carried out using a Stack Simulator facility generating complex gas matrices of the measurands across concentration ranges of 0-75 mg m⁻³ and 0-100 mg m⁻³ CO, 0-200 mg m⁻³ and 0-300 mg m⁻³ NO, 0-75 mg m⁻³ and 0-200 mg m⁻³ SO₂, 0-15 mg m⁻³ and 0-60 mg m⁻³ HCl, and 0-14 vol% H₂O. The former values are the required monitoring range for each measurand as described in the European Union (EU) Industrial Emissions Directive (2010/75/EU) for waste incineration processes, and the latter are supplementary ranges representative of emissions from some large combustion plant processes. Test data were treated in accordance with CEN/TS 14793, and it was found that equivalency test criteria could be met across all concentration ranges with the exception of the NO supplementary range. The results demonstrated in principle where TGN M22/FTIR could be used in place of the existing SRMs to provide, as required under the Industrial Emissions Directive, annual validation/calibration of automated measuring systems (AMSs being permanently installed on industrial stacks to provide continuous monitoring of emissions to air). These data take a step toward the wider regulatory acceptance of portable FTIR providing the advantages of real-time calibration and quantification of all measurands on a single technique.

The Hippocratic Collection, including the most of ancient Greek medicine, remains still interesting, despite the recent advances that transformed definitely the urological healing methods. Considering the patient as a unique psycho-somatic entity and avoiding high risk surgical manipulations were the leading principles dictating the everyday practice. Contemporary physicians can still learn from the clinical observations in times of complete absence of laboratory or imaging aid, from the prognostic thoughts, the ethics, and the philosophical concepts, represented by the Hippocratic writings, tracing into them the roots of Rational Medicine in general and Urology in particular.

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease, affecting approximately one million adults worldwide. This paper describes a young female patient who presented to the acute medical team with generalised tonic-clonic seizures and right hemiplegia on a background of MS. Radiological imaging revealed a large ring enhancing lesion exerting mass effect. We describe an unusual form of MS and discuss diagnostic pitfalls of tumefactive demyelinating lesions which can be mistaken for brain tumours and abscesses.

Aim: The aim of Acute Physicians Unit (APU) in Scarborough Hospital is consultant led delivery of acute medical care. It operates weekdays from 9am to 5pm, staffed by a consultant physician, a trained nurse and an auxiliary nurse. We reviewed the APU activity over 38 months., Results: 7170 patients were referred to APU, mainly from GPs (59.6%) and A&E (26.5%). The most common type of referrals: cardiovascular 21%, neurological 16.9% and respiratory 15.1%. It prevented admission in 2217 cases (30.9%): 22.4% were sent home after assessment in APU and in 8.5% telephone advice was sufficient., Conclusion: The APU has led to early consultant review in 53% of admissions, discharge of 31% of patients and is a useful source of consultation for GPs.

To evaluate the diagnostic efficacy of transrectal ultrasound (TRUS)-guided biopsy of the prostatic fossa in men with biochemical relapse following radical retropubic prostatectomy (RP). Thirty patients, with detectable prostate specific antigen (PSA) and negative imaging for metastases after RP, were evaluated for local recurrence. All patients underwent TRUS-guided biopsies of the prostatic fossa, with at least six cores obtained. PSA and digital rectal examination (DRE) were correlated with biopsy results. Twelve patients (40%) were found with local recurrence. Sensitivities of TRUS and DRE were 75 and 50%, while specificities were 83 and 100%, respectively. Local recurrence was detected in 25% of the patients with PSA

The activation of the inducible isoform of nitric oxide synthase (NOS) is associated with the production of large quantities of nitric oxide in response to cytokine stimulation. Bacillus Calmette-Guerin (BCG) mode of action against bladder carcinoma remains unclear, although a plethora of local and systemic events may follow its intravesical instillation. The present study was designed to investigate the expression of inducible NOS in normal and neoplastic urothelium and its alteration following tumor resection and subsequent intravesical immunotherapy. Bladder carcinoma and autologous normal bladder tissue specimens were procured from 36 patients undergoing transurethral resection. Tissue specimens were obtained from the same patients at first cystoscopy following six weekly intravesical instillations. Inducible NOS protein expression was assessed by immunohistochemistry in all tissue specimens. Immunostaining of normal urothelium for iNOS before treatment was negative in all but four cases. BCG treatment induced iNOS expression in tumor-free bladder tissue in 24 cases (66.6%). There were only four early tumor recurrences; interestingly, they corresponded to the cases with tumor cells expressing iNOS before BCG treatment, while novel tumors were also iNOS immunoreactive. BCG upregulated iNOS expression in normal human urothelial cells in vivo suggesting a role for nitric oxide in BCG mediated antitumor activity. Inducible NOS was detected in certain tumor specimens before and after BCG treatment implying a possible involvement in pro-tumor action.

TGFbeta1 is one of several cytokines produced by proximal tubular and renal cancer cells. Previous studies have been mainly focused on determining plasma or serum TGFbeta levels, its effect on RCC cultures, and the expression of TGFbeta mRNA. Cancerous and autologous normal kidney samples were obtained from 24 patients treated by radical nephrectomy. TGFbeta1 expression was determined using a semi quantitative Western blot analysis and immunohistochemistry. Blot densities and immunohistochemical expression intensities in normal and neoplastic tissue were compared, and subsequently correlated to tumor stage, histological type and nuclear grade. All tissue samples examined expressed TGFbeta1; mean tumor to non-involved kidney spot density ratio correlated with advancing stage and higher nuclear grade. The overexpression of TGFbeta1 in certain RCCs may partially explain their resistance to the growth suppression action of TGFbeta. The correlation with tumor stage and grade indicates a possible role in the development of metastatic potential as well as in host's immune response modulation.

We describe here a rare case of association of imperforate anus with transverse colon atresia in a male neonate. Preoperative X-ray studies demonstrated: a) a distended loop in the epigastrium with fluid levels on plain A/P upright radiography, b) absence of pelvic intestinal gas on the invertogram 16 hours later. A three-stage operative approach was undertaken comprising resection of the atretic loop and colostomy, posterior sagittal anorectoplasty a few months later, and finally closure of the colostomy. The postoperative outcome was good. The association of these anomalies should be kept in mind in neonates with anal atresia and abdominal distention.

Purpose: We report the continence status and urodynamic findings in 59 patients who underwent radical cystectomy and orthotopic bladder reconstruction using a modified S-ileal neobladder technique between January 1993 and July 2002., Materials and Methods: Continence status was assessed using patient interview, frequency-volume charts and the need for protective devices. Reservoir sensation, compliance, capacity and activity were assessed by enterocystometry. Post-void residual urine volume greater than 100 ml was the indication for clean intermittent self-catheterization., Results: Daytime continence was reported by 95.5% and 100% of our patients at 1 and 5 years, respectively. Overall, 77.7% of patients reported nighttime continence at 1 year and 96.5% at 5 years. The need for a protective device decreased with time and most of the patients would have undergone the operation again. Enterocystometric capacity and maximum reservoir pressure remained remarkably stable at 391.6 versus 440 ml, and 30 versus 20 cm H2O, 6 months and 5 years after surgery, respectively. Nevertheless, median post-void residual urine volume increased from 35 ml at 6 months to 55 ml at 5 years with an increase in prevalence of patients requiring intermittent self-catheterization due to post-void residual urine greater than 100 ml from 1.8% at 6 months to 10% at 5 years., Conclusions: Orthotopic bladder substitution with the modified S-ileal neobladder technique has an excellent functional outcome over time, resulting in high daytime and nighttime continence levels as well as high acceptability rates from our patients.

The retroesophageal right subclavian artery is an anatomical abnormality encountered by anatomists and pathologists and recently interventional cardiologists and thoracic surgeons have also come across this phenomenon. We report a case of a retroesophageal right subclavian artery arising from a normally located left aortic arch in a young male autopsied in the Department of Forensic Service of Warsaw Medical University. In addition to the aforementioned anomaly, the presence of a right non-recurrent inferior laryngeal nerve was noticed. The possible embryonic development of these branching patterns and their clinical significance is discussed.

Objective: To determine the efficacy and safety of two different doses of intravesical mitoxantrone and of recombinant interferon-alpha (IFNalpha-2b), instilled after transurethral resection (TUR) of superficial transitional cell carcinoma (TCC) of the bladder., Material and Methods: 208 patients (mean age 62.05 years) with primary or recurrent superficial (TaG1, T1G1, T1G2) bladder cancer were randomly allocated into four groups, after TUR of all visible tumors. Group A (45 patients) received no further therapy; group B (56 patients) received 10 mg of mitoxantrone (6 weekly and 20 fortnightly instillations), group C (54 patients) 20 mg of mitoxantrone (3 fortnightly and 10 monthly instillations) and group D (53 patients) received 100 MU of IFNalpha-2b (8 weekly, 8 fortnightly and 6 monthly instillations)., Results: During the follow-up (mean 21.09 months), 29 (64.44%) patients in group A had recurrence, compared with 19 (33.92%) in group B, 17 (31.48%) in group C and 15 (28.3%) patients in group D (p < 0.005). Furthermore, the differences in simple recurrence rates were statistically more significant (p < 0.05), when group A was compared with the three other groups in the terms of T1G2, recurrent and multiple neoplasms. Twenty-nine patients (10, 7, 8, and 4 in groups A-D) experienced tumor progression, and the differences between the four groups were not statistically significant (p > 0.05). The mean recurrence time was 9.03 months in group A, 13.74 in group B, 14.24 in group C and 17.4 months in group D (p < 0.001), and the recurrence rate per 100 patient-months was 4.39, 1.57, 1.48 and 1.06, respectively (p < 0.05). Toxicity (grade 1-3) was recorded in 23.21% in group B, in 31.48% in group C and in 9.43% in group D (p < 0.01)., Conclusion: The two doses of mitoxantrone resulted in similar efficacy for the prevention of superficial bladder cancer recurrences, with the dose of 10 mg of mitoxantrone being related to fewer side effects. In comparison with mitoxantrone, the adjuvant intravesical immunotherapy with 100 MU of IFNalpha-2b showed a better combination of efficacy and safety., (Copyright 2004 S. Karger AG, Basel)

A case of rupture of the upper ureter following creation of a continent orthotopic neobladder, treated conservatively with percutaneous nephrostomy and drainage of a paranephric collection, is reported.

Over the past few decades, a great scientific effort has been made to treat gastroesophageal reflux disease (GERD). This reflects a trend in modem medicine toward optimizing quality of life, reducing health-related lost working hours, and minimizing costs of chronic treatments. It also reflects a revived interest in diseases that can be studied using novel equipment and that can be cured using minimally invasive techniques. In an effort to further minimize surgical trauma, novel endoscopic techniques are beginning to challenge the standard therapeutic approach to GERD.

Objectives: Symptomatic benign prostate hyperplasia (BPH), besides affecting patients' quality of life through lower urinary tract symptoms (LUTS), and related acute events, may affect their partners' quality of life as well. The present study was focused on exploring partner morbidity in cases of symptomatic BPH patients being evaluated for surgical treatment., Methods: The study group was comprised of 50 couples where male partners suffered from symptomatic BPH and was referred for further evaluation and, possibly, surgical treatment. Male subjects were asked to fill out the IPSS form, while the female partners were, separately, asked to fill out another structured questionnaire about 7 items (sleep disturbance, social disruption, performance of essential tasks, psychological impact, sex life, fear of cancer, fear of surgery). Data were analyzed in relation to the severity of symptoms (IPSS), patient's and partner's age, couple's age difference, marriage duration, mode and place of living., Results: Partners' morbidity due to their husband's condition was comprised of sleep disturbance (28%); disruption of social life (30%) positively related to IPSS and negatively to the symptom duration; inability to take care of essential tasks outside and inside their house (8%); psychological burden (66%) positively related to the wife's age, the couple's age difference and the marriage duration; inadequate sex life (48%); fear of prostate cancer (62%); and fear of surgery (82%)., Conclusions: Partners of patients with symptomatic BPH experience significant morbidity because of their husband's condition. The severity of patients' symptoms, however, is not always related to partners' morbidity. Partners should be adequately informed of the benign nature of the disease, as well as, the possible operating risks.

Sertoli cell only syndrome (SECOS) was identified on histology in 21 cases (16,28%) among 129 testicular biopsies performed in our department for azoospermia over the last 5 years. In these patients history, clinical features, hormonal levels, and histological findings were analyzed. In addition DNA flow-cytometric analysis was performed and showed an almost complete absence of haploid cells. All patients presented with elevated serum FSH levels suggesting a Sertoli cell damage or reduced production of inhibin due to the absence of sermatogenic cells. An good correlation was found between histological findings and DNA histograms. In conclusion SECOS is a syndrome of unknown aetiology presenting in men with azoospermia. DNA flow-cytometric analysis is a reliable, rapid and easy method in the diagnosis of SECOS, and can replace histological examination.

Background and Purpose: Distal ureteral calculi can be treated with extracorporeal shockwave lithotripsy (SWL) in situ, which has a high rate of success. As the prostate is in vicinity of this part of the ureter, it is possible that the shockwaves may pass through the prostate also. We evaluated the effect of SWL on the serum concentration of prostate specific antigen (PSA)., Patients and Methods: A total of 44 men with distal ureteral calculi located a maximum of 20 mm from the ureteral orifice and without any history of recent urinary tract infection, benign prostatic hyperplasia, or prostate cancer underwent SWL with the Dornier HM-4 lithotripter. Their serum PSA values were measured 5 minutes before SWL as well as 3 hours and 1, 7, and 30 days afterward. The differences of these PSA values were estimated. From a control group of 10 healthy donors, two consecutive PSA values were obtained 30 days apart., Results: Of these patients, 93% (41/44) were stone free within 1 month according to plain radiographs and ultrasonography. No statistically significant difference was observed between the PSA concentration before and after treatment or between the patients who underwent SWL and the control group., Conclusion: Treatment of distal ureteral calculi with SWL does not affect the serum PSA concentration.

Objectives: To describe the surgical technique we currently use for the construction of an orthotopic ileal neobladder. We report our experience and functional results of the first 35 cases., Methods: Since 1993, 35 men have been treated with an ileal neobladder substitute after cystoprostatectomy for bladder cancer. According to the technique we call "a modified S-ileal neobladder," we place emphasis, first, on the complete detubularization of a smaller segment of bowel and its folding in an S configuration without creating a nipple mechanism, and second, on an oblique intramural ureteral reimplantation., Results: The mean postoperative observation time was 38.2 months (range 6 to 72). No perioperative or early postoperative mortality was observed, and few serious early complications have occurred. Late complications included local tumor recurrence and distant metastases in 1 patient (2.8%) and a vesicoileal fistula requiring surgical correction in 1 patient (2.8%). As of February 2000, a total of 29 patients (82.8%) were emptying their neobladder by relaxation of the urethral sphincter mechanism and/or passive expression of the neobladder by abdominal straining. Six patients (17.1%) required clean intermittent catheterization. Daytime continence was attained in 31 patients (88.5%) and nocturnal incontinence was noted in 9 (26%)., Conclusions: Several techniques may be used to create an ileal neobladder. A neobladder constructed using a smaller part of ileum that has been completely detubularized and folded in an S configuration without a nipple is easy to perform, has acceptable complication rates, achieves adequate capacity at low pressure, and provides satisfactory continence rates.

The heart, as we know, is a muscular tissue supported by collagenous structures forming the fibrous skeleton of the heart. A structure by the name of the tendon of infundibulum appeared in the literature with no definite information about its structure or even its existence. The tendon of infundibulum was described as a strip of fibrous tissue structure situated between the aortic root and pulmonary trunk. Our study involved 30, formalin fixed, adult human hearts ranging from 18 to 81 years. Classical macroscopic anatomical methods were applied to observe macroscopically all the connections between the aorto-pulmonary trunk, together with serial transverse histological sections, through roots of the aorta and pulmonary trunk, using eosin-hematoxylin and van Gieson staining. All the hearts seemed to encompass many fascial bands attended by connective tissue. However these fascial bands are not concrete structures and cannot be termed tendons. In our investigation we have been unable to demonstrate macroscopically or histologically any structure which could be significantly approximating to the initial description of the literature. However, as far as we are able to judge, the term tendon of infundibulum has erroneously been introduced into many medical textbooks since the literature cannot still prove its existence.

Purpose: The implantation of expandable microballoons has proved successful for the treatment of stress urinary incontinence. This led us to test its effectiveness in the treatment of severe fecal incontinence., Methods: Six patients (four male), of average age of 43 (range, 29-60) years, with severe fecal incontinence, underwent implantation of expandable microballoons in the submucosa of the anal canal. The implantation was performed under intravenous sedation as an outpatient procedure. Anal manometry, endosonography, and incontinence assessment with a scoring system were performed before and after the implantation., Results: With a mean follow-up of 8.6 (range, 7-12) months, the incontinence scores improved in all patients from an average of 16.16 (standard deviation: +/- 1.6) before the implantation to an average of 5 (standard deviation: +/- 1.26) after the procedure. The anal pressure at rest was not improved in any patient (mean: 50.16 before treatment to a mean of 53 after treatment). No significant adverse events were associated with the procedure, and no serious postimplantation complications were noted., Discussion: Anal implantation of expandable microballoons seems to be a simple, safe, and effective method that restores the fecal continence without hindering normal defecation.

Purpose: We compared overall sensitivity and specificity of the urinary bladder cancer antigen enzyme-linked immunosorbent assay (UBC, IDL Biotech, Sollentuna, Sweden), BTA stat test (Bion Diagnostic Sciences, Inc., Redmond, Washington) and NMP22 test kit (Matritech, Newton, Massachusetts), and the differential sensitivity regarding the histological pattern of tumors., Materials and Methods: A total of 213 patients with clinical and/or imaging signs of bladder cancer provided a single voided urine sample for the bladder cancer antigen, BTA stat test and NMP22 before cystoscopy. Of these patients 95 were monitored for superficial bladder cancer, while the remaining 118 had no history of bladder cancer. All detected bladder tumors or suspicious lesions were resected transurethrally. A group of 21 age and sex matched healthy volunteers were also evaluated with the same tests., Results: Bladder cancer was confirmed histologically in 118 patients, of whom primary and recurrent tumors were in 68 and 50, respectively. The optimal cutoffs calculated with receiver operating characteristics curves were 8 units per ml. for NMP22 and 12 microg./l. for bladder cancer antigen. Overall sensitivity and specificity were 72.9% and 64.6% for the BTA stat test, 63.5% and 75.0% for NMP22, and 80.5% and 80.2%, respectively, for bladder cancer antigen. Bladder cancer antigen proved significantly more sensitive than NMP22 for detecting bladder cancer (p = 0.001) but not more than the BTA stat test, while the specificity of it was significantly higher than that of the BTA stat test (p = 0.009). Bladder cancer antigen had a sensitivity of 80.7% for stage Ta tumors, which was significantly higher than NMP22 (52.6%, p = 0.001) and the BTA stat test (57.9%, p = 0.01). In grade I tumors the sensitivity of bladder cancer antigen (70%) did not differ significantly than that of the BTA stat test (50%) and NMP22 (50%, p = 0.14). Bladder cancer antigen had the least false-positive results in patients with a history of bladder cancer and negative cystoscopy, and those with urological disease other than bladder cancer., Conclusions: Our data indicate that bladder cancer antigen may be a more potent diagnostic marker for bladder cancer than NMP22 and the BTA stat test based on the higher sensitivity for detecting low stage and low grade tumors, and the higher specificity. The contribution of these tests for detection of bladder cancer should still be considered adjunctive to cystoscopy.

Matrix metalloproteinases (MMPs) are proteolytic enzymes important at several points during multistep neoplastic progression. Although MMP-1 and MMP-3 have been implicated in the progression of various human cancers, their expression in bladder cancer has not been addressed. Immunohistochemistry (Strept-ABC-HRP method) and in situ hybridization were performed to detect MMP-1 protein, MMP-3 protein, and MMP-3 mRNA, respectively, in 59 transitional cell bladder carcinomas. To assess the role of these MMPs in bladder cancer, their expression was evaluated in relation to known clinicopathologic parameters and patients' disease-free and overall survival. Immunoreactivity for MMP-1 and MMP-3 proteins was observed in the cytoplasm of cancer cells in 30.5% and 24% of samples, respectively. Transcripts for MMP-3 mRNA were localized in stromal cells in 71.2% of cases and in cancer cells in 49% of cases. MMP-1 immunoreactivity demonstrated a statistically significant association with deeply invasive and grade III tumors versus superficial and lower grade tumors. MMP-3 protein immunoreactivity and MMP-3 mRNA immunolocalization did not associate with the parameters studied. However, MMP-3 mRNA localization in stromal cells demonstrated a borderline association with poor patients' disease-free and overall survival. In conclusion, the authors' results demonstrate a differential expression between MMP-1 and MMP-3 in bladder cancer; MMP-1 appears to participate in invasiveness and possibly in loss of differentiation in urothelial carcinomas in contrast to MMP-3.

Aims: The nuclear enzyme DNA topoisomerase II has been shown to be required for chromatin condensation and chromosomal segregation during mitosis; its isoform topo II alpha is linked with active cell proliferation in mammalian cells. The aim of this study was to examine the relation of the expression of topo II alpha to the biological behaviour of conventional urinary bladder cancer., Methods: Formalin fixed, paraffin wax embedded tissue from 94 specimens of bladder urothelial cancer were immuno-histochemically stained for topo II alpha. For each case, a topo II alpha index was determined. A similar index had been determined for Ki-67, a known cell proliferation marker. Each case had also been graded, staged, and evaluated for DNA ploidy as well as for p53 and bcl-2 immunoreactivity., Results: Raised topo II alpha expression (in > or = 10% of malignant nuclei) correlated with two adverse prognosticators--high grade (p = 0.027) and invasion of the muscularis propria (p = 0.013), but with no other evaluated parameter. By multivariate survival analysis using Cox's proportional hazard model, high expression of topo II alpha was found to be predictive for worse survival (p = 0.0047). Patients' age, tumour stage, and grade were also retained as independent prognostic factors (p = 0.0349, p = 0.00005, and p = 0.0130, respectively). The negative influence of increased topo II alpha immunopositivity on patients' survival was also seen in the subgroup of patients with non-muscle invasive carcinomas (p = 0.0004), in patients with a bcl-2 negative phenotype (p = 0.0330), and in those with low Ki-67 indices (p = 0.0341)., Conclusions: Because topo II alpha and Ki-67 failed to demonstrate a significant interrelation, they appear to be different molecules that both function at separate phases in the complex process of cellular proliferation. The assessment of increased topo II alpha immunoreactivity in specimens from urothelial carcinomas might help to select patients (particularly among those with superficial tumours) in the worse prognostic categories for new therapeutic strategies.

Background: A gelatinous implant containing polymethylmethacrylate (PMMA) beads is successfully used to augment the diminished thickness of the chorium in patients with skin defects and wrinkles. The aim of the present study was to determine whether submucosal injection of PMMA microspheres into the lower esophageal folds decreases the severity of symptoms and acid reflux in patients with GERD., Methods: Endoscopic submucosal implantation of PMMA was carried out in 10 patients with GERD who were either refractory to or dependent on proton pump inhibitors. Symptom severity score, 24-hour pH monitoring, upper GI endoscopy, and EUS were performed to evaluate the efficacy of implantation., Results: A significant decrease in the symptom severity score and mean total time with esophageal pH less than 4 was noted after the implantation of PMMA (p < 0.05). Seven of 10 patients were taking no medication after PMMA implantation. There were no serious procedure-related complications., Conclusions: Endoscopic implantation of PMMA into the submucosa of the lower esophageal folds may be a new method for treating GERD. Further studies are required to determine the long-term efficacy of the procedure.

Although Bacillus Calmette-Guerin (BCG) intravesical instillation is widely accepted as a very effective modality in treating bladder carcinoma in situ, and in preventing superficial bladder cancer recurrence, its mechanism of action is not yet fully understood. The antitumor effects of BCG are mostly related to local immunological events but a systemic activation of the immune system cannot be excluded. The objective of the present study was to estimate the systemic production of oxidants during intravesical BCG treatment. Systemic production of oxidants was estimated by assessing the red blood cells (RBC) oxidative stress in twelve patients undergoing BCG immunotherapy for bladder carcinoma in situ. RBC oxidative stress induced by peroxynitrite was determined by luminol-enhanced chemiluminescence. During the treatment period, the RBC oxidative stress revealed a biphasic curve of changes: after an initial 5-fold increase, it dropped to pretreatment levels following the 4th instillation. Intravesical BCG administration induced systemic production of oxygen free radicals that may reflect a systemic activation of the immune system.