bluuebunny/crossref_metadata_2025 huggingface dataset:
Impaired telomerase activity in human cells expressing GFP-Ku86 fusion proteins
Authors: Badie C. , Yáñez-Muñoz R.J. , Muller C. , Salles B. , Porter A.C.G.
Published: January 2009

The Ku heterodimer is a DNA end-binding protein that promotes the non-homologous end joining (NHEJ) pathway of DNA double strand break (DSB) repair by recruiting the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). Ku is also a normal component of telomeres where it is required for telomere maintenance, interacting not only with the DNA but also with various telomere proteins including telomerase. The way in which Ku simultaneously plays such distinct roles, end-joining at DSBs and end-maintenance at telomeres, is unclear. One way to address this is to study cells in which the NHEJ and telomeric roles of Ku have been separated. Here we describe human cells that express fusions between the large human Ku subunit (Ku86) and a fluorescent protein tag. These cells have reduced telomerase activity and increased sensitivity to ionizing radiation (IR) but no change in their DNA-PK activity or in the DNA end-binding of endogenous Ku. Cells with particularly large amounts of one fusion protein undergo progressive telomere shortening and cellular senescence. These data are consistent with models in which Ku recruits telomerase to telomeres or activates recruited telomerase and suggest that the Ku86 fusion proteins specifically block this role.
Regulation of telomere length in Drosophila
Authors: Capkova Frydrychova R. , Biessmann H. , Mason J.M.
Published: January 2009

Telomeres in all organisms must perform the same vital functions to ensure cell viability: to act as a protective chromosome cap that distinguishes natural chromosome ends from DNA double strand breaks, and to balance the loss of DNA from the chromosome end due to incomplete DNA replication. Most eukaryotes rely on a specialized reverse transcriptase, telomerase, to generate short repeats at the chromosome end to maintain chromosome length. Drosophila, however, uses retrotransposons that target telomeres. Transposition of these elements may be controlled by small RNAs and spreading of silent chromatin from the telomere associated sequence, both of which limit the retrotransposon expression level. Proteins binding to the retrotransposon array, such as HP1 and PROD, may also modulate transcription. It is not clear however, that simply increasing transcript levels of the telomeric retrotransposons is sufficient to increase transposition. The chromosome cap may control the ability of the telomere-specific elements to attach to chromosome ends. As in other organisms, chromosomes can be elongated by gene conversion. Although the mechanism is not known, HP1, a component of the cap, and the Ku proteins are key components in this pathway.
Telomere capping and cellular checkpoints: clues from fruit flies
Authors: Ciapponi L. , Cenci G.
Published: January 2009

In most organisms, telomeres consist of repetitive G-rich sequences that are elongated by a specific reverse transcriptase, telomerase. A large number of proteins are recruited by these terminal repeats, forming specialized structures that regulate telomerase activity and protect telomeres from degradation and recombination. Drosophila lacks telomerase and telomere length is maintained by transposition of three specialized retrotransposons. In addition, unlike yeast and mammals, Drosophila telomeres are epigenetically determined, sequence-independent structures. However, several proteins required for Drosophila telomere behavior are evolutionarily conserved. These include the Mre11-Rad50-Nbs (MRN) complex and the Ataxia Telangiectasia Mutated (ATM) kinase, which are required to prevent telomeric fusions. In addition, recent studies have provided evidence that Drosophila uncapped telomeres elicit a DNA damage response (DDR) just as dysfunctional yeast and human telomeres. Uncapped Drosophila telomeres also activate the spindle assembly checkpoint (SAC) by recruiting the SAC kinase BubR1. Telomere-induced DDR and SAC both require the wild type function of the MRN complex. In addition, while DDR is mediated by ATR kinase, SAC activation requires both the ATM and ATR activities. These results indicate that the DNA repair systems play multiple roles at Drosophila telomeres, highlighting the importance of this model organism for investigations on the relationships between DNA repair and telomere maintenance.
Cytogenetics for the study of telomere function in plants
Authors: Siroky J.
Published: January 2009

The ends of linear chromosomes of the vast majority of eukaryotic species possess specialized nucleo-protein structures called telomeres. Regardless of many exceptions, the structure and function of telomeres share high degrees of similarity between various eukaryotes. The underlying DNA structure of telomeres determines the particular setup of telomere chromatin and protein complexes as are telomere-associated proteins and a number of repair and cell cycle checkpoint agents. The structure of telomeres is highly dynamic during the cell’s growth, replication, differentiation, senescence, or neoplastic transformation. Although the bulk of our knowledge about telomere function comes from molecular and biochemical studies in model organisms such as yeast and mouse, we want to show – with special emphasis on plants – in this short review that classical methods of plant cytogenetics can significantly complement the above experimental approaches and help in our understanding of telomere functions.
Two faces of Solanaceae telomeres: a comparison between Nicotiana and Cestrum telomeres and telomere-binding proteins
Authors: Peška V. , Sýkorová E. , Fajkus J.
Published: January 2009

While most Solanaceae genera (e.g.Solanum, Nicotiana) possess Arabidopsis-type telomeres of (TTTAGGG)n maintained by telomerase, the genera Cestrum, Vestia and Sessea (Cestrum group) lack these telomeres. Here we show that in the Cestrum-group the activity of telomerase has been lost. Nevertheless, proteins binding the single-stranded G-rich strand of the Arabidopsis-type and related human-type (TTAGGG)n telomeric sequences are present in nuclear extracts of both Nicotiana and Cestrum species. These proteins may have a role in telomere function or other cellular activities. In addition to characterizing DNA binding specificity and molecular weights of these proteins, we searched in both N. tabacum (tobacco) and C. parqui for the presence of POT1-like proteins, involved in telomere capping and telomerase regulation. Analysis of POT1-like proteins available on public databases and cloned by us from C. parqui, revealed the N-terminal OB folds typical for this protein family and a novel, plant-specific conserved C-terminal OB-fold domain (CTOB). We propose that CTOB is involved in protein-protein interactions.
Genome stability in Arabidopsis cells exhibiting alternative lengthening of telomeres
Authors: Akimcheva S. , Zellinger B. , Riha K.
Published: January 2009

Indefinite proliferation of eukaryotic cells depends on telomerase that counteracts the depletion of DNA from chromosome termini due to the end replication problem. The requirement for telomerase can, under certain conditions, be circumvented by employing homologous recombination-based mechanisms for telomere maintenance. Whereas yeast and mammalian cells lacking telomerase appear to readily adopt alternative telomere lengthening (ALT), in Arabidopsis ALT is inhibited by the Ku heterodimer. Although we failed to establish ALT cell lines from Ku-proficient lines, ALT can be efficiently induced in cells derived from mutants deficient for telomerase reverse transcriptase (TERT) and Ku70. In this study, we describe the growth performance, genome stability and long-term maintenance of telomeric DNA in Arabidopsis ku70 tert ALTcultures. ALT activation increases karyotype stability in the majority of tert ku70 cell lines, which contrasts with ongoing chromosomal rearrangements detected in survival tert cultures that lack any detectable telomeric sequences. Curiously, ku70 tert ALT lines and tert survivor cultures proliferate at a similar rate, although the latter display remarkable chromosomal abnormalities, including giant circular and linear megachromosomes that seem to arise by fusions of multiple chromosomes. This observation underlies the extraordinary tolerance of plant cells to telomere dysfunction.
Overview of the Postulated Mechanisms Linking Cancer and Thrombosis
Authors: ten Cate Hugo , Falanga Anna
Published: January 2009

Blood coagulation appears to play an important role in the occurrence of cancer and its effects may be twofold. First, in patients with cancer, blood coagulation is activated in the direction of a prothrombotic state. Second, a procoagulant environment may promote cancer in different ways. In this chapter we discuss some of the mechanisms that may be involved in this interplay between coagulation and cancer. Blood coagulation proteins interact with cells in the vasculature to maintain hemostasis. However, many proteins that are involved in coagulation and anticoagulation, as well as fibrinolysis, are also found in extravascular tissues. In different organs, these proteins may be involved in cell-signaling mechanisms, through interaction with cell receptors like protease-activated receptors (PARs). Such interactions may drive inflammation, angiogenesis and cell proliferation. The potential procarcinogenic actions of proteases like thrombin may be counteracted by the anticoagulant and anti-inflammatory actions of the protein C-thrombomodulin mechanism. In the blood of cancer patients, the balance is usually shifted towards a procoagulant direction. The resulting excess thrombin- and fibrin-forming activity promotes venous thrombosis and may in the extravascular compartment stimulate cancer progression. The activation of platelets and their interaction with leukocytes may propagate this process. In addition to the therapeutic modulation of the prothrombotic environment, the induction of specific anticoagulant proteins including thrombomodulin may have effects on tumor growth or dissemination, but the nature of these effects still remains hard to predict. The interplay between cancer and blood coagulation merits further experimental and clinical research.
Thrombophilia and Cancer
Authors: Horowitz Netanel , Brenner Benjamin
Published: January 2009

Inherited and acquired thrombophilia are well-known risk factors for venous thromboembolism. The incidence of thrombotic events in cancer patients is increased compared to normal population. Data on inherited thrombophilia and cancer is limited. Most studies are small, and results are varied by geography, tumor type, stage of disease and therapy. Nevertheless, it seems that factor V Leiden and prothrombin mutation may increase VTE risk in cancer patients. Data also exist for hyperhomocysteinemia. Cancer patients with thrombophilia who have a central vein catheter are a special group with increased venous thrombotic event (VTE) risk. Among acquired risk factors, antiphospholipid antibodies are common in cancer patients, especially in lymphoproliferative diseases. Published data suggests that the risk of thrombotic events, venous and arterial, is increased in cancer patients with antiphospholipid antibodies. The questions of screening cancer patients for inherited thrombophilia or antiphospholipid antibodies are unclear. There is no data on primary VTE prophylaxis in cancer patients with thrombophilia and prophylaxis for cancer patients with central vein catheters is controversial.
Protease-Activated Receptors, Apoptosis and Tumor Growth
Authors: Borensztajn Keren S. , Spek C. Arnold
Published: January 2009

Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. Besides the important role of blood coagulation factors in preventing bleeding after vascular injury, these serine proteinases actively engage target cells thereby fulfilling critical functions in cell biology. Cellular responses triggered by coagulation factor-induced PAR activation suggest that PARs play an important role in proliferation, survival and/or malignant transformation of tumor cells. Indeed, PAR expression correlates with cancer malignancy and clinical studies show that anticoagulant treatment is beneficial in cancer patients. In this review, we provide an overview on the PAR family, their mode of activation and mechanisms by which PAR signaling is terminated. In addition, we discuss the relationship between blood coagulation and cancer biology focusing on the potential role of PAR-induced modulation of cell survival, apoptosis and tumor growth.
Leukocytosis, JAK2V617F Mutation, and Hemostasis in Myeloproliferative Disorders
Authors: Marchetti Marina , Falanga Anna
Published: January 2009

Thrombosis is a leading cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Several mechanisms have been proposed to cause or to contribute to the acquired thrombophilic state of these patients, including platelet and red blood cell abnormalities. The increase in white blood cell count, found in most subjects with these disorders, raises the possibility that circulating leukocytes may represent another prothrombotic factor, as demonstrated for other conditions, including sickle cell, coronary heart, and peripheral arterial diseases. Published data demonstrate that neutrophil activation occurs in ET and PV patients in parallel with the appearance of laboratory signs of hemostatic system activation, suggesting an involvement of these cells in the pathogenesis of the thrombotic predisposition of these subjects. In 2005, an acquired point mutation in the pseudokinase domain of Janus kinase 2 (JAK2V617F) has been described in these disorders, and has attracted an enormous interest both as a diagnostic and prognostic tool, and as a potential therapeutic target. Retrospective data have identified JAK2V617F as a risk factor for thrombosis in ET, and have also shown a close association with abdominal vein thrombosis. JAK2V617F is variably associated with thrombosis and, more consistently, with elevations in blood cell counts. A clear link appears to exist between leukocytosis, JAK2V617F, and the hemostatic system activation in patients with Bcl-negative myeloproliferative disorders.
Modern Endoscopic Therapy of Peptic Ulcer Bleeding
Authors: Peter Shajan , Wilcox C. Mel
Published: January 2009

Acute upper gastrointestinal bleed (UGIB) remains a challenging clinical problem owing to significant patient morbidity and costs involved with management. Peptic ulcer bleeding (PUB) contributes to the majority of causes of UGIB with a growing concern of its impact on the elderly and the increasing use of non-steroidal anti-inflammatory drugs as precipitating bleeding episodes. Apart from initial critical care, endoscopy is the preferred first-line management of PUB. Early use of empirical high-dose proton pump inhibitor therapy prior, during and after endoscopy is cost-effective and reduces the need for endotherapy. Current endoscopic modalities, both thermal and non-thermal, offer a wide range of choices in high-risk PUB (active arterial bleeding or non-bleeding visible vessel). Combinations of injection (epinephrine) along with thermal therapy or endoclips are recommended for better clinical outcomes. The role of endotherapy for adherent clots is controversial. A second-look endoscopy may be beneficial in high-risk patients. A multidisciplinary team approach should be part of all treatment protocols for the ideal management of UGIB.
Efficacy, Complications and Clinical Outcomes of Endoscopic Sclerotherapy with N-Butyl-2-Cyanoacrylate for Bleeding Gastric Varices
Authors: Fry Lucía C. , Neumann Helmut , Olano Carolina , Malfertheiner Peter , Mönkemüller Klaus
Published: January 2009

Background: Bleeding gastric varices (BGV) are a severe complication of portal hypertension. Although the obliteration of gastric varices using cyanoacrylate has been shown effective to eradicate gastric varices, there are still few data available on its effectiveness for acutely BGV, cyanoacrylate-related complications and follow-up. Aims: To report on the feasibility, efficacy and outcomes of N-buytl-2-cyanoacrylate sclerotherapy in patients with BGV. Methods: This is a retrospective cohort study of consecutive patients who were evaluated for BGV at University of Magdeburg Medical Center. Data abstracted for analysis from the prospectively collected database included patient’s demographics, etiology of gastric varices, Child-Pugh score, effectiveness of endoscopic treatment, clinical and endoscopic follow-up. Immediate hemostasis was defined as visible and clinical arrest of bleeding. The following were considered as potential complications of the procedure: aspiration, fever, worsening hemorrhage due to the sclerotherapy and systemic embolization of cyanoacrylate. Results: 33 patients (17 F, 16 M; mean age 54 years, range 18–81) with BGV (29 had active bleeding and 4 had stigmata of recent bleeding) underwent endoscopic injections of N-butyl-2-cyanoacrylate for hemostasis over a 5-year period. Mean follow-up: 9 months (range: 1 month to 5 years). Initial hemostasis was achieved in 88%. Treatment-related complications occurred in 5 (15.1%), the most common being deep ulcerations, which also resulted in recurrent bleeding. One patient presented with distal cyanoacrylate embolization. During long-term follow-up, 6 patients died, 5 as a consequence of the underlying liver disease and 1 as a consequence of complications due to systemic cyanoacrylate embolization. Conclusions: N-butyl-2-cyanoacrylate sclerotherapy is highly effective for the treatment of BGV, with rare complications occurring both acutely and in the long term.
Small Bowel Endoscopy Using the Double-Balloon Technique: Four-Year Results in a Tertiary Referral Hospital in Brazil
Authors: Kuga Rogerio , Safatle-Ribeiro Adriana Vaz , Ishida Robson Kiyoshi , Retes Felipe , Uemura Ricardo Sato , Sakai Paulo
Published: January 2009

Background: Double-balloon enteroscopy (DBE) allows evaluation and therapy for various small bowel diseases. In this series the outcome of a 4-year experience in a tertiary hospital school in Brazil is reported. Methods: A total of 457 consecutive DBE were performed in 418 patients from August 2004 to August 2008. 93 patients with several indications, whose aim was not the evaluation of suspected diseases of the small bowel mucosa, were excluded, therefore leaving 364 DBE in 325 patients for analysis. Data were retrospectively collected with regard to clinical, endoscopic findings, therapy and complications. Results: Among the 364 DBE performed in 325 patients, 143/325 were males (44%) and 182/325 females (56%) with a mean age of 48.6 ± 15.7 years (range 17–89). Mean investigation time was 64 ± 22 min (range 35–135). The depth of insertion beyond the ligament of Treitz was 230 ± 85 cm (range 30–500) by the antegrade approach and 140 ± 75 cm (range 0–320) by the retrograde approach. Total enteroscopy was achieved in 41.66% of the attempts (30 of 72 patients). Overall diagnostic yield was 54.95% (200 of 364 procedures) ranging from 0 to 100% in this series, depending on the indication. Angiodysplasia was the main diagnosis in 24.5% (49 of 200 procedures) and endoscopic treatment, including biopsies, hemostasis, tattooing and polypectomy were performed in 65.38% (238 of 364 procedures). No major complications were reported. Conclusions: DBE is a feasible, safe and well-tolerated procedure allowing endoscopic therapy. Selection of indications increases its diagnostic yield.
ERCP Using Double-Balloon Enteroscopy in Patients with Roux-en-Y Anatomy
Authors: Kuga Rogério , Furuya Jr. Carlos Kiyoshi , Hondo Fábio Yuji , Ide Edson , Ishioka Shinichi , Sakai Paulo
Published: January 2009

Double-balloon enteroscopy (DBE) is a useful method for endoscopic retrograde cholangiopancreatography (ERCP) in patients with Roux-en-Y anatomy. Depending on the distorted anatomy, endoscopic therapies with conventional scopes were very difficult or impossible before the advent of DBE and patients had to be submitted to a percutaneous or surgical approach. The case of 6 patients with different types of Roux-en-Y-altered anatomy in which DBE-ERCP was performed with 83.3% successful rate (5/6) is reported confirming recent data in the literature on the feasibility of this method.
Colonic Stents for the Palliation of Malignant Colonic Obstruction
Authors: Štimac Davor
Published: January 2009

Colorectal self-expanding metal stents have revolutionized the palliative treatment of patients with advanced malignancies and those patients who present with acute colon obstruction and who were previously treated with emergent surgical decompression via formation of colostomy. The placement of stents can be fluoroscopically or non-fluoroscopically guided. The use of stents is associated with significant reduction in hospital duration, mortality and medical complications compared to surgery. The most frequent complications are stent malposition and migration, bleeding, colonic perforation and tumor ingrowth and/or overgrowth.
Polypectomy Techniques for Difficult Colon Polyps
Authors: Mönkemüller Klaus , Neumann Helmut , Fry Lucia C. , Ivekovic Hrvoje , Malfertheiner Peter
Published: January 2009

A difficult polyp is any flat or raised colonic mucosal lesion that given its size, shape or location makes it difficult for the colonoscopist to remove. Although many ‘difficult polyps’ will be an easy target for the advanced endoscopist, polyps that are >15 mm, have a large pedicle, are flat and extended, are difficult to see or are located in the cecum or any angulated portion of the colon should be always considered difficult. Post-polypectomy complications are more common in the presence of difficult polyps. This review describes several useful tips and tricks to deal with such polyps.
Prospective Assessment of Diagnostic Utility and Complications of Endoscopic Ultrasound-Guided Fine Needle Aspiration
Authors: Eloubeidi Mohamad A. , Tamhane Ashutosh
Published: January 2009

Background: It is currently unknown whether a newly developed endoscopic ultrasound (EUS) program can produce results similar to those of experienced EUS centers. We therefore prospectively evaluated the diagnostic accuracy and major complications of EUS-guided fine needle aspiration (EUS-FNA) in a newly developed EUS program. Methods: All procedures were performed by a single endosonographer in the presence of a cytopathologist. Reference standard for classification of final disease included: surgical resection, death from disease progression and repeat radiologic and/or clinical follow-up. Major complications were defined as oversedation, and those that resulted in a physician or emergency department visits, hospitalization, or death. Results: 540 patients (median age 63 years, 77% white) underwent EUS-FNAs of 656 lesions: lymph nodes (LNs, n = 248), solid pancreatic masses (SPMs, n = 229), cystic pancreatic masses (CPM, n = 57), mural lesions (n = 41), bile duct/gallbladder (n = 28), liver (n = 17), mediastinum/lung (n = 17), adrenal (n = 15), spleen (n = 3) and kidney (n = 1). SPMs and bile duct/gallbladder lesions were more likely to have suspicious/atypical cytology when compared to other lesions (8.7 vs. 4.6%; p = 0.04) and required more passes to achieve a tissue diagnosis (p < 0.001). The overall sensitivity, specificity, PPV, NPV and accuracy of EUS-FNA was 91.7, 97.1, 98.1, 87.7 and 93.8%, respectively. Six patients (1.1%) (95% CI 0.4–2.4) experienced a major complication. One patient died shortly after the procedure due to preexisting pulmonary embolus (0.18%). Conclusion: EUS-FNA is highly accurate and safe in sampling a variety of peri-intestinal organs and lymph nodes. With adequate third-tier training, a newly developed program can produce results similar to those from expert EUS centers.
Single-Step EUS-Guided Endoscopic Treatment for Sterile Pancreatic Collections: A Single-Center Experience
Authors: Ardengh José C. , Coelho Djalma E. , Coelho José F. , Pereira de Lima Luiz F. , dos Santos José S. , Pimenta Módena José L.
Published: January 2009

Background and Aims: Endoscopic ultrasound (EUS) is useful for the treatment of sterile pancreatic fluid collections (PFC), either by means of transmural drainage or by complete aspiration. The aim of this study was to evaluate the efficacy and safety of single-step EUS-guided endoscopic approaches for treatment of sterile PFC. Patients and Methods: During a 3-year period, 77 consecutive patients with symptomatic, persistent sterile PFC were evaluated and treated with the linear EUS. We excluded patients with grossly purulent collections, chronic pseudocyst and those whose cytology diagnostic was neoplastic cyst of pancreas. 44 patients received a single 10-Fr plastic straight stent under EUS or fluoroscopic control (group I) and 33 of these underwent a single-step complete aspiration with a 19-gauge needle (group II). Results: The mean size of the sterile PFC was 48 mm in group I and 28 mm in group II (p < 0.001). Overall, endoscopic treatment was successful in 70 (90.9%) patients. The mean volume aspirated was 25 (18–65) ml. The total number of procedures was 50 in group I and 41 punctures in group II. After a mean follow-up of 64 ± 15.6 weeks there were 6 complications (13.6%): 2 recurrences (referred to surgery), 2 developing abscesses (submitted a new EUS-guided endoscopic drainage with success), 1 perforation that died (2.2%), and 1 case of bleeding (sent to surgery) in group I. In group II there were only 6 (18.1%) recurrences (submitted a new EUS-guided aspiration). None of the patients undergoing single-step aspiration developed infections, perforation or hemorrhage. Conclusion: The recurrence of pancreatic pseudocysts after endoscopic treatment was similar, either by means of plastic stents or by complete single-step aspiration.
Secondary Lymphangiectasia of the Small Bowel: Utility of Double Balloon Enteroscopy for Diagnosis and Management
Authors: Safatle-Ribeiro Adriana Vaz , Iriya Kiyoshi , Sampaio Couto Décio , Kawaguti Fábio Shiguehiss , Retes Felipe , Ribeiro Jr. Ulysses , Sakai Paulo
Published: January 2009

Sporadic lymphangiectasias are commonly found throughout the small bowel and are considered to be normal. Not uncommonly, lymphangiectasias are pathologic and can lead to mid-gastrointestinal bleeding, abdominal pain and protein-losing enteropathy. Pathologic lymphangiectasias of the small bowel include primary lymphangiectasia, secondary lymphangiectasia and lymphaticovenous malformations. In this report we present three different cases of small bowel lymphangiectasia detected by double balloon enteroscopy. The patients were diagnosed with South American blastomycosis, tuberculosis and primary small bowel lymphangioma.
Diagnostic and Therapeutic Applications of Endoscopic Ultrasound-Guided Punctures
Authors: Al-Haddad Mohammad , Eloubeidi Mohamad A.
Published: January 2009

Endoscopic ultrasound (EUS) has emerged as an excellent tool for the imaging of the gastrointestinal wall and surrounding structures. EUS-guided fine needle aspiration has broadened the applicability of this tool by allowing tissue sampling of a variety of lesions within or accessible from the gastrointestinal (GI) tract. In particular, EUS became the test of choice for evaluating pancreatic cysts and mass lesions, biliary strictures and masses, abnormal adenopathy accessible from the GI tract, and GI submucosal lesions. There appears to be an increasing role for EUS in the staging of lung cancer, evaluating adrenal lesions and GI mesenchymal tumors. More recently, EUS has acquired a new dimension in interventional applications. This includes, but is not limited to, celiac plexus block and celiac neurolysis for the management of pain associated with chronic pancreatitis and locally advanced pancreaticobiliary malignancies, respectively.
Intrauterine Programmierung von Störungen der Hirnfunktion im späteren Leben
Authors: Schwab Matthias
Published: January 2009

Die Entwicklung der Hirnfunktion wird pränatal durch epigenetische Faktoren, die insbesondere mit einer fetalen Mangelversorgung oder erhöhten fetalen Stresshormonkonzentrationen einhergehen, beeinflusst. Schon eine moderate Mangelernährung hat Effekte auf die Hirnentwicklung u.a. über eine Hemmung des Systems des insulinähnlichen Wachstumsfaktors. Daneben führt sie zu einer Erhöhung von mütterlichen Kortisolkonzentrationen im fetalen Kreislauf. Erhöhte fetale Kortisolkonzentrationen, sei es aufgrund fetaler Mangelversorgung, Stress oder pränataler Gabe von Glukokortikoiden, führen ebenfalls zu Störungen der Hirnentwicklung. Darüber hinaus induzieren sie in den letzten Wochen der Schwangerschaft, wenn die kindliche Hypophysen-Hypothalamus-Nebennieren-(HHN)-Achse reift, eine dauerhafte Desensitivierung von Glukokortikoidrezeptoren im Hippokampus. Diese bewirkt eine verminderte negative Rückkopplung der HHN-Achse mit der Folge einer verstärkten Kortisolausschüttung und einer erhöhten Stressempfindlichkeit im späteren Leben. Die Störungen der Hirnentwicklung und die dauerhaft erhöhten Kortisolspiegel induzieren subtile kognitive Störungen, Verhaltensauffälligkeiten und eine Prädisposition für depressive und schizophrene Erkrankungen.
Negative Prognostic Impact of the Coexpression of Epidermal Growth Factor Receptor and c-erbB-2 in Locally Advanced Cervical Cancer
Authors: Pérez-Regadera José , Sánchez-Muñoz Alfonso , De-la-Cruz Javier , Ballestín Claudio , Lora David , García-Martín Rosa , Mendiola Cesar , Alonso Lorenzo , Alba Emilio , Lanzós Eduardo
Published: January 2009

Objective: The objective was to determine the impact of the coexpression of epidermal growth factor receptor (EGFR) and tumor marker c-erbB-2 on disease-free survival (DFS) and pelvic relapse-free survival (PRFS) in patients with locally advanced cervical cancer (LACC) receiving concurrent chemoradiotherapy. Methods: The expression of EGFR and c-erbB-2 was assessed by immunohistochemistry, which was centralized and blinded to outcome. Univariate and multivariate analyses were used to evaluate the impact of EGFR and c-erbB-2 on DFS and PRFS. Results: 170 patients with LACC were included and received concurrent chemoradiotherapy. 25 (15%) biopsies were considered EGFR and c-erbB-2 positive; 100 (59%) were either EGFR or c-erbB-2 positive, and 45 (26%) were EGFR and c-erbB-2 negative. The 3- and 5-year DFS was 39% each for EGFR- and c-erbB-2-positive patients, 54 and 49%, respectively, for EGFR- or c-erbB-2-positive patients, and 76 and 72%, respectively, for EGFR- and c-erbB-2-negative patients (p = 0.006). EGFR- and c-erbB-2-positive tumors were significantly associated with a decrease in PRFS (hazard ratio, HR, 3.99; 95% confidence interval, CI, 1.44–11.05, p = 0.007), and DFS (HR 2.9; 95% CI, 1.26–6.66, p = 0.01). Conclusion: Patients with LACC coexpressing EGFR and c-erbB-2, and treated with concurrent chemoradiotherapy, had a worse clinical prognosis with shorter DFS and PRFS.
Molecular Evolution of HA1 in Influenza A (H3N2) Viruses Isolated in Japan from 1989 to 2006
Authors: Saitoh Mika , Kimura Hirokazu , Kozawa Kunihisa , Shoji Akira
Published: January 2009

Objectives: To evaluate the trend of phylogenetic evolution among influenza A (H3N2) viruses isolated in Gunma and A (H3N2) vaccine strains, we studied the transition of gene mutations and amino acid substitution of the sites A and B in HA1 during long-term seasons. Methods: A total of 15 A (H3N2) strains were obtained from patients in Gunma, Japan, during the 1989–2006 seasons. A partial HA1 gene was amplified by reverse transcription-polymerase chain reaction (RT-PCR). The phylogenetic tree and amino acid sequences were determined with nucleotide sequences. Results: We found that the nucleotide sequences of the isolates in the 1989–1990 and 1997–1998 seasons were similar to those of the A/Beijing/352/89 and the A/Sydney/5/97 strains, respectively, indicating a lag between the circulated virus and the vaccine strains. Phylogenetic analysis made possible to classify into two clusters in genetic evolutions among these strains, which showed large antigenic conversion. Moreover, we confirmed that basic amino acids tended to substitute uncharged polar amino acids, like K135T (lysine-to-threonine substitution at position 135), K145N, H155T, K156Q, R189S and R197Q, as confirmed by multiple alignment of amino acid sequences. Conclusions: We showed a new understanding of genetic evolution and amino acid substitutions of HA1 to recur pandemic.
PAX6 Immunoreactivity in the Diencephalon and Midbrain of Alligator during Early Development
Authors: Pritz M.B. , Ruan Y.-W.
Published: January 2009

PAX6 expression was examined during early development of the diencephalon and midbrain of Alligator using an immunocytochemical methodology. These observations focused on the basal plate to determine whether diencephalic prosomere organization in this region followed a pattern previously identified for alar plate areas. PAX6 expression was also described in alar diencephalic regions and the adjacent midbrain. PAX6 (+) cells in the basal plate were first seen in prosomere 1 at stage 7, in the midbrain at stage 10, and lastly in prosomeres 2 and 3 at stage 11. By stage 12, a nearly continuous column of PAX6 (+) cells extended from the midbrain basal plate through the entire diencephalon. In the diencephalon, PAX6 (+) cells in the basal plate were of greatest number in prosomere 1, least in prosomere 2, and intermediate in prosomere 3. This pattern of PAX6 expression distinguished these individual basal plate prosomeres. These results indicate that basal plate prosomeres follow a pattern similar to alar plate prosomereric organization during the later stages of early diencephalon development. Over a comparable time period of early diencephalon development, similar observations have been made in chick basal plate. In Alligator and chick, PAX6 expression in the basal plate is similar in the midbrain and prosomere 1 but different in prosomeres 2 and 3: present in Alligator and absent in chick. In alar plate areas of the Alligator diencephalon, PAX6 expression follows a similar pattern to that described for chick and mouse. These similarities in PAX6 expression in alar diencephalic prosomeres suggest that this is a common feature of amniotes. Differential PAX6 expression in alar prosomere 1 and the midbrain in Alligator is similar to that described for a wide range of species which suggests that these features are common to all vertebrates.
Staged Gamma Knife Radiosurgery after Tailored Surgical Resection
Authors: Miller Jonathan P. , Semaan Maroun , Einstein Douglas , Megerian Cliff A. , Maciunas Robert J.
Published: January 2009

Object: Although benign and slow growing, glomus jugulare tumors can be locally aggressive because of their proximity to lower cranial nerves and major vascular structures. Surgical resection frequently leads to complications, and radiosurgery alone often does not relieve symptoms. We report a novel treatment paradigm of tailored surgical resection followed by staged radiosurgery that allows for tissue diagnosis and immediate improvement of symptoms and tumor control without the morbidity of radical surgical resection. Methods: Five patients with glomus jugulare tumors and contraindications to extensive surgery each underwent an outpatient otologic procedure to resect the portion of the tumor in the middle ear and mastoid with no attempt to remove tumor in the jugular bulb. Each patient returned 2–5 months later for Gamma Knife radiosurgery to the remainder of the tumor, which consisted of one 15-Gy dose prescribed to the 50% isodose curve. Patients were followed through outpatient visits and surveillance MR imaging for up to 3 years. Results: All patients were successfully treated as outpatients. Each had improvement or resolution of pulsatile tinnitus and otalgia and preserved or improved hearing. One patient developed a delayed facial palsy prior to radiosurgery that resolved completely; there were no other changes in cranial nerve function after either procedure. Tumor volume was stable or reduced in all patients at most recent follow-up, and there were no immediate or delayed complications. Conclusions: Staged outpatient microsurgical and radiosurgical therapy for glomus jugulare tumors in the symptomatic patient is safe and yields favorable results regarding tumor size, tinnitus, hearing and cranial nerve status.
Radiosurgery for Desmoplastic Melanoma of the Head and Neck Using the Leksell Gamma Knife Perfexion Technology
Authors: Kano Hideyuki , Niranjan Ajay , Novotny Jr. Josef , Bhatnagar Jagdish , Flickinger John C. , Lunsford L. Dade
Published: January 2009

A 44-year-old male developed chronic cancer pain caused by a progressive desmoplastic melanoma involving the mandibular division of the trigeminal nerve. The patient had failed local resection, conformal radiation therapy and chemotherapy, but was eligible for stereotactic radiosurgery using a new technology. Intraoperative stereotactic magnetic resonance and computed tomography imaging were fused to define the tumor volume and to create a conformal radiosurgery dose plan. The radiosurgery target volume was 8.6 ml. A marginal dose of 17 Gy at the 50% isodose was prescribed. The entire procedure was performed on an outpatient basis. The Leksell Gamma Knife® Perfexion™ technology increases the spectrum of treatable pathologies located in the cranial base and head and neck regions.
Intrathoracic Displacement of Pleuroamniotic Shunt after Successful in utero Treatment of Fetal Hydrops Secondary to Hydrothorax
Authors: Alkazaleh Fawaz , Saleem Mohamed , Badran Eman
Published: January 2009

Background: Primary fetal pleural effusion can be associated with high perinatal morbidity and mortality, especially when it is associated with the presence of fetal hydrops. Pleuroamniotic shunting results in effective drainage and lung expansion which prolong the pregnancy and improve neonatal survival. Intrathoracic displacement of the shunt is a rare but a known complication of shunt insertion and can cause some infant morbidity. We present a case of successful antenatal treatment of primary fetal pleural effusion complicated with intrathoracic displacement of the shunt without any fetal and long-term infant morbidity. Case Report: Our case presented with severe bilateral fetal pleural effusion, causing fetal hydrops treated successfully by pleuroamniotic shunting at 25 weeks of gestation which was complicated by dislodgement of the shunt into the fetal chest documented by antenatal ultrasound at 30 weeks. There was no recurrence of fetal pleural effusion or other antenatal complication. After delivery there were no postnatal complications, so removal of the shunt was not considered, and clinical follow-up of the infant to the age of 12 months was uneventful. Conclusion: The complication of intrathoracic displacement of a pleuroamniotic shunt can be recognized antenatally by ultrasound. Since there are no postnatal pulmonary complications related to the presence of the shunt inside the infant chest, conservative management in these cases appears to be a safe approach.
Retrospective Analysis of Thyroid Nodules by Clinical and Pathological Characteristics, and Ultrasonographically Detected Calcification Correlated to Thyroid Carcinoma in South China
Authors: Chen G. , Zhu X.Q. , Zou X. , Yao J. , Liang J.X. , Huang H.B. , Li L.T. , Lin L.X.
Published: January 2009

Objective: To investigate the clinical and pathological characteristics of thyroid nodules, as well as to evaluate the significance of ultrasonographically detected thyroid calcification in the diagnosis of thyroid carcinomas. Methods: Retrospective data were studied from 1,051 consecutive patients who underwent a thyroidectomy in the Provincial Hospital of Fujian Medical University in South China between January 2003 and July 2006 for nodular thyroid disease. Complete sonographical information before surgery was only collected from 758 of the 1,051 patients. Results: Among the 1,051 patients, benign lesions were found in 857 (81.54%) patients, of whom 612 (71.41%) were nodular goiter; malignant lesions were found in 194 (18.46%) patients, in whom benign thyroid lesions were also found in 85 (43.81%) patients. A total of 48 patients suffered from microcarcinomas, of whom 37 patients had benign lesions; these 37 accounted for 43.53 and 77.08%, respectively, of the 85 malignant cases with benign lesions and the 48 cases with microcarcinomas. In the 758 patients who underwent thyroid ultrasonography before surgery, intrathyroidal calcifications were apparent in 243 patients (32.06%). The incidence of calcification was significantly higher in patients with thyroid carcinoma (54.17%) than in those with benign lesions (26.87%; p < 0.005). Detection of calcification in thyroid lesions by ultrasound had a sensitivity of 32.38% and a specificity of 87.35%, with an OR of 3.31 (95% CI, 2.24–4.63), positive likelihood ratio of 2.56, negative likelihood ratio of 0.77 and a κ value of 0.23. Conclusion: Thyroid carcinoma, especially microcarcinoma, often coexists with benign thyroid disease. Calcification detected by thyroid ultrasound represents a risk factor for malignancy, but is of limited use as a sole marker of malignancy.
Antiplatelet Activity of Allium ursinum and Allium sativum
Authors: Hiyasat Bahi , Sabha Dina , Grötzinger Kristina , Kempfert Joerg , Rauwald Johann-Wilhelm , Mohr Friedrich-Wilhelm , Dhein Stefan
Published: January 2009

Objectives: Garlic (Allium sativum) has a well-established reputation as a protective agent against cardiovascular disease, while nearly nothing is known about its cousin Allium ursinum. The aim of this study was to evaluate the antiaggregatory mechanism of garlic and to compare the effects of A. ursinum and A. sativum. Methods: In a prospective study, extracts were prepared from A. sativum powder made from fresh A. sativum bulbs and fresh A. ursinum leaves by maceration. The extracts were characterized by thin layer chromatography. Their in vitro effects on human platelet aggregation were examined by light transmission aggregometry after induction by adenosine diphosphate (ADP), collagen, A23187, epinephrine and arachidonic acid (ARA) in platelets from healthy volunteers. Results:A. ursinum and A. sativum exert similar antiaggregatory effects: they inhibit platelet aggregation induced via the ADP pathway and to a lesser extent aggregation induced by epinephrine, whereas ARA-, collagen- and A23187-induced aggregation was not affected. It became clear that the alcoholic extract of A. ursinum is the potent form, while the aqueous extract exerted an unspecific activity. The effects were strictly dose related. A. ursinum and A. sativum extracts exhibited similar potencies. Conclusion: Both A. ursinum and A. sativum exert antiaggregatory effects. Garlic extracts are acting by inhibition of the ADP pathway; their mechanisms of action are comparable to that of the clinically used drug clopidogrel. The pharmacologically active component of the extracts appears to be lipophilic rather than hydrophilic, but the precise chemical substance is still unknown. This is the first report on the antiplatelet activity of A. ursinum.
Effects of the Phosphodiesterase Type 4 Inhibitor Roflumilast on Early and Late Allergic Response and Airway Hyperresponsiveness in Aspergillus-fumigatus-Sensitized Mice
Authors: Hoymann Heinz-Gerd , Wollin Lutz , Müller Meike , Korolewitz Regina , Krug Norbert , Braun Armin , Beume Rolf
Published: January 2009

Background: Inhibitory effects of roflumilast on responses characteristic of allergic asthma were investigated in a fungal asthma model in BALB/c mice. Methods: Mice were sensitized with Aspergillus antigen (Afu) and exposed to Afu or vehicle, and given roflumilast 1 or 5 mg/kg. Early airway response (EAR) and late airway hyperresponsiveness (AHR) to methacholine were measured via plethysmography. Bronchoalveolar lavage (BAL) was used to assess inflammatory cell count. Results: In Afu-exposed mice, roflumilast dose-dependently reduced the EAR [26% at 1 mg/kg (NS) and 94% at 5 mg/kg (p < 0.01)] and AHR [46% at 1 mg/kg (NS) and 128% at 5 mg/kg (p < 0.05)]. Roflumilast 5 mg/kg reduced neutrophil, eosinophil and lymphocyte counts [87% (p < 0.01), 40% (NS) and 67% (p < 0.01), respectively] in BAL fluid versus controls. Conclusions: In this model, roflumilast inhibited the EAR, suppressed AHR and reduced inflammatory cell infiltration.
Prenatal Cardiac Ultrasound Finding in Congenital Disorder of Glycosylation Type 1a
Authors: Malhotra A. , Pateman A. , Chalmers R. , Coman D. , Menahem S.
Published: January 2009

We present the antenatal cardiac findings in an infant in whom a postnatal diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia) was confirmed. The antenatal findings at 34 weeks’ gestation included biventricular cardiac hypertrophy with pericardial effusion, multiple skeletal anomalies and cerebral ventricular dilatation. A severe CDG-Ia multisystem clinical phenotype evolved in the postnatal period, with the infant succumbing at 3.5 weeks of age secondary to a large pericardial effusion with tamponade. A literature review suggests that this is the first case of cardiac manifestations of CDG-Ia observed antenatally. We would also like to suggest that CDG-Ia should be considered and if possible prenatal diagnosis performed in cases with hypertrophic cardiomyopathy, and/or pericardial effusion.
Safety and Efficacy of MRI-Based Selection for Recombinant Tissue Plasminogen Activator Treatment: Responder Analysis of Outcome in the 3-Hour Time Window
Authors: Sølling Christine , Hjort Niels , Ashkanian Mahmoud , Østergaard Leif , Andersen Grethe
Published: January 2009

Introduction: The use of MRI may alter the target population for intravenous recombinant tissue plasminogen activator (rtPA) treatment relative to conventional CT. If selection changes, it remains crucial to demonstrate safety and efficacy of rtPA for the overall population, as well as in subpopulations hypothesized to benefit from MRI. Materials and Methods: Clinical outcome and incidence of symptomatic intracerebral hemorrhage (ICH) was recorded in 112 consecutive patients treated with intravenous rtPA (0–3 h) with MRI as first-choice imaging modality. According to the responder analysis, favorable outcome was separately defined for mild (NIHSS <8; n = 51), moderate (NIHSS 8–14; n = 30) and severe (NIHSS >14; n = 31) stroke. Results: Eighty-three patients were treated with rtPA after MRI, and 29 after CT. Adjusted for baseline severity, 42% of all patients had a favorable outcome, compared to 37% in NINDS. Among patients with severe stroke, MR-selected patients showed a good outcome in 52% of patients compared to 29% in NINDS (p < 0.05). Symptomatic ICH occurred in 2 patients (1.9 %), and 7 patients died during hospitalization (6.3%). Conclusion: MRI-based rtPA is safe and time-efficient. Outcome data compares well with NINDS data. Diagnostic information obtained from multimodal MRI may affect the target group. Our data support the hypothesized benefit of MRI in patients with severe stroke.