bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations
Authors: Bavi Prashant , Prabhakaran Sarita E , Abubaker Jehad , Qadri Zeeshan , George Thara , Al-Sanea Nasser , Abduljabbar Alaa , Ashari Luai H , Alhomoud Samar , Al-Dayel Fouad , Hussain Azhar R , Uddin Shahab , Al-Kuraya Khawla S
Published: August 2010

Background

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4) and TRAIL receptor 2 (DR5). Expression of TRAIL receptors is higher in colorectal carcinoma (CRC) as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells.

Methods

We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival.

Results

CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251) and a histology subtype of adenocarcinomas (p = 0.0355). Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p < 0.0001), histology subtype of adenocarcinomas (p = 0.0010) and tumors in left colon (p = 0.0009). Over expression of pro apoptotic markers: p27KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011). Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L) phenotype (p = 0.0003) and with absence of KRAS mutations (p = 0.0481).

Conclusion

TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.
XIAP gene expression and function is regulated by autocrine and paracrine TGF-β signaling
Authors: Van Themsche Céline , Chaudhry Parvesh , Leblanc Valérie , Parent Sophie , Asselin Eric
Published: August 2010

Background

X-linked inhibitor of apoptosis protein (XIAP) is often overexpressed in cancer cells, where it plays a key role in survival and also promotes invasiveness. To date however, the extracellular signals and intracellular pathways regulating its expression and activity remain incompletely understood. We have previously showed that exposure to each of the three TGF-β (transforming growth factor beta) isoforms upregulates XIAP protein content in endometrial carcinoma cells in vitro. In the present study, we have investigated the clinical relevance of TGF-β isoforms in endometrial tumours and the mechanisms through which TGF-β isoforms regulate XIAP content in uterine cancer cells.

Methods

TGF-β isoforms immunoreactivity in clinical samples from endometrial tumours was assessed using immunofluorescence. Two model cancer cell lines (KLE endometrial carcinoma cells and HeLa cervical cancer cells) and pharmacological inhibitors were used to investigate the signalling pathways regulating XIAP expression and activity in response to autocrine and paracrine TGF-β in cancer cell.

Results

We have found immunoreactivity for each TGF-β isoform in clinical samples from endometrial tumours, localizing to both stromal and epithelial/cancer cells. Blockade of autocrine TGF-β signaling in KLE endometrial carcinoma cells and HeLa cervical cancer cells reduced endogenous XIAP mRNA and protein levels. In addition, each TGF-β isoform upregulated XIAP gene expression when given exogenously, in a Smad/NF-κB dependent manner. This resulted in increased polyubiquitination of PTEN (phosphatase and tensin homolog on chromosome ten), a newly identified substrate for XIAP E3 ligase activity, and in a XIAP-dependent decrease of PTEN protein levels. Although each TGF-β isoform decreased PTEN content in a XIAP- and a Smad-dependent manner, decrease of PTEN levels in response to only one isoform, TGF-β3, was blocked by PI3-K inhibitor LY294002.

Conclusions

XIAP gene expression and function is positively regulated by exposure to the three TGF-β isoforms in a Smad-dependent manner, similar to constitutive XIAP gene expression which depends on autocrine TGF-β/Smad signalling.
Rational design of HIV vaccine and microbicides: report of the EUROPRISE annual conference
Authors: Wahren Britta , Biswas Priscilla , Borggren Marie , Coleman Adam , Da Costa Kelly , De Haes Winni , Dieltjens Tessa , Dispinseri Stefania , Grupping Katrijn , Hallengärd David , Hornig Julia , Klein Katja , Mainetti Lara , Palma Paolo , Reudelsterz Marc , Seifried Janna , Selhorst Philippe , Sköld Annette , van Gils Marit J , Weber Caroline , Shattock Robin , Scarlatti Gabriella
Published: August 2010

EUROPRISE is a Network of Excellence sponsored from 2007 to 2011 by the European Commission within the 6th Framework Program. The Network encompasses a wide portfolio of activities ranging from an integrated research program in the field of HIV vaccines and microbicides to training, dissemination and advocacy. The research program covers the whole pipeline of vaccine and microbicide development from discovery to early clinical trials. The Network is composed of 58 partners representing more than 65 institutions from 13 European countries; it also includes three major pharmaceutical companies (GlaxoSmithKline, Novartis and Sanofi-Pasteur) involved in HIV microbicide and vaccine research. The Network displays a dedicated and informative web page:http://www.europrise.org. Finally, a distinguishing trait of EUROPRISE is its PhD School of students from across Europe, a unique example in the world of science aimed at spreading excellence through training.

EUROPRISE held its second annual conference in Budapest in November, 2009. The conference had 143 participants and their presentations covered aspects of vaccine and microbicide research, development and discovery. Since training is a major task of the Network, the students of the EUROPRISE PhD program summarized certain presentations and their view of the conference in this paper.
Bioelectrical impedance analysis in clinical practice: implications for hepatitis C therapy BIA and hepatitis C
Authors: Kahraman Alisan , Hilsenbeck Johannes , Nyga Monika , Ertle Judith , Wree Alexander , Plauth Mathias , Gerken Guido , Canbay Ali E
Published: August 2010

Background

Body composition analysis using phase angle (PA), determined by bioelectrical impedance analysis (BIA), reflects tissue electrical properties and has prognostic value in liver cirrhosis. Objective of this prospective study was to investigate clinical use and prognostic value of BIA-derived phase angle and alterations in body composition for hepatitis C infection (HCV) following antiviral therapy.

Methods

37 consecutive patients with HCV infection were enrolled, BIA was performed, and PA was calculated from each pair of measurements. 22 HCV genotype 3 patients treated for 24 weeks and 15 genotype 1 patients treated for 48 weeks, were examined before and after antiviral treatment and compared to 10 untreated HCV patients at 0, 24, and 48 weeks. Basic laboratory data were correlated to body composition alterations.

Results

Significant reduction in body fat (BF: 24.2 ± 6.7 kg vs. 19.9 ± 6.6 kg, genotype1; 15.4 ± 10.9 kg vs. 13.2 ± 12.1 kg, genotype 3) and body cell mass (BCM: 27.3 ± 6.8 kg vs. 24.3 ± 7.2 kg, genotype1; 27.7 ± 8.8 kg vs. 24.6 ± 7.6 kg, genotype 3) was found following treatment. PA in genotype 3 patients was significantly lowered after antiviral treatment compared to initial measurements (5.9 ± 0.7° vs. 5.4 ± 0.8°). Total body water (TBW) was significantly decreased in treated patients with genotype 1 (41.4 ± 7.9 l vs. 40.8 ± 9.5 l). PA reduction was accompanied by flu-like syndromes, whereas TBW decline was more frequently associated with fatigue and cephalgia.

Discussion

BIA offers a sophisticated analysis of body composition including BF, BCM, and TBW for HCV patients following antiviral regimens. PA reduction was associated with increased adverse effects of the antiviral therapy allowing a more dynamic therapy application.
Integration of metabolic databases for the reconstruction of genome-scale metabolic networks
Authors: Radrich Karin , Tsuruoka Yoshimasa , Dobson Paul , Gevorgyan Albert , Swainston Neil , Baart Gino , Schwartz Jean-Marc
Published: August 2010

Background

Genome-scale metabolic reconstructions have been recognised as a valuable tool for a variety of applications ranging from metabolic engineering to evolutionary studies. However, the reconstruction of such networks remains an arduous process requiring a high level of human intervention. This process is further complicated by occurrences of missing or conflicting information and the absence of common annotation standards between different data sources.

Results

In this article, we report a semi-automated methodology aimed at streamlining the process of metabolic network reconstruction by enabling the integration of different genome-wide databases of metabolic reactions. We present results obtained by applying this methodology to the metabolic network of the plant Arabidopsis thaliana. A systematic comparison of compounds and reactions between two genome-wide databases allowed us to obtain a high-quality core consensus reconstruction, which was validated for stoichiometric consistency. A lower level of consensus led to a larger reconstruction, which has a lower quality standard but provides a baseline for further manual curation.

Conclusion

This semi-automated methodology may be applied to other organisms and help to streamline the process of genome-scale network reconstruction in order to accelerate the transfer of such models to applications.
p53 nuclear accumulation and ERα expression in ductal hyperplasia of breast in a cohort of 215 Chinese women
Authors: Mao Xiao-yun , Fan Chui-feng , Zheng Hua-chuan , Wei Jing , Yao Fan , Jin Feng
Published: August 2010

Introduction

Women with ductal hyperplasia including usual ductal hyperplasia (UDH) and atypical ductal hyperplasia (ADH) have an increased risk of developing invasive ductal carcinoma (IDC) of breast. The importance of several molecular markers in breast cancer has been of considerable interest during recent years such as p53 and estrogen receptor alpha (ERα). However, p53 nuclear accumulation and ERα expression have not been assessed in ductal hyperplasia co-existing with ductal carcinoma in situ (DCIS) or IDC versus pure ductal hyperplasia without DCIS or IDC.

Materials and methods

We investigated p53 nuclear accumulation and ERα expression in breast ductal hyperplasia in a cohort of 215 Chinese women by immunohistochemistry (IHC), which included 129 cases of pure ductal hyperplasia, 86 cases of ductal hyperplasia co-existing with DCIS (41 cases) or IDC (45 cases).

Results

Nuclear p53 accumulation was identified in 22.8% of ADH (31/136), 41.5% of DCIS (17/41) and 42.2% of IDC (19/45), and no case of UDH (0/79). No difference in nuclear p53 accumulation was observed between pure ADH and ADH co-existing with DCIS (ADH/DCIS) or IDC (ADH/IDC) (P > 0.05). The positive rate of ERα expression was lower in ADH (118/136, 86.8%) than that in UDH (79/79, 100%) (P < 0.001), but higher than that in DCIS (28/41, 68.3%) or IDC (26/45, 57.8%) respectively (P < 0.001). The frequency of ERα expression was lower in ADH/DCIS (23/29, 79.31%) and ADH/IDC (23/30, 76.67%) than that in pure ADH (72/77, 93.51%) respectively (P < 0.05). There was a negative weak correlation between p53 nuclear accumulation and ERα expression as for ADH (coefficient correlation -0.51; P < 0.001).

Conclusions

Different pathological types of ductal hyperplasia of breast are accompanied by diversity in patterns of nuclear p53 accumulation and ERα expression. At least some pure ADH is molecularly distinct from ADH/CIS or ADH/IDC which indicated the two types of ADH are molecularly distinct entities although they have the same morphological appearance.
"Mi voglio bene": a pediatrician-based randomized controlled trial for the prevention of obesity in Italian preschool children
Authors: Brambilla Paolo , Bedogni Giorgio , Buongiovanni Carmen , Brusoni Guido , Di Mauro Giuseppe , Di Pietro Mario , Giussani Marco , Gnecchi Manuel , Iughetti Lorenzo , Manzoni Paola , Sticco Maura , Bernasconi Sergio
Published: August 2010

Background

The first years of life are crucial to start preventive interventions that can have an impact on lifestyle and later overweight and obesity. Under the Italian National Health System (INHS), children are cared for by family pediatricians who perform health balances at regular intervals. The Italian Society of Preventive and Social Pediatrics (SIPPS) has designed a randomized controlled trial (RCT) to evaluate the effectiveness of family pediatricians for the prevention of childhood obesity in preschool children. We report the rationale and protocol of such trial, named the "Mi voglio bene" ("I love myself") study.

Methods

"Mi voglio bene" is a parallel-arm RCT. Family pediatricians willing to participate to the trial will be randomly assigned to a control group and to an experimental group. The control group will provide the usual standard of care while the experimental group will implement 10 preventive actions (promotion of breastfeeding, avoidance of solid foods, control of protein intake, avoidance of sugar-sweetened beverages, avoidance of bottle, active means of transportation, identification of early adiposity rebound, limitation of television viewing, promotion of movement, and teaching portion size) at 10 time points during a 6-yr follow-up. The main outcome measures is the prevalence of overweight and obesity at 6 years of age. The experimental intervention is expected to reduce the prevalence of overweight and obesity from 25% to 20% and the study requires a total of 3610 children. Each pediatrician will enroll 30 consecutive newborns into the study so that a total of 120 pediatricians will participate to the study.

Discussion

"Mi voglio bene" is expected to provide important information for the INHS and possibly other institutional child care settings about the effectiveness of a pediatrician-based approach to the prevention of childhood obesity. We published this study protocol with the aim of opening a discussion with all people interested in fighting childhood obesity and to receive useful criticisms.
Atherosclerosis in early rheumatoid arthritis: very early endothelial activation and rapid progression of intima media thickness
Authors: Södergren Anna , Karp Kjell , Boman Kurt , Eriksson Catharina , Lundström Elisabet , Smedby Torgny , Söderlund Lisbet , Rantapää-Dahlqvist Solbritt , Wållberg-Jonsson Solveig
Published: August 2010

Introduction

In this study we aimed to investigate whether there are indications of premature atherosclerosis, as measured by endothelial dependent flow-mediated dilation (ED-FMD) and intima media thickness (IMT), in patients with very early RA, and to analyze its relation to biomarkers of endothelial dysfunction, taking inflammation and traditional cardiovascular disease (CVD) risk factors into account.

Methods

Patients from the three northern counties of Sweden diagnosed with early RA are followed in an ongoing prospective study of CVD co-morbidity. Of these, all patients aged ≤60 years were consecutively included in this survey of CVD risk factors (n = 79). Forty-four age and sex matched controls were included. IMT of common carotid artery and ED-FMD of brachial artery were measured using ultrasonography. Blood was drawn for analysis of lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA)-mass, VonWillebrand factor (VWF), soluble intercellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), sE-selectin, sL-selectin and monocyte chemotactic protein-1 (MCP-1). In a subgroup of 27 RA patients and their controls the ultrasound measurements were reanalysed after 18 months.

Results

There were no significant differences between RA patients and controls in terms of IMT or ED-FMD at the first evaluation. However after 18 months there was a significant increase in the IMT among the patients with RA (P < 0.05). Patients with RA had higher levels of VWF, sICAM-1 (P < 0.05) and of MCP-1 (P = 0.001) compared with controls. In RA, IMT was related to some of the traditional CVD risk factors, tPA-mass, VWF (P < 0.01) and MCP-1 and inversely to sL-selectin (P < 0.05). In RA, ED-FMD related to sL-selectin (P < 0.01). DAS28 at baseline was related to PAI-1, tPA-mass and inversely to sVCAM-1 (P < 0.05) and sL-selectin (P = 0.001).

Conclusions

We found no signs of atherosclerosis in patients with newly diagnosed RA compared with controls. However, in patients with early RA, IMT and ED-FMD were, to a greater extent than in controls, related to biomarkers known to be associated with endothelial dysfunction and atherosclerosis. After 18 months, IMT had increased significantly in RA patients but not in controls.
Control of Plasma Uric Acid in Adults at Risk for Tumor Lysis Syndrome: Efficacy and Safety of Rasburicase Alone and Rasburicase Followed by Allopurinol Compared With Allopurinol Alone—Results of a Multicenter Phase III Study
Authors: Cortes Jorge , Moore Joseph O. , Maziarz Richard T. , Wetzler Meir , Craig Michael , Matous Jeffrey , Luger Selina , Dey Bimalangshu R. , Schiller Gary J. , Pham Dat , Abboud Camille N. , Krishnamurthy Muthuswamy , Brown Archie , Laadem Abderrahmane , Seiter Karen
Published: August 2010

Purpose

Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid.

Patients and Methods

Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid ≤ 7.5 mg/dL during days 3 to 7.

Results

Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol.

Conclusion

In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol.
Benefit of Consolidative Radiation Therapy in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP Chemotherapy
Authors: Phan Jack , Mazloom Ali , Jeffrey Medeiros L. , Zreik Tony G. , Wogan Christine , Shihadeh Ferial , Rodriguez Maria Alma , Fayad Luis , Fowler Nathan , Reed Valerie , Horace Patrecia , Dabaja Bouthaina Shbib
Published: August 2010

Purpose

The current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) in the setting of R-CHOP chemotherapy is not well reported. This retrospective analysis is an attempt to clarify this role.

Patients and Methods

Subjects were 469 patients with histologically confirmed DLBCL treated between January 2001 and December 2007. Variables including age, sex, Ann Arbor disease stage, bulky disease status, standardized uptake values (SUVs) on positron emission tomography (PET), International Prognostic Index (IPI), and Ki67 staining (proliferation).

Results

Of 469 patients, 190 (40.5%) had stage I or II disease and 279 (59.5%) had stage III or IV disease, 327 (70%) had at least six cycles of R-CHOP, and 142 (30.2%) had involved-field RT (dose, 30 to 39.6 Gy) after complete response to chemotherapy. Median follow-up was 36 months (range, 8 to 85 months). Multivariate analysis showed that RT (P < .0001), IPI score (P = .001), response to therapy (P = .001), use of six to eight cycles of R-CHOP (P < .001), and combined presence (P = .006) or absence (P = .025) of high Ki67, high PET SUV, and bulky disease influenced overall survival (OS) and progression-free survival (PFS). Matched-pair analyses of patients who received six to eight cycles of R-CHOP with stage I or II disease (44 pairs) and all stages (74 pairs) indicated that RT improved OS (hazard ratio [HR], 0.52 and 0.29, respectively) and PFS (HR, 0.45 and 0.24, respectively) compared with no RT.

Conclusion

This study showed significant improvements in OS and PFS among patients who received consolidation RT after R-CHOP chemotherapy for DLBCL.
Vitamin D Insufficiency and Prognosis in Non-Hodgkin's Lymphoma
Authors: Drake Matthew T. , Maurer Matthew J. , Link Brian K. , Habermann Thomas M. , Ansell Stephen M. , Micallef Ivana N. , Kelly Jennifer L. , Macon William R. , Nowakowski Grzegorz S. , Inwards David J. , Johnston Patrick B. , Singh Ravinder J. , Allmer Cristine , Slager Susan L. , Weiner George J. , Witzig Thomas E. , Cerhan James R.
Published: August 2010

Purpose

Vitamin D insufficiency is common in the United States, with low levels linked in some studies to higher cancer incidence, including non-Hodgkin's lymphoma (NHL). Recent data also suggest that vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data for NHL.

Patients and Methods

We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels were measured by liquid chromatography-tandem mass spectrometry.

Results

Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)2D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity did not explain the 25(OH)D associations.

Conclusion

25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials.
Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice
Authors: Ayala Julio E. , Samuel Varman T. , Morton Gregory J. , Obici Silvana , Croniger Colleen M. , Shulman Gerald I. , Wasserman David H. , McGuinness Owen P.
Published: August 2010

The Mouse Metabolic Phenotyping Center (MMPC) Consortium was established to address the need to characterize the growing number of mouse models of metabolic diseases, particularly diabetes and obesity. A goal of the MMPC Consortium is to propose standard methods for assessing metabolic phenotypes in mice. In this article, we discuss issues pertaining to the design and performance of various tests of glucose metabolism. We also propose guidelines for the description of methods, presentation of data and interpretation of results. The recommendations presented in this article are based on the experience of the MMPC Consortium and other investigators.
Validation of a new automatic smoking machine to study the effects of cigarette smoke in newborn lambs
Authors: Duvareille Charles , Beaudry Benoit , St-Hilaire Marie , Boheimier Mathieu , Brunel Cyril , Micheau Philippe , Praud Jean-Paul
Published: August 2010

The aim of this study was to describe the characteristics and validate the use of a new, custom-built automatic smoking machine (ASM), primarily designed to study the effects of an environmental tobacco smoke surrogate (ETS surrogate) exposure in animals of various sizes, including large animals. The equipment includes a programmable ASM coupled to a vented whole body chamber, where animals can be exposed to both mainstream and sidestream smoke. The user-friendly interface allows for full programming of puff volume (1–60 mL), time interval between two puffs (1–60 s) and between two cigarettes (1–60 min). Eight newborn lambs were exposed to either 10 (4 lambs, C10 group) or 20 (4 lambs, C20 group) cigarettes, 8 h per day for 15 days. Four additional control, lambs were exposed to air (C0 group). Weight gain was identical in all three groups of lambs. Urinary cotinine/creatinine ratio increased with the number of cigarettes smoked (C0: 11 ± 7 ng/mg; C10: 961 ± 539 ng/mg; C20: 1821 ± 312 ng/mg), with levels in the C10 and C20 groups in keeping with values published in infants exposed to ETS. Overall, results show that our new ASM is especially well suited for ETS surrogate exposure in non-restrained, non-anaesthetized large animals such as sheep.
The effects of urethane on the isoflurane minimum alveolar concentration in rats
Authors: Bauquier S H , Golder F J
Published: August 2010

Urethane is often used as a sole anaesthetic agent for non-recovery studies in laboratory animals. However, the use of urethane is controversial, in part, because the electroencephalogram after urethane administration is similar to the electroencephalogram recorded from unanaesthetized animals. Here, we assessed the minimum alveolar concentration (MAC)-sparing effects of urethane by measuring the effect of two doses of urethane on the MAC of isoflurane in male Sprague Dawley rats. Isoflurane MAC was measured before and after intravenous administration of urethane at 1.0 g/kg (Group G1, n = 6) and 1.5 g/kg (Group G1.5, n = 6), or an equal volume of 0.9% saline (Group Gs, n = 6). Baseline isoflurane MAC was not statistically different between groups (isoflurane concentration: 1.47 ± 0.08%, 1.40 ± 0.19% and 1.42 ± 0.12% for G1, G1.5 and Gs, respectively). Intravenous injection of saline did not alter isoflurane MAC (post-saline MAC: 1.43 ± 0.11%). After urethane administration, isoflurane MAC decreased in a dose-dependent manner (new MAC G1: 0.19 ± 0.06%; G1.5: 0.03 ± 0.01%; P < 0.05). The isoflurane MAC after 1.5 g/kg urethane was not significantly different from room air isoflurane concentrations (0.01 ± 0.01%), demonstrating a 100% MAC reduction at this dose. In conclusion, high-dose urethane (1.5 g/kg intravenously) was suitable as a sole anaesthetic agent to prevent gross purposeful movement during the conditions of the study, whereas low-dose urethane (1.0 g/kg intravenously) was not.
Original Document Needed to Safely Scan Orders to Pharmacy; Ketek's Unit-Dose Package Has Ambiguous Label; “Units” Not IU
Authors: Cohen Michael R.
Published: August 2010

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them in your inservice training programs.

Your assistance is required to continue this feature. The reports described here were received through the USP Medication Errors Reporting Program (MERP), which is presented in cooperation with the Institute for Safe Medication Practices. If you have encountered medication errors and would like to report them, you may call USP toll-free, 24 hours a day, at 800-233-7767 (800-23-ERROR).

Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below.

Errors, close calls, or hazardous conditions may be reported through the ISMP ( www.ismp.org ) or USP ( www.usp.org ) Web sites or communicated directly to ISMP by calling 800-FAIL-SAFE or via E-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Priapism Associated with Propofol; Recurrent Acute Nitrofurantoin-Induced Pulmonary Toxicity; Piperacillin/Tazobactam-Induced Paresthesiae; Peripheral Neuropathy Induced by Cancer Chemotherapy Agents; Interferon-Induced Depression; Review – Bisphosphonates and Osteonecrosis of the Jaw; Review – Antidepressants and Pregnancy; A Final Review – Evaluation and Management of Statin Therapy Complications
Authors: Shuster Joel
Published: August 2010

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the FDA's medWatch program (800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.
Citalopram: Fibromyalgia
Authors: Generali Joyce , Cada Dennis J.
Published: August 2010

Off-Label Drug Uses

This Hospital Pharmacy feature is extracted from Off-Label DrugFacts, a quarterly publication available from Wolters Kluwer Health. Off-Label DrugFacts is a practitioner-oriented resource for information about specific FDA-unapproved drug uses. This new guide to the literature will enable the health care professional/clinician to quickly identify published studies on off-label uses and to determine if a specific use is rational in a patient care scenario. The most relevant data are provided in tabular form, so the reader can easily identify the scope of information available. A summary of the data—including background, study design, patient population, dosage information, therapy duration, results, safety, and therapeutic considerations—precedes each table of published studies. References direct the reader to the full literature for more comprehensive information prior to patient care decisions. Direct questions or comments regarding “Off-Label Drug Uses” to hospitalpharmacy@drugfacts.com .
Cilansetron: A New Selective Serotonin Type 3 (5-HT3)-Receptor Antagonist for the Treatment of Irritable Bowel Syndrome in Males and Females
Authors: Albertson Brent A.
Published: August 2010

Irritable Bowel Syndrome (IBS) is a significant problem that affects a large proportion of the US population. The past several years have seen advances in our understanding of the pathophysiology associated with IBS and the development of new therapies. Older therapies have few well-designed clinical studies to support their use. The older studies tended to evaluate the impact of therapy on only one symptom and were ineffective at improving the overall symptomology in this functional disorder. In addition, the older drugs tended to produce side effects that often led to discontinuation of the therapy. Newer therapies, such as the FDA approved serotonergic agents (eg, alosetron and tegaserod), target abnormalities in gut physiology seen in IBS and not just the symptomatic presentation of the disease. In women, these medications have shown to be effective treatments for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). Pending FDA approval, cilansetron represents the second 5-HT3 antagonist for the treatment of IBS-D. It has shown promising results in both men and women, which is an improvement over alosetron, since it is only approved for use in females. Similar to alosetron, the most common side effect seen with cilansetron therapy is constipation. Few cases of ischemic colitis, like those seen during alosetron therapy, have been reported in the cilansetron clinical trials and all have resolved without complication. A thorough review of the available data regarding cilansetron will be discussed in this article.
Abatacept
Authors: Cada Dennis J. , Levien Terri , Baker Danial E.
Published: August 2010

Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to your Pharmacy and Therapeutics Committee. Subscribers also receive monthly one-page summary monographs on the agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and CD ROM forms and are available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The FI.X.

Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The August 2006 monograph topics are ibuprofen lysine, rasagiline, fentanyl iontophoretic transdermal system, quadrivalent human papillomavirus vaccine, and zoster vaccine. The DUE is on lubiprostone.
New Drugs Approved by the FDA; New Dosage Forms and Indications; Agents Pending FDA Approval; Significant Labeling Changes
Authors: Baker Danial E.
Published: August 2010

This monthly feature will help readers keep current on new drugs, indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of the information; however, if there are any questions, let us know at hospitalpharmacy@drugfacts.com .
Core Competencies in Hospital Pharmacy Practice: Regulatory Compliance
Authors: Sanborn Michael
Published: August 2010

The focus of this Director's Forum is on regulatory compliance and it serves as the last in the small series of articles on core practices or competencies in hospital pharmacy practice. Future Director's Forum topics will include decentralized pharmacy services, medication safety clinical program development, and automation. The goal of the Director's Forum throughout 2006 is to provide readers with information on all of the necessary core competencies of hospital pharmacy practice, comprising a “toolkit” in establishing a patient-centered pharmacy department.
Adacel (Tdap) and Daptacel (DTaP) Confusion; Diastat AcuDial: Dial, Set, and Lock the Dose; Why the Abbreviation “PCN” Should Be Avoided
Authors: Cohen Michael R.
Published: August 2010

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them in your inservice training programs.

Your assistance is required to continue this feature. The reports described here were received through the USP Medication Errors Reporting Program (MERP), which is presented in cooperation with the Institute for Safe Medication Practices. If you have encountered medication errors and would like to report them, you may call USP toll-free, 24 hours a day, at 800-233-7767 (800-23-ERROR).

Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below.

Errors, close calls, or hazardous conditions may be reported through the ISMP ( www.ismp.org ) or USP ( www.usp.org ) Web sites or communicated directly to ISMP by calling 800-FAIL-SAFE or via E-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Spontaneous Abdominal Hematoma with Clopidogrel and Aspirin; Hypotension Associated with Aerosolized Colistin; Ziprasidone Associated with Worsening Hypertension; Zonisamide-Induced Mania; Baclofen-Induced Sexual Dysfunction; Quetiapine-Induced Obsessive-Compulsive Symptoms; Represcription after Adverse Drug Reactions in the Elderly: Bar Code Technology and the Reduction of Dispensing Errors and Potential Adverse Drug Events
Authors: Shuster Joel
Published: August 2010

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the FDA's medWatch program (800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.
Docetaxel and Cisplatin (DP) Regimen for Solid Tumors
Authors: Franklin Kaitlyn , Solimando Dominic A. , Waddell J. Aubrey
Published: August 2010

The increasing complexity of cancer chemotherapy increases the requirement that pharmacists be familiar with these highly toxic agents. This column will review various issues related to preparation, dispensing and administration of cancer chemotherapy, and review various agents, both commercially available and investigational, used to treat malignant diseases.
Medication Prescribing Errors Involving the Route of Administration
Authors: Lesar Timothy S.
Published: August 2010

Context

Administration of medications by the wrong route or as a wrong dose for the ordered route presents significant risk for adverse drug events.

Objective

To quantify and identify the characteristics of prescribing errors involving the route of drug administration.

Design

Evaluation of medication orders with errors involving the route of administration detected by pharmacists in a 631-bed tertiary care teaching hospital over a 42-month period.

Main Outcome Measures

Type, frequency, characteristics, potential for adverse effects, contributors, and enabling factors of medication prescribing errors involving the route of administration.

Results

A total of 862 prescribing errors were detected. Sixty-one different types of route-related prescribing errors, involving 135 different medications, were detected. The most common type of these errors involved prescribing the wrong route of administration (39.2%) and prescribing the same or similar medications to be given concurrently by two routes (21.1 %). The most common class of medications involved were cardiovascular agents (23.5%). The most common medication characteristic identified as contributing to route-related prescribing errors was the common and routine use of a drug by multiple routes (75.9%).

Conclusions

Prescribing errors involving the route of administration are common, occur in a wide variety of ways, and involve a wide variety of medications. A number of commonly recommended medication safety practices should reduce risk to patients from route-related medication prescribing errors.
Improving Safety Throughout the Medication Use Process in a Neonatal Intensive Care Unit
Authors: Asdigha Mehran Nesari
Published: August 2010

Safety is the top priority for our institution. Safety has been reinforced since it became a priority of federal and state governments, the Institute for Safe Medication Practices (ISMP), and accrediting bodies (eg, the Joint Commission on Accreditation of Healthcare Organizations [JCAHO], the National Committee for Quality Assurance). Neonatal practice has required additional attention because of the nature of the specialty and the high-risk drugs and patients in this practice area. Our institution created several multidisciplinary teams to address deficiencies in our medication use process. Each team had a member from the nursing staff, neonatology staff, nurse practitioner group, and a clinical pharmacy specialist; the neonatal intensive care nurse manager and pharmacy manager were ad hoc members. The systems involved defining and standardizing prescribing practices and processing and administration of medications. This paper is a description of changes made in a hospital medication use system without direct evaluation of the implementation of the changes. All the changes were successfully implemented within a 10-month period (September 2004 through June 2005) that encompassed 7 steps, including the elimination of the rule-of-6 method of drug preparation and administration, and utilization of an infusion device with decision-support software (smart pump).
Meeting JCAHO Medication Management Standards: Getting Everyone Involved
Authors: Fogel Tina Psihogios , Todd Mark W. , Wilson Peggy C. , Como Jackson A.
Published: August 2010

This continuing feature highlights the experiences of various health care organizations regarding the Joint Commission on Accreditation of Healthcare Organizations' (JCAHO) Medication Management Standards and National Patient Safety Goals implementation. Practical information on what worked and how organizations have been surveyed regarding the standards and goals will be provided along with updates on revisions and recommendations being established by JCAHO. To share your success stories, contact Sondra K. May, PharmD, Department of Pharmacy Services, University of Colorado Hospital, 4200 East Ninth Avenue, Box A-027, Denver, CO 80262. E-mail: sondra.may@uch.edu .

Purpose

Changes in the JCAHO survey process and in the scope of the standards governing medication management (MM) make it no longer possible to have the Pharmacy Department as the sole contact point for JCAHO questions pertaining to medication use. In an effort to raise awareness of MM standards to the institutional level, we conducted an exhaustive review of individual standards and communicated shared points of responsibility to persons outside the Pharmacy Department.

Methods

Organizational changes were implemented to direct our efforts. These included instituting an ad hoc Pharmacy Department Committee and creating a Coordinator for MM standards position. Hospital organizational structure changed, so the Pharmacy Director now reports directly to the Chief Operating Officer. A spreadsheet outlined each MM standard including existing policies, those requiring revision, and departmental or interdisciplinary actions needed. Other disciplines were involved as indicated in policy revisions and improvements in medication-use systems. A new process for holding other departments accountable for medications purchased and stored outside of Pharmacy was implemented. Staff education focused on key issues and standards. Mock surveys were regularly conducted.

Results

Policies were revised in collaboration with the Pharmacy and Therapeutics Committee and other interdisciplinary teams. Departments purchasing their own medications routinely inspect their stock. Pharmacy staff education became routine.

Conclusions

Through focused interdisciplinary efforts, our institution addressed potential deficiencies, improved medication safety and was better prepared for the JCAHO survey. The first unannounced survey was just completed. There were no Recommendations for Improvement (RFIs) regarding the MM standards.
Strategies for Evaluating Clinical Pharmacy Services
Authors: Sanborn Michael
Published: August 2010

These series of articles of the Director's Forum switch their focus from the core competencies of hospital pharmacy practice to programs that enhance the ability of the pharmacy to provide patient-centered services. In the September 2006 issue, decentralized pharmacy services were reviewed and recommended as an effective patient-centered strategy for a hospital pharmacy. In the October 2006 issue, strategies for developing advanced practice clinical programs were discussed. These services place the pharmacist closer to patients, enhancing their ability to be involved directly in all aspects of effective medication therapy management.
Recent Publications on Medications and Pharmacy
Authors: Sterling Jacyntha
Published: August 2010

Hospital Pharmacy presents this feature to keep pharmacists abreast of new publications in the medical/pharmacy literature. Articles of interest will be abstracted monthly regarding a broad scope of topics. Suggestions or comments may be addressed to: Jacyntha Sterling, Drug Information Specialist at Saint Francis Hospital, 6161 S Yale Ave, Tulsa, OK 74136 or E-mail: jasterling@saintfrancis.com .
Time-Resolved Ultrastructural Detection of Phosphatidylinositol 3-Phosphate
Authors: Stuffers Susanne , Malerød Lene , Schink Kay Oliver , Corvera Silvia , Stenmark Harald , Brech Andreas
Published: August 2010

Phosphatidylinositol 3-phosphate [Ptdlns(3)P] playsan important role in recruitment of various effector proteins in the endocytic and autophagic pathways. In an attempt to follow the distribution of Ptdlns(3)P at the ultrastructural level, we are using the Fab1, YOTB, Vac1, and EEA1 (FYVE) domain, which is a zinc finger motif specifically binding to Ptdlns(3)P. To follow Ptdlns(3)P trafficking during a defined time window, here we have used a mono-meric dimerizable FYVE probe, which binds with high avidity to Ptdlns(3)P only after rapalog-induced dimerization. The probe localized to early and late endocytic compartments according to the time period of dimerization, which indicates that Ptdlns(3)P is turned over via the endocytic machinery. In the functional context of epidermal growth factor (EGF) stimulation, we observed that dimerization of the probe led to clustering of mainly early endocytic structures, leaving most of the probe localized to the limiting membrane of endosomes. Interestingly, these clustered endosomes contained coats positive for the Ptdlns(3)P-binding protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs), indicating that the probe did not displace Hrs binding. We conclude that the dimerizer-inducible probe is useful for the time-resolved detection of Ptdlns(3)P at the ultrastructural level, but its effects on endosome morphology after EGF stimulation need to be taken into account.