bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Early Diagnosis of Pancreatic Cancer Fiction? Surveillance of Individuals at High Risk for Pancreatic Cancer
Authors: Harinck F. , Poley J.W. , Kluijt I. , Fockens P. , Bruno M.J. ,   On behalf of the Dutch Research Group of Pancreatic Cancer Surveillance in High-Risk Individuals
Published: November 2010

Pancreatic cancer represents one of the most deadly human malignancies with an overall 5-year survival of less than 5%. Despite improvements in imaging techniques and surgical techniques, survival statistics have hardly improved over the past decades. To improve the dismal outlook it would be highly desirable to develop a program to detect precursor lesions or small asymptomatic early cancers at the time when the disease is still at a curable stage. Screening the general population for disease presence is not feasible at present because of the relatively low disease incidence and the lack of a noninvasive, reliable and cheap screening tool. Targeted surveillance programs, however, in individuals at high risk for developing pancreatic cancer, like mutation carriers of pancreatic cancer prone hereditary (tumor) syndromes or individuals with a strong family history of pancreatic cancer without a known underlying genetic defect, might be feasible. Careful consideration of the criteria put forward by Wilson and Jungner as published by the World Health Organization on the principles and practice of screening for disease, indicate that surveillance in this high-risk population by means of endosonography (EUS) and/or magnetic resonance imaging (MRI) represents a promising development, though experimental. It nicely points out which open questions need to be addressed. Among others, these include how to acquire a better understanding of the natural behavior and progression of precursor lesions towards invasive cancer, how to firmly establish the performance characteristics of EUS and MRI for the detection of (early) lesions in individuals at high risk for pancreatic cancer, and how to determine which lesions can be safely observed with continued surveillance and which lesions justify resection.
Adjuvant Therapy in Pancreatic Cancer
Authors: Thomas Amy , Dajani Khaled , Neoptolemos John P. , Ghaneh Paula
Published: November 2010

Pancreatic cancer is one of the major causes of cancer death in Europe with a 5-year survival rate of less than 5%. Although surgery cannot guarantee a cure, the 5-year survival does improve to around 10% following resection and increases to 20–30% with adjuvant chemotherapy. The European Study Group for Pancreatic Cancer (ESPAC) 1 trial was the first adequately powered, randomized study to assess chemoradiotherapy (CRT), concurrent with 5-fluorouracil (5-FU) and chemotherapy [5-FU/folinic acid (FA)] in resected pancreatic cancer. There was a survival benefit for adjuvant chemotherapy, but not for adjuvant CRT. Adjuvant CRT also did not improve survival in the EORTC multicenter prospective randomized trial by Klinkenbijl et al. (1999). The phase 3 RTOG 9704 trial compared pre- and postchemoradiation gemcitabine to pre- and postchemoradiation 5-FU. Overall there was no difference in overall survival between the 2 arms. Adjuvant gemcitabine significantly improved disease-free survival and later overall survival compared to surgery alone in the CONKO-001 randomized trial. The ESPAC-3(v2) trial compared adjuvant gemcitabine versus 5-FU/FA. The final 2-year analysis demonstrated median survival from resection of patients treated with 5-FU/FA was 23.0 months (95% CI: 21.1, 25.0) and 23.6 months (95% CI: 21.4, 26.4) for patients treated with gemcitabine. Further randomized studies will assess the role of adjuvant combination chemotherapy (ESPAC-4). The key to the future of adjuvant therapy in pancreatic cancer will be the identification of novel and effective agents, and better biomarker technology underpinned by translational research which will inform the design of future trials.
Etiology and Risk Factors for Esophageal Carcinoma
Authors: Lundell Lars R.
Published: November 2010

Trends toward increasing incidence rates were observed for esophageal and gastric cardia adenocarcinoma in Western countries and were associated with trends toward stabilizing or declining incidence rates for esophageal squamous cell carcinoma, suggesting that these tumors might be associated with distinct risk factors. Overweight and obesity have been consistently related to esophageal adenocarcinoma, but not to squamous cell carcinoma. Body mass index seems to be inversely related to the risk of esophageal squamous cell carcinoma. The influence of obesity on esophageal adenocarcinoma and gastric cardia adenocarcinoma may be related to higher incidence of gastroesophageal reflux in obese persons since the risk of gastroesophageal reflux is strongly related to the risk for Barrett’s esophagus. Tobacco smoking is a strong risk factor for esophageal squamous cell carcinoma, but is only a weak risk factor for esophageal adenocarcinoma. Alcohol consumption is a strong risk factor for esophageal squamous cell carcinoma, but is not consistently related to esophageal adenocarcinoma. Selenium, dietary fiber, fruits, vegetables and antioxidants are seen as protective factors. Male gender seems to be a risk factor for both types of tumors in the region, while infection with human papillomavirus does not seem to play a major part in the development of esophageal cancers. Infection with Helicobacter pylori is, however, an interesting factor to this region of tumors as discussed in many reports. It has been suggested that infection with H. pylori is protective to adenocarcinoma, but might be a risk factor for squamous cell carcinoma, although the role of H. pylori in the etiology of these cancers remains somewhat unclear.
Treatment of Hemodialyzed Patients with Sunitinib in Renal Cell Carcinoma
Authors: Park Silvia , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Kang Won Ki , Park Young Suk , Cho Jin Hyun , Lim Ho Yeong
Published: November 2010

Background: Understanding the effect of adverse events from commonly used agents such as sunitinib in hemodialyzed renal cell carcinoma (RCC) patients is important in clinical practice. Despite its clinical relevance, little information has been provided on the safety and toxicity profile of sunitinib when administered in hemodialyzed patients with RCC. Methods: Six patients undergoing hemodialysis were treated with sunitinib for metastatic RCC between February 2007 and May 2009. We retrospectively reviewed the medical records of these patients and examined the administered dose of sunitinib, treatment-related toxicity, and the clinical response to therapy. Results: The initial dose of sunitinib was 25 mg (cases 1 and 5), 37.5 mg (cases 2 and 3), and 50 mg (cases 4 and 6), respectively. Toxicities greater than grade 3 were observed in cases 3 and 6, and subsequently the dose was reduced in case 6. No patient had to stop sunitinib due to toxicities. Among the 6 patients, 3 (cases 2, 3, and 5) had disease progression after 1, 2, and 2 cycles of sunitinib, respectively. Three patients (cases 1, 4, and 6) had stable disease after 12, 5, and 4 cycles of treatment, respectively, and 2 of them (cases 4 and 6) were still on sunitinib 8 and 7 months, respectively, after the start of treatment. Conclusions: The toxicity of and response to sunitinib in dialyzed patients seem to be comparable to those in patients with normal renal function. However, due to the limitations of this study, i.e. a small number of participants and lack of pharmacokinetic data, prospective clinical trials with pharmacokinetic studies in a larger cohort of patients are required.
Inflammation and Immunity in the Tumor Environment
Authors: Maletzki C. , Emmrich J.
Published: November 2010

The relationship between inflammation, innate immunity and cancer is widely accepted. Cancer-associated inflammation includes infiltrating leukocytes, cytokines, chemokines, growth factors, lipid messengers and matrix-degrading enzymes. Tumor-associated macrophages and lymphocyte subpopulations are major components of the leukocyte infiltrate in most tumors. However, the cytokine and chemokine expression profile of the tumor microenvironment may be more relevant than its specific immune cell content. Apart from inflammatory cells, tumor stroma consists of new blood vessels and connective tissue. Many factors produced by tumor cells promote tumor angiogenesis and generation of extracellular matrix. Investigations regarding the link between inflammation and cancer are vital for identifying cell or protein targets for cancer prevention and therapy. Based on the relation between inflammation and cancer, different forms of immunotherapy have been developed. In a mouse model, we investigated the potential of Streptococcus pyogenes to achieve a bacteria-related immune response against tumor cells followed by tumor regression. As a model of pancreatic carcinoma, the aggressively growing and poorly immunogenic Panc02 tumor model was chosen. Our findings showed that a local application of bacteria mediates complete tumor regression. Future investigations should focus on the optimization of immunotherapeutic approaches that incorporate live bacteria or bacterial components.
Uric Acid in Hypertension and Renal Disease: The Chicken or the Egg
Authors: Kanbay Mehmet , Solak Yalcin , Dogan Ekrem , Lanaspa Miguel A. , Covic Adrian
Published: November 2010

After uric acid was recognized as the causative factor in gout, increased prevalence of renal disease and hypertension in this patient population caught the attention of the medical community. Thus, it has been proposed that uric acid might have caused these disorders. However, uric acid suffered a long period of ignorance in which it was considered a metabolically inert substance. However, recent years has witnessed a resurrection of interest. Experimental studies showed an association between increased uric acid and renal arteriolar disease and hypertension. These preliminary results were supported with clinical studies. However, controversy regarding the precise pathophysiologic role of uric acid in inducing hypertension and renal disease remains to be elucidated. Despite being limited at this time, a few randomized intervention studies showed that even treatment of asymptomatic hyperuricemia was beneficial in terms of blood pressure regulation and kidney function. In this review, we focus on the pathophysiologic role of uric acid in the development and progression of renal disease and hypertension. We also discuss recent clinical evidence suggesting a causal role of uric acid in these disease states.
Multiple Basal Cell Carcinomas after Long-Term Exposure to Hydrazine: Case Report and Review of the Literature
Authors: Aigner B.A. , Darsow U. , Grosber M. , Ring J. , Plötz S.G.
Published: November 2010

Hydrazine (N2H4) is a clear, inorganic colourless liquid. It is known to be a skin sensitizer, a corrosive agent and it causes dermatitis on contact. Hydrazine is employed in chemical plants, used as a corrosion inhibitor for feed waters and may be added to rocket fuels. The authors report the case of a 68-year-old man with multiple basal cell carcinomas (BCCs) covering his arms and face. The patient worked in a steam power plant with extensive exposure to hydrazine for a period of over 10 years. The present case report strongly suggests that there may be a correlation between the long-term exposure to hydrazine and an increased risk for multiple BCCs.
Priming of Neutrophils and Differentiated PLB-985 Cells by Pathophysiological Concentrations of TNF-α Is Partially Oxygen Dependent
Authors: Volk A. Paige Davis , Barber Brieanna M. , Goss Kelli L. , Ruff Jake G. , Heise Christine K. , Hook Jessica S. , Moreland Jessica G.
Published: November 2010

Activation of polymorphonuclear leukocytes (PMN) can be modulated to intermediate ‘primed’ states characterized by enhanced responsiveness to subsequent stimuli. We studied priming in response to TNF-α in human PMN and PLB-985 cells, a myeloid cell line differentiated to a neutrophilic phenotype (PLB-D). PMN generated reactive oxygen species (ROS) in response to TNF-α alone, and NADPH oxidase activity increased in response to stimulation with formyl-Met-Leu-Phe after priming. PLB-D cells also demonstrated priming of NADPH oxidase activity. Similar to priming by endotoxin, priming of the respiratory burst by TNF-α was predominantly oxygen dependent, with marked attenuation of ROS generation if primed anaerobically. Both PMN and PLB-D cells displayed significant increases in cell surface CD11b and gp91phox expression after TNF-α priming and PMN displayed activation of MAPK. In response to TNF-α priming, neither mobilization of intracellular proteins nor activation of MAPK pathways was NADPH oxidase dependent. Priming of PMN and PLB-D cells by low TNF-α concentrations enhanced chemotaxis. These data demonstrate that pathophysiological concentrations of TNF-α elicit NADPH oxidase-derived ROS and prime cells for enhanced surface protein expression, activation of p38 and ERK1/2 MAPK pathways, and increased chemotaxis. Furthermore, PLB-D cells undergo TNF-α priming and provide a genetically modifiable model to study priming mechanisms.
Expression of E-Selectin and Vascular Cell Adhesion Molecule-1 in So-Called ‘Negative’ Appendices: First Results to Support the Pathological Diagnosis in Borderline Cases
Authors: Brochhausen C. , Bittinger F. , Schmitt V.H. , Kommoss F. , Lehr H.-A. , Heintz A. , Kirkpatrick C.J.
Published: November 2010

Background: Since the rate of histologically ‘negative’ appendices still ranges between 15 and 20%, appendicitis in ‘borderline’ cases remains a challenging disease. As previously described, cell adhesion molecule expression correlates with different stages of appendicitis. Therefore, it was of interest to determine whether the ‘negative’ appendix correlated with the absence of E-selectin or vascular cell adhesion molecule-1 (VCAM-1). Methods: Nineteen grossly normal appendices from a series of 120 appendectomy specimens from patients with suspected appendicitis were analysed in frozen sections for the expression of E-selectin and VCAM-1. As control, 5 normal appendices were stained. Results: This study showed a coexpression of E-selectin and VCAM-1 in endothelial cells in early and recurrent appendicitis. In patients with symptoms for less than 6 h, only E-selectin was detected. Cases with fibrosis and luminal obliteration were only positive for VCAM-1. In cases of early appendicitis with symptoms of less than 6 h duration, a discordance between histological and immunohistochemical results was found. Conclusions: This report indicates that E-selectin and VCAM-1 expression could be useful parameters in the diagnosis of appendicitis in borderline cases.
Improved Outcome after ‘Bottom-Up’ Immunosuppression in Liver Transplant Recipients with Preoperative Renal Impairment
Authors: Schnitzbauer Andreas A. , Doenecke Axel , Sothmann Johannes L. , Loss Martin , Farkas Stefan A. , Hartl Janine , Tsui Tung-Yu , Baier Lucia , Kirchner Gabriele , Obed Aiman , Bein Thomas , Geissler Edward K. , Scherer Marcus N. , Schlitt Hans J.
Published: November 2010

Background: Most patients with high MELD scores have impaired renal function prior to transplantation. Patient and Methods: A retrospective case control study was conducted with initial low immunosuppression, which was increased when patients rejected or were clinically stable beyond day 30 (‘bottom-up’). Results: Thirty patients with impaired renal function were included. Fifteen were treated with de novo cyclosporine A (CsA; group A), and 15 had ‘bottom-up’ immunosuppression (group B). Baseline renal function was similar: serum creatinine (SCr) median 1.8 mg/dl (range: 1.5–4.0 mg/dl; group A) versus 2.4 mg/dl (range: 1.5–4.0 mg/dl; group B; p = 0.24). The requirement for renal replacement therapy was significantly lower in group B (p = 0.032). Ten received ‘bottom-up’ immunosuppression [4 CsA/1 sirolimus (Sir) ‘on demand’ after rejection, 5 Sir (stable)] beyond day 30. By months 6 and 12 (1.6 mg/dl vs. 1.2 mg/dl), SCr values were significantly better in group B (p = 0.006). Renal function in group B did not differ between patients receiving CsA or Sir. Overall complication rates, survival and biopsy-proven acute rejection were similar, although BANFF scores were higher in group B (p = 0.004). Conclusion: Successful implementation of ‘bottom-up’ immunosuppression in liver transplant recipients with high lab-MELD scores and renal dysfunction at the time of transplantation has the potential to substantially improve short- and long-term outcomes.
Ethyl Chloride as an Antipruritic Agent: A Double-Blind Placebo-Controlled Prospective Study
Authors: Gal-Oz Amir , Rogowski Ori , Swartzon Michael , Kivity Shmuel
Published: November 2010

Background: Ethyl chloride (EC) is usually used as a topical anesthetic spray agent. However, its antipruritic effects have never been studied, to the best of our knowledge. Methods: A double-blind placebo-controlled prospective study. Overall, 51 healthy volunteers underwent a histamine skin prick test on both arms in order to trigger local pruritus. Thereafter, the affected areas were treated with an EC spray on one arm and a saline spray (placebo) on the other. Subjects as well as researchers were blind to which sprays were used. Subjects reported improvement in pruritus following EC/placebo and rated the intensity of pruritus by using a validated questionnaire and a visual analog scale. The flare and wheal reactions were measured in both arms before and following treatment with EC/placebo. Results: Significant improvement in pruritus was reported more frequently following treatment with EC compared with placebo (84 vs. 16%; p < 0.0001). Significant reduction in pruritus intensity was reported immediately and 15 min following treatment with EC compared with placebo (p < 0.05). There was no significant difference between EC and placebo in terms of the flare and wheal reactions. Conclusions: EC is an effective antipruritic agent, and it does not change the wheal and flare reactions, making it ideal for treating pruritus secondary to allergy skin tests without masking their results.
Plasma Glial Fibrillary Acidic Protein Levels in a Child with Sickle Cell Disease and Stroke
Authors: Savage William J. , Everett Allen D. , Casella James F.
Published: November 2010

A 12-year-old boy with HbSS sickle cell disease (SCD) was admitted with an acute febrile illness and developed overt stroke 3 days later. Plasma glial fibrillary acidic protein levels were elevated, as compared to pediatric controls, 32 h prior to the clinical diagnosis of stroke, peaked immediately prior to the exchange transfusion, and remained elevated 1 year later despite chronic transfusion therapy. Stroke in SCD can occur in the setting of acute illness, and a biomarker that could predict the onset and triage ill children to therapeutic intervention more quickly would be useful.
Human Cord Blood-Derived Mast Cells Are Activated by the Nod1 Agonist M-TriDAP to Release Pro-Inflammatory Cytokines and Chemokines
Authors: Enoksson Mattias , Ejendal Karin F.K. , McAlpine Sarah , Nilsson Gunnar , Lunderius-Andersson Carolina
Published: November 2010

Mast cells are among the first cells of our immune system to encounter exogenous danger. Intracellular receptors such as nucleotide-binding oligomerization domain (Nod) play an important role in responding to invading pathogens. Here, we have investigated the response of human mast cells to the Nod1 ligand M-TriDAP. Human cord blood-derived mast cells (CBMCs) were activated with M-TriDAP alone, or in combination with the Toll-like receptor (TLR) ligands lipopolysaccharide (LPS) and zymosan. Release of pro-inflammatory chemokines and cytokines was measured by ELISA, cytometric bead array and LUMINEX, and degranulation was evaluated by analysis of histamine release. M-TriDAP induced a dose-dependent release of IL-8, MIP-1α, MIP-1β and TNF. In contrast, degranulation could not be observed. When cells were treated with M-TriDAP in combination with the TLR4 agonist LPS, but not with TLR2 agonist zymosan, the secretion of cytokines was augmented. We here present results demonstrating that human CBMCs are stimulated by the Nod1 agonist M-TriDAP alone and in combination with LPS to produce pro-inflammatory cytokines and chemokines. Our results add to the concept that mast cells constitute an important part of our host defense, as they are equipped with several types of important pattern recognition receptors, including TLRs and Nod.
Characterization of Skin Friction Coefficient, and Relationship to Stratum Corneum Hydration in a Normal Chinese Population
Authors: Zhu Y.H. , Song S.P. , Luo W. , Elias P.M. , Man M.Q.
Published: November 2010

Background and Objectives: Studies have demonstrated that some cutaneous biophysical properties vary with age, gender and body sites. However, the characteristics of the skin friction coefficient in different genders and age groups have not yet been well established. In the present study, we assess the skin friction coefficient in a larger Chinese population. Methods: A total of 633 subjects (300 males and 333 females) aged 0.15–79 years were enrolled. A Frictiometer® FR 770 and Corneometer® CM 825 (C&K MPA 5) were used to measure the skin friction coefficient and stratum corneum hydration, respectively, on the dorsal surface of the hand, the forehead and the canthus. Results: In the females, the maximum skin friction coefficients on both the canthus and the dorsal hand skin were observed around the age of 40 years. In the males, the skin friction coefficient on the dorsal hand skin gradually increased from 0 to 40 years of age, and changed little afterward. Skin friction coefficients on some body sites were higher in females than in age-matched males in some age groups. On the canthus and the dorsal hand skin of females, a positive correlation was found between skin friction coefficient and stratum corneum hydration (p < 0.001 and p < 0.0001, respectively). In contrast, in males, the skin friction coefficient was positively correlated with stratum corneum hydration on the forehead and the dorsal hand skin (p < 0.05 and p < 0.0001, respectively). Conclusion: The skin friction coefficient varies with age, gender and body site, and positively correlates with stratum corneum hydration on some body sites.
An Intergenerational Approach in Promoting Balance and Strength for Fall Prevention: Evidence-Based or Evidence-Inspired?
Authors: Burtscher Martin , Kopp Martin
Published: November 2010

Recently, Granacher et al. (2010) proposed an intergenerational approach to promoting balance and strength for fall prevention in children and elderly subjects together. Although this sounds like a stimulating idea, its effectiveness for fall prevention in both groups has yet to be demonstrated. Undoubtedly, fall prevention remains a big challenge to scientists and health professionals. The idea of implementing prevention programs on an intergenerational basis will probably have to undergo a complex and long-lasting evaluation process before a firm conclusion about its effectiveness can be made.
Target vessel reopening by guidewire insertion in ST-elevation myocardial infarction is a predictor of final TIMI flow and survival
Authors: Adlbrecht Christopher , Distelmaier Klaus , Gündüz Duygu , Redwan Bassam , Plass Christian , Bonderman Diana , Kaider Alexandra , Christ Günter , Lang Irene
Published: November 2010

ST-elevation myocardial infarction (STEMI) results from acute thrombotic obstruction of a coronary artery. Percutaneous coronary intervention (PCI) is the treatment of choice to restore blood flow. The incidence of guidewire-induced reopening of the infarct-related coronary artery (IRA) and its association with post-procedural TIMI flow and long-term mortality were assessed. Angiograms of consecutive STEMI patients admitted to the catheter laboratory of the Medical University of Vienna between January 2003 and December 2005 were analysed. TIMI flow was graded prior to and after guidewire insertion into the distality of the IRA, and at the end of the procedure. Initial TIMI 0 flow was present in 476 (47.0%) of 1,012 cases. Target vessel reopening after guidewire insertion defined as any flow >TIMI 0 flow occurred in 150 patients (37.2%), and was associated with improved survival after a median of 914 (609–1,238) days (p=0.017). Reflow after guidewire insertion was an independent predictor of post-procedural TIMI flow (odds ratio=3.10, 95% confidence interval [CI]=1.64 – 5.86], p<0.001) and mortality (hazard ratio=0.51, CI=0.28 – 0.94], p=0.029). Target vessel reopening by guidewire insertion is a new predictor of prognosis. Target vessel flow after guidewire insertion should be assessed in a standardised fashion during PCI.
Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia
Authors: Visser Jantien , Ulander Veli-Matti , Helmerhorst Frans , Lampinen Katja , Morin-Papunen Laure , Bloemenkamp Kitty , Kaaja Risto
Published: November 2010

Recurrent miscarriage affects 1–2% of women. In more than half of all recurrent miscarriage the cause still remains uncertain. Thrombophilia has been identified in about 50% of women with recurrent miscarriage and thromboprophylaxis has been suggested as an option of treatment. A randomised double-blind (for aspirin) multicentre trial was performed among 207 women with three or more consecutive first trimester (<13 weeks) miscarriages, two or more second trimester (13–24 weeks) miscarriages or one third trimester fetal loss combined with one first trimester miscarriage. Women were analysed for thrombophilia. After complete work-up, women were randomly allocated before seven weeks’ gestation to either enoxaparin 40 mg and placebo (n=68), enoxaparin 40 mg and aspirin 100 mg (n=63) or aspirin 100 mg (n=76). The primary outcome was live-birth rate. Secondary outcomes were pregnancy complications, neonatal outcome and adverse effects. The 0.92–1.48] was found for enoxaparin and placebo and 65% [RR 1.08, 95% CI 0.83–1.39] for enoxaparin and aspirin when compared to aspirin alone (61%, reference group). In the whole study group the live birth rate was 65% (95% CI 58.66–71.74) for women with three or more miscarriages (n=204). No difference in pregnancy complications, neonatal outcome or adverse effects was observed. No significant difference in live birth rate was found with enoxaparin treatment versus aspirin or a combination of both versus aspirin in women with recurrent miscarriage.
Expression and localisation of vascular ribonucleases in endothelial cells
Authors: Dadkhahi Sara , Gansler Julia , Saffarzadeh Mona , Shibamiyama Aya , Kral Nicolé , Baal Nelli , Koyama Takatoshi , Deindl Elisabeth , Fischer Silvia , Nishio Miwako , Preissner Klaus
Published: November 2010

The functions of extracellular RNA in the vascular system as new procoagulatory and permeability-increasing factor in vivoand in vitrowere shown to be counteracted by pancreatic type RNase1. Based on the identification of RNase1 in plasma and serum, it is proposed that the enzyme is expressed by vascular cells to contribute in the regulation of extracellular RNA. It is demonstrated that RNase1 and RNase5 (also termed angiogenin) were differentially expressed in various types of endothelial cells, whereby human umbilical vein endothelial cells (HUVEC) expressed and released the highest concentration of active RNase1. Expression and release of RNase5 were similar in all types of endothelial cells tested. Both RNases were constitutively produced and secreted, whereby a portion of RNase1, but not RNase5, was stored in Weibel-Palade bodies, co-localising with von Willlebrand factor and P-selectin. Accordingly, immediate release of RNase1 from these granules was demonstrated in vitroand in vivousing Weibel-Palade body exocytosis-inducing agents. Additionally, extracellular RNA or poly:IC (but not DNA) induced this short-term release of RNase1. Our results indicate that vascular RNase1 and RNase5 are mainly produced by vascular endothelial cells and can serve, depending on the vascular bed, different functions in vascular homeostasis and endothelial cell responses.
Identification of VKORC1 interaction partners by split-ubiquitin system and coimmunoprecipitation
Authors: Schaafhausen Anne , Rost Simone , Oldenburg Johannes , Müller Clemens
Published: November 2010

Since the discovery of vitamin K epoxide reductase complex subunit 1 (VKORC1), the key enzyme for the regeneration of vitamin KH2, numerous studies have addressed the role of VKORC1 in the posttranslational modification of vitamin K-dependent proteins. VKORC1 is also the target protein of anticoagulant drugs of the coumarin type (e.g. warfarin). Genetic variants in VKORC1 have recently been shown to significantly affect the coumarin dose and international normalised ratio level. In the present study, we have used the split-ubiquitin yeast two-hybrid system to identify potential interaction partners of VKORC1. With this system we could identify 90 candidates. Out of these, we focused on VKORC1 itself, its paralog VKORC1L1, emopamil binding protein (EBP) and stress-associated endoplasmic reticulum protein 1 (SERP1). By coimmunprecipitation and colocalisation experiments, we were able to demonstrate evidence for the interaction of these proteins. Mutations in the EBP gene cause X-linked dominant chondrodysplasia punctata (CDPX2) which can be considered as a phenocopy of warfarin embryo-pathy. The interaction could be a link between these phenotypes. SERP1 represents an oxidative stress-associated endoplasmatic reticulum protein with chaperon-like functions. Antioxidant capacities have been described for vitamin K hydroquinone, the substrate of VKORC1. Both VKORC1 and SERP1, might have a synergistic function in eliminating reactive oxygen species generated during the VKOR redox process. Further studies are needed to investigate the role of these proteins in the vitamin K pathway.
Characterisation of two novel large F8 deletions in patients with severe haemophilia A and factor VIII inhibitors
Authors: Marschalek Rolf , Oldenburg Johannes , Oyen Florian , Schneppenheim Reinhard , Roth Lukas
Published: November 2010

Large deletions are found in approximately 5% of patients with severe haemophilia A, but only a few deletion breakpoints have been char-acterised precisely so far. In this study we characterised the deletion breakpoints of two patients with severe haemophilia A, large deletions and factor VIII (FVIII) inhibitors, and subsequently established deletion-specific assays for the identification of carriers. Patient 1 had a deletion of 37,410 bp comprising exon 1 and the F8promoter region, and a 5 bp homology (GGGCC) is present at the chromosomal fusion site. In patient 2, a deletion of 22,230 bp including parts of intron 25, exon 26 and 3‘-UTR was identified. No homologous repetitive elements were found at the breakpoints. However, both breakpoints were located within long terminal repeats of endogenous retroviruses and the DNA motif TTTAAA – known to be able to bend DNA molecules – was identified at the centromeric breakpoint. By deletion-specific PCR experiments we were able to identify a heterozygous state in mother 2 (carrier) while mother 1 presented only with wild-type alleles (non-carrier). Both deletions are most likely created by DNA double strand breaks and subsequent DNA repair by the non-homologous end joining DNA repair pathway (NHEJ). The exact identification of the deletion breakpoints provides a reliable diagnostic tool for carrier identification in affected families by means of a deletion-specific PCR.
Magnetic Resonance–Guided Cardiac Interventions Using Magnetic Resonance–Compatible Devices
Authors: Tzifa Aphrodite , Krombach Gabriele A. , Krämer Nils , Krüger Sascha , Schütte Adrian , von Walter Matthias , Schaeffter Tobias , Qureshi Shakeel , Krasemann Thomas , Rosenthal Eric , Schwartz Claudia A. , Varma Gopal , Buhl Alexandra , Kohlmeier Antonia , Bücker Arno , Günther Rolf W. , Razavi Reza
Published: November 2010

Background—

Percutaneous cardiac interventions are currently performed under x-ray guidance. Magnetic resonance imaging (MRI) has been used to guide intravascular interventions in the past, but mainly in animals. Translation of MR-guided interventions into humans has been limited by the lack of MR-compatible and safe equipment, such as MR guide wires with mechanical characteristics similar to standard guide wires. The aim of the present study was to evaluate the safety and efficacy of a newly developed MR-safe and compatible passive guide wire in aiding MR-guided cardiac interventions in a swine model and describe the 2 first-in-man solely MR-guided interventions.

Methods and Results—

In the preclinical trial, the new MR-compatible wire aided the performance of 20 interventions in 5 swine. These consisted of balloon dilation of nondiseased pulmonary and aortic valves, aortic arch, and branch pulmonary arteries. After ethics and regulatory authority approval, the 2 first-in-man MR-guided interventions were performed in a child and an adult, both with elements of valvar pulmonary stenosis. Catheter manipulations were monitored with real-time MRI sequence with interactive modification of imaging plane and slice position. Temporal resolution was 11 to 12 frames/s. Catheterization procedure times were 110 and 80 minutes, respectively. Both patients had successful relief of the valvar stenosis and no procedural complications.

Conclusions—

The described preclinical study and case reports are encouraging that with the availability of the new MR-compatible and safe guide wire, certain percutaneous cardiac interventions will become feasible to perform solely under MR guidance in the future. A clinical trial is underway in our institution.
Identifying Important Risk Factors for Survival in Patient With Systolic Heart Failure Using Random Survival Forests
Authors: Hsich Eileen , Gorodeski Eiran Z. , Blackstone Eugene H. , Ishwaran Hemant , Lauer Michael S.
Published: November 2010

Background—

Heart failure survival models typically are constructed using Cox proportional hazards regression. Regression modeling suffers from a number of limitations, including bias introduced by commonly used variable selection methods. We illustrate the value of an intuitive, robust approach to variable selection, random survival forests (RSF), in a large clinical cohort. RSF are a potentially powerful extensions of classification and regression trees, with lower variance and bias.

Methods and Results—

We studied 2231 adult patients with systolic heart failure who underwent cardiopulmonary stress testing. During a mean follow-up of 5 years, 742 patients died. Thirty-nine demographic, cardiac and noncardiac comorbidity, and stress testing variables were analyzed as potential predictors of all-cause mortality. An RSF of 2000 trees was constructed, with each tree constructed on a bootstrap sample from the original cohort. The most predictive variables were defined as those near the tree trunks (averaged over the forest). The RSF identified peak oxygen consumption, serum urea nitrogen, and treadmill exercise time as the 3 most important predictors of survival. The RSF predicted survival similarly to a conventional Cox proportional hazards model (out-of-bag C-index of 0.705 for RSF versus 0.698 for Cox proportional hazards model).

Conclusions—

An RSF model in a cohort of patients with heart failure performed as well as a traditional Cox proportional hazard model and may serve as a more intuitive approach for clinicians to identify important risk factors for all-cause mortality.
Long-Term Cardiovascular and Noncardiovascular Mortality of 1023 Patients With Confirmed Acute Pulmonary Embolism
Authors: Ng Austin Chin Chwan , Chung Tommy , Sze Chiang Yong Andy , Siu Ping Wong Helen , Chow Vincent , Celermajer David Stephen , Kritharides Leonard
Published: November 2010

Background—

There are currently no guidelines advising long-term surveillance of patients following an acute pulmonary embolism (PE), because long-term outcome studies are rare. We investigated the long-term cardiovascular and all-cause mortality of a large patient cohort with confirmed PE in relation to baseline cardiovascular disease (CVD).

Methods and Results—

Clinical details of all patients presenting with acute PE to a tertiary hospital were retrieved from medical records, and their survival tracked from a statewide death registry. There were 1023 (45% males) patients admitted with confirmed PE from 2000 to 2007. During a mean follow-up of 3.8±2.6 years, 363 patients died (35.5%), of whom only 31 (3.0%) died in-hospital during the index PE admission. The 3-month, 6-month, 1-year, 3-year, and 5-year cumulative mortality rates were 8.3%, 11.1%, 16.3%, 26.7%, and 31.6% respectively. Annual mortality did not improve over the 7-year period. The postdischarge mortality of 8.5%/patient-year was 2.5-fold that of an age- and sex-matched general population, being 12.6-fold in the youngest quintile (<55 years) and 1.9-fold in the oldest quintile (≥83 years). Patients with known CVD at baseline had 2.2-fold greater all-cause mortality than those without CVD, and this effect, although at a lower level of risk, remained significant after multivariate analysis. Of the 332 deaths occurring postdischarge, 40% were attributed to cardiovascular causes.

Conclusions—

In a contemporary adult population, PE is associated with a substantially increased long-term mortality, of which nearly half is cardiovascular. Our study highlights the urgent need to develop long-term surveillance strategies in this population.
Assessment of Left Ventricular Function in Older Medicare Beneficiaries With Newly Diagnosed Heart Failure
Authors: Curtis Lesley H. , Greiner Melissa A. , Shea Alisa M. , Whellan David J. , Hammill Bradley G. , Schulman Kevin A. , Douglas Pamela S.
Published: November 2010

Background—

Assessment of left ventricular function is a recommended performance measure for the care of patients with newly diagnosed heart failure. Little is known about the extent to which left ventricular function is assessed in real-world settings.

Methods and Results—

We analyzed a 5% national sample of data from the Centers for Medicare and Medicaid Services from 1991 through 2008. Patients were 65 years or older, with incident heart failure in 1995, 1999, 2003, or 2007. We searched for evidence of tests of left ventricular function from 30 days before through 60 days after an incident heart failure diagnosis. We used logistic regression to identify patient characteristics associated with assessment of left ventricular function. There were 45 005 patients with incident heart failure in 1995, 38 425 in 1999, 39 529 in 2003, and 32 629 in 2007. Assessment of left ventricular function increased from 46% to 60%, with rest echocardiography being the predominant mode. Patients diagnosed with heart failure during a hospitalization had the highest assessment rates (58% in 1995, 64% in 1999, 69% in 2003, and 73% in 2007). After adjustment for other patient characteristics, odds of assessment were 4 times higher among patients diagnosed in inpatient settings.

Conclusions—

Nearly 40% of Medicare beneficiaries do not undergo assessment of left ventricular function when newly diagnosed with heart failure. Quality-improvement strategies are needed to optimize the care of these patients, especially in outpatient settings.
“You Ain't No Christian, Not ‘Cordin’ to Gospel Truth”: The Literary Theology of Rose Terry Cooke
Authors: Holly Carol
Published: November 2010

New England regionalist writer Rose Terry Cooke, energized by the transformation of nineteenth-century evangelical Protestantism, used a variety of narrative strategies to convey her practical theology. Her fiction, which appeared in mainstream literary magazines as well as antebellum Protestant periodicals, betrays religious anxieties not dissimilar to those dominating public discourse today.
The Forms of International Institutional Law: An Historical Analysis of the scheduling Decisions of Narcotic Drugs and Psychotropic substances taken by the United Nations' Commission on Narcotics Drugs
Authors: Corte Cristián Gimenez
Published: November 2010

The objective of this study is to analyze the legal form of the drug scheduling decisions made by the United Nations' Commission on Narcotic Drugs (CND) to place a given narcotic drug or psychotropic substance under international control in accordance with the drug control treaties. In particular, this study will focus upon the historical evolution of the legal form of the decisions of the CND from the inception of the 1961 Single Convention until the latest decision on this matter in 2007. This study will also seek to show how and to explain why the form of the decisions 'evolved' from a very informal and vague way to a strict and concrete legal form. By doing so, this study will interpret these decisions, systematizing them within the general framework of UN law. This exercise will lead, ultimately, to the determination of the meaning of the decisions.
Amsterdam Center for International Law Introduction to the symposium on Responsibility of International Organizations and of (Member) states: Attributed or Direct Responsibility or Both?
Authors: Kuijper Pieter Jan
Published: November 2010

This is the introduction to three articles that resulted from the Symposium on Responsibility of International Organizations and of (Member) States organized by the Amsterdam Center for International Law (ACIL) under direction of Professors André Nollkaemper and Pieter Jan Kuijper in April 2009. The Symposium concentrated on those articles of the ILC draft articles on the Responsibility of International Organizations which are concerned with the responsibility of States for the unlawful acts of International Organizations as well as with the responsibility of International Organizations for unlawful acts of States, and in particular Member States. This introductory article seeks to place the articles relating to these issues in the context of the draft articles as a whole and of their predecessors, the draft articles on State Responsibility. Moreover, since the articles in question are based on the notion of a directly incurred responsibility on the part of the international organization or State concerned, rather than the classical conception of responsibility through attribution, they are also analyzed in the light of these two conceptions of responsibility. The issue of shared responsibility deserves special attention in this respect.
Classification of Weather Patterns and Associated Trajectories of High-Ozone Episodes in the Houston–Galveston–Brazoria Area during the 2005/06 TexAQS-II
Authors: Ngan Fong , Byun Daewon
Published: November 2010

The 850-hPa synoptic flow patterns over eastern Texas and adjacent states during the 2005/06 Second Texas Air Quality Studies (TexAQS-II) period were classified into six groups using a two-stage clustering method. This study identifies synoptic weather patterns that are conducive to creating high-ozone events and reveals potential emission source regions leading to ozone exceedances through backward trajectory analysis. Clusters with dominant southerly synoptic flows and higher average wind speeds (C1 and C2 clusters) were related to low mean daytime ozone levels. Easterly (C3) and northerly (C5) clusters showed a higher probability to exceed the 8-h ozone standard than the other clusters. The dry and sunny postfrontal days with weak northerly or easterly weather patterns were often associated with ozone exceedances in the Houston–Galveston–Brazoria (HGB) area during September 2006. The majority of backward trajectories on ozone episode days were from the east, which brought polluted air from the Houston Ship Channel resulting in high ozone in the southwestern part of the metropolitan area. The shifting trajectories of the C3 and C5 weather patterns were associated with surface wind turning from weak northerly to southeasterly/southerly because of the development of bay/sea breeze. Pollutants were shifting inside the metropolitan area and high ozone built up in the afternoon or early evening. A small portion of trajectories of C3 and C5 that caused high ozone passed over a short distance from the south of Houston, picking up emissions from the industries along the coast.
Estimation of the Upper-Layer Rotation and Maximum Wind Speed of Tropical Cyclones via Satellite Imagery
Authors: Chao Chun-Chieh , Liu Gin-Rong , Liu Chung-Chih
Published: November 2010

The movement of convective rainbands embedded in a tropical cyclone (TC) is usually derived from satellite images via the atmospheric motion vector (AMV) method or through the calculation of a radar’s echo track. In estimating the rotation speed of a TC rainband, however, the land-based radar can only detect approaching tropical cyclones within the vicinity. The AMV method is unable to fully account for the TC eyewall movement, thus making it difficult to estimate the TC intensity. The widely used method in estimating the TC maximum wind speed is the Dvorak technique in which the cloud pattern is extracted from only one image. In this study, the rainband rotation speeds are computed via satellite imagery and further applied in estimating the TC maximum wind speed. In contrast to previous research, this study adopts an innovative method by using two subsequent geostationary satellite images. The TC spin rates observed by weather satellites could often be seen to be positively related to the TC intensity. Analyses of the relationship between the typhoon wind intensity and estimated rotation speed at the 130–260-km ring via infrared channels are conducted for major typhoon cases that occurred during 2000–05 in the northwestern Pacific Ocean. Results show that the correlation between the wind intensity and estimated rotation speeds is strong for most of the cases. The highest R2 value from the individual cases could reach 0.93, and on an annual basis it could attain a value of 0.67. The mean R2 value for the 2000–05 dataset was roughly 0.53. The correlation between the wind intensity and estimated rotation speeds is further improved by factoring in the previous 6-h average rotation speeds. A regression equation is derived from the chosen typhoon cases between 2000 and 2005, which is utilized in verifying the major typhoon occurrences during 2006–08. The mean absolute error (MAE) of the hourly and 6-h average intensity estimates during 2000–08 was 20 and 18.7 kt, respectively (1 kt ≃ 0.5 m s−1). The best verification result occurred during 2008, for which the R2 value and MAE could reach 0.7 and 15.6, respectively. These research results demonstrate the suitability of using geostationary satellite image data in estimating the maximum wind speed. Nevertheless, the drawback of this study is that sometimes the rotation speeds will become slower when tropical cyclones mature because of the strong outflow of the secondary circulation. It is assumed that the relationship between the estimated rotation speeds and wind intensity can be further improved if the outflow speed of the tropical cyclones is also considered.
The Resonant Interaction of a Tropical Cyclone and a Tropopause Front in a Barotropic Model. Part II: Frontal Waves
Authors: Scheck Leonhard , Jones Sarah C. , Juckes Martin
Published: November 2010

The influence of frontal waves on the interaction of a tropical cyclone and a tropopause front is investigated in an idealized framework. In a nondivergent barotropic model the front is represented by a vorticity step with a superimposed sinusoidal perturbation. This gives rise to a jet that meanders to the north and south and can be viewed as a sequence of upper-level troughs and ridges. The model evolution depends sensitively on the position of the cyclone relative to the troughs and ridges. Here a bifurcation point is identified that is located on the trough axis at a distance where the zonal speed of the background flow equals the phase speed of the wave. Arbitrarily small displacements from this position determine whether a cyclone is advected toward the front or repelled. Only a limited range of wavelengths can lead to track bifurcations. The largest effects are obtained for resonant frontal waves propagating with a phase speed matching the initial zonal translation speed of the cyclone. Weak and large-scale vortices can be disrupted when approaching the bifurcation point, where they are exposed to continuously strong shear deformation.