bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection and HER2 Expression of Circulating Tumor Cells: Prospective Monitoring in Breast Cancer Patients Treated in the Neoadjuvant GeparQuattro Trial
Authors: Riethdorf Sabine , Müller Volkmar , Zhang Liling , Rau Thomas , Loibl Sibylle , Komor Martina , Roller Marc , Huober Jens , Fehm Tanja , Schrader Iris , Hilfrich Jörn , Holms Frank , Tesch Hans , Eidtmann Holger , Untch Michael , von Minckwitz Gunter , Pantel Klaus
Published: April 2010

Purpose: This study was aimed at detecting and characterizing circulating tumor cells (CTC) before and after neoadjuvant therapy (NT) in the peripheral blood of patients with breast cancer.

Experimental Design: The clinical trial GeparQuattro incorporated NT approaches (epirubicin/cyclophosphamide prior to randomization to docetaxel alone, docetaxel in combination with capecitabine, or docetaxel followed by capecitabine) and additional trastuzumab treatment for patients with HER2-positive tumors. We used the Food and Drug Administration–approved CellSearch system for CTC detection and evaluation of HER2 expression and developed HER2 immunoscoring for CTC.

Results: We detected ≥1 CTC/7.5 mL in 46 of 213 patients (21.6%) before NT and in 22 of 207 patients (10.6%) after NT (P = 0.002). Twenty (15.0%) initially CTC-positive cases were CTC-negative after NT, whereas 11 (8.3%) cases were CTC-positive after NT, although no CTC could be found before NT. CTC detection did not correlate with primary tumor characteristics. Furthermore, there was no association between tumor response to NT and CTC detection. HER2-overexpressing CTC were observed in 14 of 58 CTC-positive patients (24.1%), including 8 patients with HER2-negative primary tumors and 3 patients after trastuzumab treatment. CTC scored HER2-negative or weakly HER2-positive before or after NT were present in 11 of 21 patients with HER2-positive primary tumors. HER2 overexpression on CTC was restricted to ductal carcinomas and associated with high tumor stage (P = 0.002).

Conclusion: CTC number was low in patients with primary breast cancer. The decrease in CTC incidence during treatment was not correlated with standard clinical characteristics and primary tumor response. Information on the HER2 status of CTC might be helpful for stratification and monitoring of HER2-directed therapies. Clin Cancer Res; 16(9); 2634–45. ©2010 AACR.
TRAIL and Doxorubicin Combination Induces Proapoptotic and Antiangiogenic Effects in Soft Tissue Sarcoma In vivo
Authors: Wang Suizhao , Ren Wenhong , Liu Jeffery , Lahat Guy , Torres Keila , Lopez Gonzalo , Lazar Alexander J. , Hayes-Jordan Andrea , Liu Kebin , Bankson Jim , Hazle John D. , Lev Dina
Published: April 2010

Purpose: Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xenografts in vivo.

Experimental Design: TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes.

Results: TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro.

Conclusions: Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted. Clin Cancer Res; 16(9); 2591–604. ©2010 AACR.
Chromosomal and MicroRNA Expression Patterns Reveal Biologically Distinct Subgroups of 11q− Neuroblastoma
Authors: Buckley Patrick G. , Alcock Leah , Bryan Kenneth , Bray Isabella , Schulte Johannes H. , Schramm Alexander , Eggert Angelika , Mestdagh Pieter , De Preter Katleen , Vandesompele Jo , Speleman Frank , Stallings Raymond L.
Published: April 2010

Purpose: The purpose of this study was to further define the biology of the 11q− neuroblastoma tumor subgroup by the integration of array-based comparative genomic hybridization with microRNA (miRNA) expression profiling data to determine if improved patient stratification is possible.

Experimental Design: A set of primary neuroblastoma (n = 160), which was broadly representative of all genetic subtypes, was analyzed by array-based comparative genomic hybridization and for the expression of 430 miRNAs. A 15-miRNA expression signature previously shown to be predictive of clinical outcome was used to analyze an independent cohort of 11q− tumors (n = 37).

Results: Loss of 4p and gain of 7q occurred at a significantly higher frequency in the 11q− tumors, further defining the genetic characteristics of this subtype. The 11q− tumors could be split into two subgroups using a miRNA expression survival signature that differed significantly in clinical outcome and the overall frequency of large-scale genomic imbalances, with the poor survival subgroup having significantly more imbalances. miRNAs from the expression signature, which were upregulated in unfavorable tumors, were predicted to target downregulated genes from a published mRNA expression classifier of clinical outcome at a higher-than-expected frequency, indicating the miRNAs might contribute to the regulation of genes within the signature.

Conclusion: We show that two distinct biological subtypes of neuroblastoma with loss of 11q occur, which differ in their miRNA expression profiles, frequency of segmental imbalances, and clinical outcome. A miRNA expression signature, combined with an analysis of segmental imbalances, provides greater prediction of event-free survival and overall survival outcomes than 11q status by itself, improving patient stratification. Clin Cancer Res; 16(11); 2971–8. ©2010 AACR.
The Histone Deacetylase Inhibitor MGCD0103 Induces Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells through a Mitochondria-Mediated Caspase Activation Cascade
Authors: El-Khoury Victoria , Moussay Etienne , Janji Bassam , Palissot Valérie , Aouali Nasséra , Brons Nicolaas H.C. , Van Moer Kris , Pierson Sandrine , Van Dyck Eric , Berchem Guy
Published: April 2010

Clinical trials have shown activity of the isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in different hematologic malignancies. There are data to support the use of HDAC inhibitors in association with other cancer therapies. To propose a rational combination therapy, it is necessary to depict the molecular basis behind the cytotoxic effect of MGCD0103. In this study, we found that MGCD0103 was substantially more toxic in neoplastic B cells relative to normal cells, and we described the death pathways activated by MGCD0103 in B-cell chronic lymphocytic leukemia (CLL) cells from 32 patients. MGCD0103 decreased the expression of Mcl-1 and induced translocation of Bax to the mitochondria, mitochondrial depolarization, and release of cytochrome c in the cytosol. Caspase processing in the presence of the caspase inhibitor Q-VD-OPh and time course experiments showed that caspase-9 was the apical caspase. Thus, MGCD0103 induced the intrinsic pathway of apoptosis in CLL cells. Moreover, MGCD0103 treatment resulted in the activation of a caspase cascade downstream of caspase-9, caspase-dependent amplification of mitochondrial depolarization, activation of calpain, and Bax cleavage. We propose a model whereby the intrinsic pathway of apoptosis triggered by MGCD0103 in CLL is associated with a mitochondrial death amplification loop. Mol Cancer Ther; 9(5); 1349–60. ©2010 AACR.
Dasatinib Is Preclinically Active against Src-Overexpressing Human Transitional Cell Carcinoma of the Urothelium with Activated Src Signaling
Authors: Levitt Jonathan M. , Yamashita Hideyuki , Jian Weiguo , Lerner Seth P. , Sonpavde Guru
Published: April 2010

Dasatinib is an orally administered multitargeted kinase inhibitor that targets Src family tyrosine kinases, Abl, c-Kit, and PDGFR. A preclinical study was conducted to evaluate dasatinib alone or combined with cisplatin for human transitional cell carcinoma (TCC). Expression of Src in a human TCC tissue microarray was evaluated by immunohistochemistry. The activity of dasatinib and/or cisplatin was evaluated in six human TCC cell lines. Western blot was done to assess Src and phosphorylated-Src (p-Src) expression. The activity of dasatinib alone and in combination with cisplatin was determined in murine subcutaneous xenografts. Sixty-two percent to 75% of human TCC expressed Src. Dasatinib displayed significant antiproliferative activity at nanomolar concentrations against two human TCC cell lines (RT4 and Hu456) that exhibited high Src and p-Src expression and were cisplatin-resistant. RT4 cells were the most sensitive and displayed the highest level of Src pathway activation (p-Src/Src ratio). Dasatinib downregulated p-Src in either sensitive or resistant cells. TCC cells that were sensitive to cisplatin (5637 and TCC-SUP) were highly resistant to dasatinib and exhibited low Src expression. Dasatinib showed antitumor activity in RT4 murine xenografts, and the combination of dasatinib and cisplatin was significantly more active than placebo. Combination dasatinib plus cisplatin significantly inhibited proliferation and promoted apoptosis in vivo. In conclusion, dasatinib displayed significant preclinical antitumor activity against Src-overexpressing human TCC with active Src signaling and was highly active in combination with cisplatin in vivo. Further clinical development might be warranted in selected human subjects. Mol Cancer Ther; 9(5); 1128–35. ©2010 AACR.
X-Linked Inhibitor of Apoptosis Protein Inhibits Apoptosis in Inflammatory Breast Cancer Cells with Acquired Resistance to an ErbB1/2 Tyrosine Kinase Inhibitor
Authors: Aird Katherine M. , Ghanayem Rami B. , Peplinski Sharon , Lyerly Herbert K. , Devi Gayathri R.
Published: April 2010

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer that is often characterized by ErbB2 overexpression. ErbB2 targeting is clinically relevant using trastuzumab (anti-ErbB2 antibody) and lapatinib (small-molecule ErbB1/2 inhibitor). However, acquired resistance is a common outcome even in IBC patients who show an initial clinical response, which limits the efficacy of these agents. In the present study, using a clonal population of GW583340 (lapatinib analogue, ErbB1/2 inhibitor)–resistant IBC cells, we identified the overexpression of an antiapoptotic protein, X-linked inhibitor of apoptosis protein (XIAP), in acquired resistance to GW583340 in both ErbB2-overexpressing SUM190 and ErbB1-activated SUM149 cell lines derived from primary IBC tumors. A marked decrease in p-ErbB2, p-ErbB1, and downstream signaling was evident in the GW583340-resistant cells (rSUM190 and rSUM149) similar to parental counterparts treated with the drug, suggesting that the primary mechanism of action of GW583340 was not compromised in resistant cells. However, rSUM190 and rSUM149 cells growing in GW583340 had significant XIAP overexpression and resistance to GW583340-mediated apoptosis. Additionally, stable XIAP overexpression using a lentiviral system reversed sensitivity to GW583340 in parental cells. The observed overexpression was identified to be caused by IRES-mediated XIAP translation. XIAP downregulation in rSUM190 and rSUM149 cells using a small-molecule inhibitor (embelin), which abrogates the XIAP/procaspase-9 interaction, resulted in decreased viability, showing that XIAP is required for survival of cells with acquired resistance to GW583340. These studies establish the feasibility of development of an XIAP inhibitor that potentiates apoptosis for use in IBC patients with resistance to ErbB2-targeting agents. Mol Cancer Ther; 9(5); 1432–42. ©2010 AACR.
Epithelial-to-Mesenchymal Transition and Oncogenic Ras Expression in Resistance to the Protein Kinase Cβ Inhibitor Enzastaurin in Colon Cancer Cells
Authors: Serova Maria , Astorgues-Xerri Lucile , Bieche Ivan , Albert Sebastien , Vidaud Michel , Benhadji Karim A. , Emami Shahin , Vidaud Dominique , Hammel Pascal , Theou-Anton Nathalie , Gespach Christian , Faivre Sandrine , Raymond Eric
Published: April 2010

Identifying molecular factors of sensitivity and resistance of cancer cells to enzastaurin, a drug inhibiting protein kinase C (PKC) β, remains a major challenge to improve its clinical development. Investigating the cellular effects of enzastaurin in a panel of 20 human cancer cell lines, we found that most cells displaying oncogenic K-Ras mutations also display resistance to enzastaurin. Wild-type (WT) K-Ras cancer cells displaying high sensitivity to enzastaurin also expressed high mRNA levels of epithelial markers, such as E-cadherin (CDH1), and low mRNA expressions of mesenchymal markers, such as vimentin, N-cadherin (CDH2), and other genes frequently expressed in mesenchymal transition such as ZEB1, TWIST, SLUG, SNAIL, and TGFβ. WT K-Ras enzastaurin-resistant cells also expressed high levels of mesenchymal markers. Based on this observation, the effects of enzastaurin were investigated in epithelial colon COLO205-S cells that expressed WT Ras/Raf and its derived COLO205-R mesenchymal counterpart selected for resistance to most PKC modulators and displaying oncogenic K-Ras (G13D/exon 2). In COLO205-S cells, inhibition of phosphorylated PKCβ led to the inactivation of AKT and glycogen synthase kinase 3β and was associated with apoptosis without significant effect on cell cycle progression. In COLO205-R cells, enzastaurin induced mainly necrosis at high concentrations. In COLO205-R cells, a strong activation of extracellular signal-regulated kinase 1/2 possibly due to oncogenic K-Ras was predominantly associated with transcription of potent antiapoptotic genes, such as BCL2, GADD45B, and CDKN1A, as well as the multidrug resistance gene ABCB1. From this study, colon cancer cells undergoing apoptosis under enzastaurin exposure seem to frequently express a WT Ras and an epithelial phenotype. Mol Cancer Ther; 9(5); 1308–17. ©2010 AACR.
Nek6 Mediates Human Cancer Cell Transformation and Is a Potential Cancer Therapeutic Target
Authors: Nassirpour Rounak , Shao Lihua , Flanagan Peter , Abrams Tinya , Jallal Bahija , Smeal Tod , Yin Min-Jean
Published: April 2010

We investigated the role of Nek6, a member of the NIMA-related serine/threonine kinase family, in tumorigenesis. Transcript, protein, and kinase activity levels of Nek6 were highly elevated in the malignant tumors and human cancer cell lines compared with normal tissue and fibroblast cells. Expression of exogenous wild-type Nek6 increased anchorage-independent growth of a variety of human cancer cell lines, whereas overexpression of the kinase-dead Nek6 and RNAi knockdown of endogenous Nek6 suppressed cancer cell transformation and induced apoptosis. Additionally, in in vivo xenograft nude mouse model, knockdown of Nek6 in HeLa cells resulted in reduction of tumor size relative to control siRNA tumors. Most importantly, knocking down endogenous Nek6 levels or exogenous expression of the kinase-dead form did not inhibit cell proliferation, nor did it induce apoptosis in normal fibroblast cells. Taken together, our data indicate a pivotal role for Nek6 in tumorigenesis and establish Nek6 as a potential target for treatment of a variety of human cancers. Mol Cancer Res; 8(5); 717–28. ©2010 AACR.
Targeted Knockdown of SEPT9_v1 Inhibits Tumor Growth and Angiogenesis of Human Prostate Cancer Cells Concomitant with Disruption of Hypoxia-Inducible Factor-1 Pathway
Authors: Amir Sharon , Golan Maya , Mabjeesh Nicola J.
Published: April 2010

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor in the hypoxic response pathway. We recently identified a novel interaction between HIF-1α and the mammalian septin family member, septin 9 protein, isoform 1 (SEPT9_i1), a protein product of septin 9 transcript variant 1 (SEPT9_v1). Septins are a highly conserved family of GTP-binding cytoskeletal proteins that are implicated in multiple cellular functions, including oncogenesis. SEPT9_i1 binds and stabilizes HIF-1α protein and stimulates HIF-1 transcriptional activity by preventing its RACK1-mediated ubiquitination and degradation. SEPT9_i1–HIF-1 activation promotes tumor growth and angiogenesis. The effect of SEPT9_v1 silencing in prostate cancer cells was studied. SEPT9_v1 stable knockdown was generated in PC-3 cells using a specific shRNA. SEPT9_v1 silencing reduced HIF-1α protein expression and inhibited HIF-1 transcriptional activity. SEPT9_v1 knockdown affected cell morphology, deregulated cell cycle, and decreased migration. The antiproliferative effect of shSEPT9_v1 was abolished in HIF-1α knockout colon cancer cells. In vivo, SEPT9_i1 depletion reduced HIF-1α protein expression, cellular proliferation, tumor growth, and angiogenesis. These results provide new insights and validation for applying SEPT9_v1 as a potential target for antitumor therapy by interrupting the HIF-1 pathway. Mol Cancer Res; 8(5); 643–52. ©2010 AACR.
Sedation Practices for Gastrointestinal Endoscopy in Europe, North America, Asia, Africa and Australia
Authors: Ladas Spiros D. , Satake Yoshiharu , Mostafa Ibrahim , Morse John
Published: April 2010

Gastroscopy and colonoscopy are standard practice for diagnosing upper gastrointestinal and colonic diseases. Sedation improves tolerance of the endoscopic procedures, but may be responsible for about 50% of the complication rate of the examination. Data from countries of the five continents regarding the rate of using sedation for gastrointestinal endoscopy are rare. We performed a literature search (PubMed) to identify published national or international studies and summarize data on the rate of using sedation for diagnostic gastrointestinal endoscopic procedures in countries of Europe, North America, Asia, Africa and Australia. In continents where data were not available, we used mailed questionnaires to endoscopy centers in countries of these continents. Our data indicate that the use of sedation for diagnostic gastrointestinal endoscopy is high in North America and Australia, but varies considerably among countries in Europe, Asia and Africa.
Throat Spray, Sedation or Anaesthetic?
Authors: Axon Anthony T.R.
Published: April 2010

Digestive endoscopy covers a wide variety of procedures; the need for sedation is governed by the invasiveness and length of the procedure, the wishes of the patient, the desire of the operator for a compliant patient, and safety. Many patients are prepared to undergo upper digestive endoscopy using throat spray without sedation, while fewer accept unsedated colonoscopy. There are clinical advantages as well as disadvantages in employing sedation and sometimes general anaesthesia is the preferred option. This paper provides an introduction to the choices available and the approaches that are employed in endoscopic sedation practice.
Level of Intended Sedation
Authors: Paspatis G.A. , Tribonias G. , Paraskeva K.
Published: April 2010

Sedation and analgesia is the standard of care during diagnostic and therapeutic endoscopic gastrointestinal procedures in most areas of the world. Unsedated endoscopy is feasible in selected patients, but requires commitment on the part of both the patient and the provider. The American Society of Anesthesiologists has defined four stages of sedation, ranging from minimal to moderate, deep and general anesthesia. The level of sedation as well as the choice of sedative is based on the type of procedure, patient characteristics and the existence of the required structural conditions. Individuals administering sedation/analgesia should be trained to rescue a patient who has reached a level of sedation deeper than that intended.
Extended Monitoring of the Sedated Patient: Bispectral Index, Narcotrend® and Automated Responsiveness Monitor
Authors: Wehrmann Till
Published: April 2010

It has been demonstrated that a processed EEG derivative may reflect the patient’s level of consciousness during endoscopic sedation. However, to date a clinical benefit of EEG monitoring with respect to relevant safety parameters in routine gastrointestinal endoscopy has not been demonstrated. During long-lasting procedures (e.g. ERCP, ESD) a propofol-sparing effect has been shown, but a benefit regarding patient safety could not be documented. The use of an automated responsiveness monitor may help to achieve and to maintain the level of conscious sedation with propofol, but its precise role in endoscopic sedation is undefined.
Ability to Reverse Deeper Levels of Unintended Sedation
Authors: Morse John , Bamias Giorgos
Published: April 2010

During gastrointestinal endoscopy, patients may reach a level of sedation that is deeper (i.e. deep sedation) than intended to be (i.e. moderate sedation). In such cases the ability to restore respiratory and cardiovascular function is critical. Supportive measures should be combined with administration of specific pharmacologic antagonists in cases of imminent ventilatory failure. Naloxone rapidly reverses sedation and respiratory depression due to previously administered narcotics, whereas flumazenil overturns the effects of midazolam on the central nervous system. Both agents are administered intravenously in repeated doses according to the patient’s response. Caution, however, is required, as the half-lives of these reversal agents are shorter than those of the respective agonists and re-sedation may occur. Acute withdrawal syndromes may take place in chronic users of opiates or benzodiazepine. Product monographs along with administration protocols may be demonstrated as a wall chart, to ascertain their safe and effective use in endoscopy units.
Emergencies and Treatment of Complications
Authors: Fassoulaki Argyro , Staikou Chryssoula , Tsaroucha Athanassia
Published: April 2010

Sedation for gastrointestinal endoscopy may induce central respiratory depression and/or airway obstruction. Early diagnosis and treatment of these complications is mandatory as the resulting hypoxia may cause irreversible damage, particularly to vital organs, or death. Sedatives and centrally acting analgesics depress respiration in a dose-dependent manner. However, significant untoward events are preventable by titrating the doses for sedation and by monitoring patient oxygenation and respiration. Cardiovascular adverse events may also occur during gastrointestinal endoscopy, and can be major or minor. Hypotension needs treatment as well as severe hypertension. Cardiac dysrhythmias may occur due to stress, pain and/or hypercarbia, which may accompany endoscopies. The anesthesia provider must be able to diagnose, assess the risk and treat all the adverse events during gastrointestinal endoscopy. The resuscitation equipment, including the defibrillator, must be readily accessible.
Sedation in Gastrointestinal Endoscopy: An Anesthesiologist’s Perspective
Authors: Van der Linden Philippe
Published: April 2010

Sedation is required to treat an ever increasing number of patients for medical diagnostic or therapeutic procedures, in particular in gastrointestinal endoscopy. Due to the apparent ease of administration of sedative techniques, and due to the shortage of anesthetic staff in many Western countries, sedation is being carried out more and more frequently by non-anesthesiologist doctors or even paramedical staff. Due to its pharmacokinetic properties, propofol has become the preferred sedative drug used by non-anesthesiologists. However, uncritical use of propofol by nonqualified persons might result in much higher complications rates and even fatal events. Several guidelines have been published with common issues, but also some significant differences. Whether they contribute to improved patient safety or not will depend on the practical application and interpretation of these guidelines. Although further evaluation is needed, computer-assisted systems might contribute to the safe administration of propofol through a better control of the level of sedation.
Propofol Sedation in Gastrointestinal Endoscopy: A Gastroenterologist’s Perspective
Authors: Wehrmann Till , Triantafyllou Konstantinos
Published: April 2010

The present article describes the recommendations regarding the use of propofol by non-anesthesiologists from published guidelines. Furthermore, safety and efficacy data regarding the use of propofol in the hands of gastroenterologists are also reviewed. Although there are no studies comparing the safety and efficacy of propofol administration by anesthesiologists versus non-anesthesiologists for sedation during endoscopy, there is strong evidence that propofol administration by non-anesthesiologists is safe and efficacious for the majority of patients undergoing routine endoscopic procedures.
Computer-Assisted Propofol Administration
Authors: O’Connor J.P.A. , O’Moráin C.A. , Vargo J.J.
Published: April 2010

The use of propofol for sedation in endoscopy may allow for better quality of sedation, quicker recovery and facilitate greater throughput in endoscopy units. The cost-effectiveness and utility of propofol sedation for endoscopic procedures is contingent on the personnel and resources required to carry out the procedure. Computer-based platforms are based on the patients response to stimulation and physiologic parameters. They offer an appealing means of delivering safe and effective doses of propofol. One such means is the bispectral index where continuous EEG recordings are used to assess the degree of sedation. Another is the closed-loop target-controlled system where a set of physical parameters, such as muscle relaxation and auditory-evoked potential, determine a level of medication appropriate to achieve sedation. Patient-controlled platforms may also be used. These electronic adjuncts may help endoscopists who wish to adopt propofol sedation to change current practices with greater confidence.
Sedation by Non-Anesthesiologists: Are Opioids and Benzodiazepines Outdated?
Authors: Dinis-Ribeiro M. , Vargo J.J.
Published: April 2010

At least 3 systematic reviews have assessed the safety of propofol versus traditional agents used for sedation in gastrointestinal endoscopic procedures. These reviews uncovered a marked variability in study design and found the quality of the included randomized controlled trials to be poor. To date there is no demonstrated difference in the endoscopic safety or efficacy of propofol sedation compared to sedation with benzodiazepine with or without an opioid. However, a trend towards reduced complications and higher levels of satisfaction and cost-effectiveness with propofol during colonoscopies, and higher levels of patient satisfaction and improved efficacy may also be expected by using propofol during upper gastrointestinal endoscopies.
Nuevas infecciones emergentes: importancia en la salud de los niños
Authors: van Seventer Jean M. , DeLoureiro Amanda , Hamer Davidson H.
Published: April 2010

Una interacción compleja entre factores ambientales y humanos, incluyendo factores ecológicos, genéticos, políticos y socioeconómicos, es responsable de la emergencia y la resurgencia de enfermedades infecciosas. Estos factores poseen a menudo un efecto claro sobre los niños y, en consecuencia, las infecciones emergentes pueden ejercer impactos únicos sobre las poblaciones más jóvenes en términos de salud física y mental, así como de bienestar social. Los niños son los miembros más vulnerables de nuestra sociedad. Con el objeto de protegerles mejor frente al impacto de las enfermedades infecciosas emergentes, es imperativo comprender cómo factores que determinan la emergencia de enfermedades y las enfermedades emergentes de por sí pueden afectar al niño. Esto nos permitirá centrarnos en las medidas más apropiadas para no sólo prevenir la infección de poblaciones pediátricas sino también prepararnos para el tratamiento y el cuidado de los niños cuando emerge una enfermedad infecciosa. La gripe es un prototipo de enfermedad infecciosa emergente/resurgente. La gripe epidémica emerge de nuevo cada año en periodos entre las pandemias gripales. Tanto la gripe epidémica como la gripe pandémica pueden ejercer impactos considerables sobre el bienestar de los niños. Durante más de una década hemos previsto la mutación de la gripe aviaria (H5N1) en un virus que puede ser transmitido eficientemente entre humanos. Esto ha dado lugar a esfuerzos considerables para prepararnos frente a una pandemia gripal virulenta. Aunque el potencial pandémico de la gripe aviaria no ha sido tomado (todavía) en consideración, los esfuerzos realizados para prepararnos frente a una pandemia generalizada no han sido en vano. La emergencia imprevista y la rápida propagación de la gripe porcina [gripe A(H1N1)] han dado lugar a una pandemia mundial que ha producido ya efectos considerables sobre niños y adultos. Las escuelas, los hospitales de día, el transporte moderno y los viajes internacionales han facilitado la propagación de esta nueva cepa gripal. La gripe porcina ejemplifica perfectamente cómo interactúan factores ambientales y humanos para dar lugar a la emergencia de una enfermedad infecciosa con impactos únicos sobre los niños.
Las infecciones emergentes transmitidas por garrapatas
Authors: Mutz Ingomar
Published: April 2010

Las infecciones transmitidas por garrapatas aparecen por todo el mundo y son bien conocidas desde hace más de 100 años. Algunas enfermedades transmitidas por garrapatas son muy comunes mientras que otras son extremadamente raras. Las técnicas genéticas moleculares modernas (y la mayor disponibilidad de la reacción en cadena de la polimerasa) han llevado al descubrimiento y la clasificación de nuevos agentes patógenos, especialmente del orden de los Rickettsiales. En esta revisión se abordan los agentes víricos, bacterianos y protozoarios que pueden causar enfermedades humanas. La mayoría de las picaduras de garrapatas y, en consecuencia, las enfermedades transmitidas por garrapatas, aparecen durante el periodo más cálido del año. Con respecto a los reservorios naturales, existe una fuerte variación geográfica entre diferentes enfermedades transmitidas por garrapatas. La historia de una picadura de garrapata no siempre es confiable, debido a que dicha picadura puede pasar inadvertida. Las enfermedades más corrientes son la borreliosis de Lyme y la encefalitis transmitida por garrapatas, causada por un falvivirus. Lo más frecuente es que las infecciones víricas presenten signos neurológicos de encefalitis, mientras que las infecciones rickettsiales se caracterizan por fiebre (bifásica), síntomas sistémicos de infección y, a menudo, erupción con petequias. Algunas de las enfermedades transmitidas por garrapatas son evitables por inmunización, como la encefalitis transmitida por garrapatas. Las infecciones cuyo origen no es vírico deben ser tratadas precozmente con antibióticos, predominantemente después de la sospecha clínica, con objeto de obtener un resultado satisfactorio. Bien sea debido a la virulencia del patógeno, la falta de utilización de medidas preventivas o a causa del retraso en el diagnóstico y el tratamiento, las tasas de mortalidad pueden variar; sin embargo, las infecciones transmitidas por garrapatas todavía siguen costando vidas.
Infecciones fúngicas emergentes
Authors: Garnica Marcia , Nucci Marcio
Published: April 2010

La epidemiología de las infecciones fúngicas invasivas se encuentra en una fase evolutiva. Han aparecido levaduras distintas de Candida albicans y mohos distintos de Aspergillus fumigatus como causas significativas de micosis invasivas en pacientes gravemente inmunodeprimidos. Mientras que en algunos casos estos cambios pueden estar relacionados con intervenciones médicas, como el uso de agentes antifúngicos profilácticos, en la mayoría de los casos parecen constituir una consecuencia de variaciones en el hospedador. La inmunosupresión más grave o diferentes tipos de inmunosupresión impactan tanto sobre el riesgo como sobre las infecciones que aparecen. Estos factores han alterado la epidemiología de la infección en receptores de trasplantes de órganos, recién nacidos prematuros y pacientes gravemente enfermos. En nuestra revisión se comenta la epidemiología de algunas infecciones fúngicas que han aparecido en los años más recientes, destacando los factores potenciales asociados a su emergencia y las implicaciones prácticas de estos cambios epidemiológicos. Además, se abordan por separado algunas características especiales registradas en niños y en recién nacidos.
Oxidative Stress among Non-Anemic Adults following Flour Fortification with Iron: Baseline Data
Authors: Pouraram Hamed , Elmadfa Ibrahim , Siassi Fereidon , Dorosty Motlagh Ahmadreza , Heshmat Ramin , Abtahi Mitra
Published: April 2010

Background: It has been suggested that food fortification might be an inexpensive, simple and effective way to control and prevent iron deficiency and its related anemia in many countries. Despite the advantages of this approach and the fact that it has been implemented in some provinces in Iran for more than 6 years, many scientists in the country worry about the negative aspects of the extra iron distributed among non-anemic persons in the community. Objective: This study was designed to assess the effect of the flour fortification program on oxidative stress biomarkers and iron status among non-anemic 40- to 65-year-old adults. Study Design: This study had a special design that was implemented in 3 different parts. The main and first part was a field study. We randomized 2 cities in 1 province. In each city, 200 volunteers (100 men and 100 women) were selected using a multi-stage stratified method. Examination and interview (filling out data collection forms) were the methods of data gathering. In each of the 3 phases, demographic, anthropometric, blood pressure, micro- and macronutrient intakes, physical activities, and some oxidative stress biomarkers were the main data that were gathered. The results of this study can help health policy makers in designing future interventions in the country based on food fortification.
Vascular Calcification in Animal Models of CKD: A Review
Authors: Shobeiri Navid , Adams Michael A. , Holden Rachel M.
Published: April 2010

Vascular calcification is a significant contributor to the cardiovascular mortality observed in chronic kidney disease (CKD). This review discusses the animal models (5/6 nephrectomy, mouse electrocautery model and dietary adenine) that have been employed in the study of vascular calcification outcomes in CKD. Rodent models of CKD generate a range of severity in the vascular calcification phenotype. Major limitations of the 5/6th nephrectomy model include the requirement for surgery and the need to use either excessive dietary phosphorus or vitamin D. Major limitations of the mouse electrocautery model include the requirement for surgery, the mortality rate when very advanced CKD develops, and resistance to vascular calcification without the use of transgenic animals. This is balanced against the major advantage of the ability to study transgenic animals to further understand the mechanisms associated with either the acceleration or inhibition of calcification. Dietary adenine generates severe CKD and does not require surgery. The major disadvantage is the weight loss that ensues when rats receive a diet containing 0.75% adenine. In summary, animal models are useful to study CKD-associated vascular calcification and the results obtained in these pre-clinical animal studies appear to translate to the evidence, however limited, which exists in humans with CKD.
Macrophage Activation Syndrome in Autoimmune Disease
Authors: Deane Sean , Selmi Carlo , Teuber Suzanne S. , Gershwin M. Eric
Published: April 2010

Macrophage activation syndrome (MAS) is a phenomenon characterized by cytopenia, organ dysfunction, and coagulopathy associated with an inappropriate activation of macrophages. Current diagnostic criteria are imprecise, but the syndrome is now recognized as a form of hemophagocytic lymphohistiocytosis that is characteristically associated with autoimmune diatheses. The diagnosis of incipient MAS in patients with autoimmune disease requires a high index of suspicion, as several characteristics of the disorder may be present in the underlying condition or infectious complications associated with the treatment thereof. Proposed treatment regimens include aggressive approaches that require validation in future controlled studies. This review discusses the major aspects of the pathophysiology, diagnosis, and management of MAS with a focus on the association with autoimmune disease.
Identification of an IgE-Binding Epitope of a Major Buckwheat Allergen, BWp16, by SPOTs Assay and Mimotope Screening
Authors: Satoh Rie , Koyano Satoru , Takagi Kayoko , Nakamura Rika , Teshima Reiko
Published: April 2010

Background: The buckwheat 16-kDa protein (BWp16), as reported in our previous study, is a major allergen in buckwheat; however, the IgE-binding epitopes of BWp16 have not as yet been identified. Methods: We screened candidates for IgE-binding epitopes on BWp16 by using arrays of overlapping peptides synthesized on activated cellulose membranes (SPOTs membrane). The mimotope method was also used to analyze IgE-binding epitopes of BWp16. Nine single alanine (Ala) mutants of BWp16 expressed in Escherichia coli were used to confirm the epitopes of BWp16. The IgE-binding activity of single Ala mutants of BWp16 was determined by ELISA with mouse anti-BWp16 polyclonal antiserum or ELISA inhibition with sera from buckwheat allergic patients. Results: The SPOTs assay identified amino acid residues 99–110, i.e. EGVRDLKELPSK, as a candidate for the linear IgE-binding epitope of BWp16. The mimotope method indicated that peptides similar to EGVRDLKE were candidate sequences for epitopes of BWp16. Ala scanning of rBWp16 revealed that all EGVRDLKE peptides containing a single amino acid mutation had weaker IgE-binding activity than rBWp16 WT. An ELISA inhibition assay for rBWp16 WT revealed the inhibitory effect of rBWp16 D103A to be less than that of rBWp16 WT. Conclusions: We identified the peptide EGVRDLKE as a very likely candidate for the IgE-binding epitope of BWp16, and Asp103 as the critical amino acid in BWp16. This is the first report on the identification of IgE-binding epitopes of BWp16. Our findings will contribute to the production of BWp16 hypoallergens, and to allergen-specific immunotherapy for buckwheat allergy.
Recombinant Fusion Proteins Assembling Der p 1 and Der p 2 Allergens from Dermatophagoides pteronyssinus
Authors: Bussières Laetitia , Bordas-Le Floch Véronique , Bulder Ingrid , Chabre Henri , Nony Emmanuel , Lautrette Aurélie , Berrouet Christelle , Nguefeu Yvette , Horiot Stéphane , Baron-Bodo Véronique , Van Overtvelt Laurence , De Conti Anne Marie , Schlegel Anne , Maguet Nicolas , Mouz Nicolas , Lemoine Pierrick , Batard Thierry , Moingeon Philippe
Published: April 2010

Background: Fusion proteins assembling multiple allergens can be engineered by recombinant DNA technologies in order to produce tools for diagnostic and immunotherapeutic purposes. Herein, we developed and characterized chimeras assembling Der p 1 and Der p 2 allergens as potential candidate vaccines against house dust mite allergy. Methods: Fusion proteins encompassing Der p 2 with either mature or proDer p 1 were expressed in Escherichia coli or Pichia pastoris. Forms with mutation in Der p 1 catalytic site were also engineered. Purified chimeras were characterized by immunoblotting, circular dichroism, disulfide bond mapping, basophil and T lymphocyte stimulation assays. Results: Four fusion proteins were expressed in E. coli as inclusion bodies, whereas only chimeras comprising proDer p 1 were obtained in yeast. All such hybrids formed polymers and aggregates, and yeast-expressed chimeras were unstable. Circular dichroism analysis performed after refolding of bacteria expressed chimeras encompassing mature Der p 1 confirmed partial folding, consistent with the occurrence of both correct and inappropriate intramolecular disulfide bonds. All fusion molecules were recognized by Der p 1- and Der p 2-specific human IgEs, monoclonal and polyclonal antibodies. Fusion proteins activate basophils from mite-allergic patients and trigger the proliferation of specific CD4+ T cells, albeit to a lower level when compared to individual allergens. Conclusions: Production of multiple Der p 1-Der p 2 fusion proteins exhibiting partial folding and proper antigenic properties has been achieved. Nonetheless, significant solubility and stability issues currently limit the application of such chimeras for immunotherapy or diagnostic.
Measures of Effect in Epidemiological Research
Authors: Tripepi Giovanni , Jager Kitty J. , Dekker Friedo W. , Zoccali Carmine
Published: April 2010

The study of the relationship between risk factors and outcomes is important both in etiological and prognostic research. To assess the strength of a given risk factor-outcome relationship we use measures that are calculated in relative and absolute terms. Risk ratio, incidence rate ratio and odds ratio are relative measures of this relationship. Risk difference (or attributable risk) and rate difference (or attributable rate) are absolute measures of the same relationship. Risk difference and rate difference are calculated by subtracting the risk and the incidence rate in exposed individuals from that in unexposed individuals, respectively. The choice of these measures depends on the study aim. Relative measures are commonly used in etiological studies while absolute measures are mainly used in public health research.
Selection Bias and Information Bias in Clinical Research
Authors: Tripepi Giovanni , Jager Kitty J. , Dekker Friedo W. , Zoccali Carmine
Published: April 2010

The internal validity of an epidemiological study can be affected by random error and systematic error. Random error reflects a problem of precision in assessing a given exposure-disease relationship and can be reduced by increasing the sample size. On the other hand, systematic error or bias reflects a problem of validity of the study and arises because of any error resulting from methods used by the investigator when recruiting individuals for the study, from factors affecting the study participation (selection bias) or from systematic distortions when collecting information about exposures and outcomes (information bias). Another important factor which may affect the internal validity of a clinical study is confounding. In this article, we focus on two categories of bias: selection bias and information bias. Confounding will be described in a future article of this series.
Albuminuria among Alaska Natives – Findings from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study
Authors: Jolly Stacey E. , Noonan Carolyn J. , Roubideaux Yvette D. , Goldberg Jack H. , Ebbesson Sven O.E. , Umans Jason G. , Howard Barbara V.
Published: April 2010

Background: The prevalence and associated risk factors for albuminuria and low-grade albuminuria in Alaska Natives is not known. Methods: Cross-sectional analysis of the Genetics of Coronary Artery Disease in Alaska Natives Study. We included 1,026 individuals, who represent 85% of the study participants for whom complete data were available. Risk factors examined were age, sex, education, diabetes, hypertension, obesity, lipids, C-reactive protein, angiotensin-converting enzyme inhibitor use, and smoking status. Urine albumin excretion was estimated by the albumin/creatinine ratio measured from a single random morning urine sample. Albuminuria was defined as an albumin/creatinine ratio of ≧30 mg/g. Low-grade albuminuria was defined as an albumin/creatinine ratio of 10 to <30 mg/g. Results: The mean age was 42 years and over half were female. Diabetes prevalence was low at 3% and the prevalence of hypertension was 20%. The prevalence of albuminuria was 6%; the prevalence of low-grade albuminuria was 12%. Individuals with diabetes or hypertension were 3 times more likely to have albuminuria than those without these conditions [odd ratios: diabetes 3.0 (1.2–7.9) and hypertension 3.0 (1.2–7.3)]. Conclusions: The burden of albuminuria is low. Comprehensive programs and policies are important given the rise in diabetes and hypertension among Alaska Natives.
High Ferritin, but Not Hepcidin, Is Associated with a Poor Immune Response to an Influenza Vaccine in Hemodialysis Patients
Authors: Eiselt Jaromír , Kielberger Lukáš , Sedláčková Terezie , Racek Jaroslav , Pazdiora Petr
Published: April 2010

Background: The immune response to vaccination in hemodialysis (HD) patients can be influenced by disorders of iron metabolism, iron overload or chronic inflammatory state. Elevated levels of hepcidin are considered a new marker of iron metabolism impairment and anemia of inflammation in HD patients. Methods: We studied the effects of hepcidin, other markers of iron status and intravenous iron (Feiv) on the response to an influenza vaccine (Influvac® subunit 2008/2009) in 40 HD patients. The immune response of HD patients was compared with that of 46 controls without renal disease according to serum antihemagglutinin antibody titer (anti-HA). Results: A total of 31 HD patients (responders) attained seroconversion (at least a 4-fold increase in anti-HA) to at least 1 of 3 vaccine strains; 9 patients (nonresponders) did not respond to any strain. Responders did not differ from nonresponders in hepcidin [99 µg/l (36–200) vs. 97 µg/l (23–216), p = 0.97]. Responders had lower ferritin (571 ± 291 vs. 821 ± 309 µg/l, p = 0.031) and were administered higher doses of Feiv within the last 12 weeks prior to vaccination [625 mg (312–625) vs. 312 mg (0–625), p = 0.029]. The seroconversion to A(H1N1), A(H3N2) and B strains was noted in 20, 52 and 40% of HD and in 11, 39 and 48% of controls, respectively (HD vs. controls, p = nonsignificant). The rates of seroprotection (anti-HA ≧40) to vaccine strains in HD (27, 85 and 95%) and controls (24, 96 and 98%) were also comparable. Conclusion: Antibody production following influenza vaccination in HD patients may be suppressed by very high ferritin levels. Hepcidin does not correlate with immune response and high levels of hepcidin may reflect its retention in HD patients. Feiv administration was not associated with a poorer immune response. The immunogenicity of the A(H1N1) strain was inadequate in HD patients and controls alike.