bluuebunny/crossref_metadata_2025 huggingface dataset:
Deoxysphingoid bases as plasma markers in Diabetes mellitus
Authors: Bertea Mariana , Rütti Markus F. , Othman Alaa , Marti-Jaun Jaqueline , Hersberger Martin , von Eckardstein Arnold , Hornemann Thorsten
Published: August 2010

Background

Sphingoid bases are formed from the precursors L-serine and palmitoyl-CoA-a reaction which is catalyzed by the serine-palmitoyltransferase (SPT). SPT metabolizes, besides palmitoyl-CoA also other acyl-CoAs but shows also variability towards the use of other amino acid substrates. The enzyme is also able to metabolize alanine, which results in the formation of an atypical deoxy-sphingoid base (DSB). This promiscuous activity is greatly increased in the case of the sensory neuropathy HSAN1, and pathologically elevated DSB levels have been identified as the cause of this disease. Clinically, HSAN1 shows a pronounced similarity to the diabetic sensory neuropathy (DSN), which is the most common chronic complication of diabetes mellitus. Since serine and alanine metabolism is functionally linked to carbohydrate metabolism by their precursors 3-phosphoglycerate and pyruvate, we were interested to see whether the levels of certain sphingoid base metabolites are altered in patients with diabetes.

Results

In a case-control study we compared plasma sphingoid base levels between healthy and diabetic individuals. DSB levels were higher in the diabetic group whereas C16 and C18 sphingoid bases were not significantly different. Plasma serine, but not alanine levels were lower in the diabetic group. A subsequent lipoprotein fractionation showed that the DSBs are primarily present in the LDL and VLDL fraction.

Conclusion

Our results suggest that DSBs are a novel category of plasma biomarkers in diabetes which reflect functional impairments of carbohydrate metabolism. Furthermore, elevated DSB levels as we see them in diabetic patients might also contribute to the progression of the diabetic sensory neuropathy, the most frequent complication of diabetes.
Psychometric validation of the Dutch translation of the quality of life in reflux and dyspepsia (QOLRAD) questionnaire in patients with gastroesophageal reflux disease
Authors: Engels Leopold GJB , Klinkenberg-Knol Elly C , Carlsson Jonas , Halling Katarina
Published: August 2010

Background

The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire is one of the best-characterized disease-specific instruments that captures health-related problems and symptom-patterns in patients with gastroesophageal reflux disease (GERD). This paper reports the psychometric validation of a Dutch translation of the QOLRAD questionnaire in gastroenterology outpatients with GERD.

Methods

Patients completed the QOLRAD questionnaire at visit 1 (baseline), visit 2 (after 2, 4 or 8 weeks of acute treatment with esomeprazole 40 mg once daily), and visit 4 (after 6 months with on-demand esomeprazole 40 mg once daily or continuous esomeprazole 20 mg once daily). Symptoms were assessed at each visit, and patient satisfaction was assessed at visits 2 and 4.

Results

Of the 1166 patients entered in the study, 97.3% had moderate or severe heartburn and 55.5% had moderate or severe regurgitation at baseline. At visit 2, symptoms of heartburn and regurgitation were mild or absent in 96.7% and 97.7%, respectively, and 95.3% of patients reported being satisfied with the treatment. The internal consistency and reliability of the QOLRAD questionnaire (range: 0.83-0.92) supported construct validity. Convergent validity was moderate to low. Known-groups validity was confirmed by a negative correlation between the QOLRAD score and clinician-assessed severity of GERD symptoms. Effect sizes (1.15-1.93) and standardized response means (1.17-1.86) showed good responsiveness to change. GERD symptoms had a negative impact on patients' lives.

Conclusions

The psychometric characteristics of the Dutch translation of the QOLRAD questionnaire were found to be satisfactory, with good reliability and responsiveness to change, although convergent validity was at best moderate.
PET-CT staging of the neck in cancers of the oropharynx: patterns of regional and retropharyngeal nodal metastasis
Authors: Tauzin Marcie , Rabalais Amy , Hagan Joseph L , Wood Charles G , Ferris Robert L , Walvekar Rohan R
Published: August 2010

Objective

To study the retropharyngeal lymph node status (RPLN) by pretreatment PET-CT imaging in patients with squamous cell carcinomas of the oropharynx (OPSCC). Study Design: Retrospective.

Methods

101 patients with a biopsy proven OPSCC were identified. 53 patients meeting inclusion criteria were further analyzed.

Results

The frequency of RPLN was 20.8% (11/53). Advanced T stage cancer (OR = 5.6250, 95% CI: 1.06 - 29.80, p = 0.0410) and advanced clinical N stage cancer (i.e. N2+) had higher odds (OR = 3.9773, 95% CI: 0.9628 - 16.4291) of being RPLN positive as compared to N0-1 patients.

Conclusions

Pre-treatment PET-CT can be used as a staging tool to aid in treatment planning of OPSCC, as rates of RPLN and nodal metastasis are consistent with those reported in the literature. Advanced T and N stage are associated with a greater odds ratio of being RPLN positive by PET-CT imaging.
Whole ovary immunohistochemistry for monitoring cell proliferation and ovulatory wound repair in the mouse
Authors: Singavarapu Rajasekhar , Buchinsky Natalie , Cheon Dong-Joo , Orsulic Sandra
Published: August 2010

Background

Ovarian surface epithelial cells are thought to be a precursor cell type for ovarian carcinoma. It has been proposed that an increased rate of ovarian surface epithelial cell proliferation during ovulatory wound repair contributes to the accumulation of genetic changes and cell transformation. The proliferation of ovarian surface epithelial cells during ovulatory wound repair has been studied primarily using immunohistochemical staining of paraffin-embedded ovary sections. However, such analyses require complex reconstruction from serially-cut ovary sections for the visualization and quantification of the cells on the ovarian surface. In order to directly visualize the proliferation and organization of the ovarian surface epithelial cells, we developed a technique for immunohistochemical staining of whole mouse ovaries. Using this method, we analyzed cell proliferation and morphologic changes in mouse ovarian surface epithelial cells during follicle growth and ovulatory wound repair.

Methods

Three-week old FVB/N female mice were superovulated by sequential administration of pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). Ten hours after hCG administration, mice were given 5-bromo-2-deoxyuridine (BrdU) and euthanized two hours after BrdU administration for ovary isolation. The levels of incorporated BrdU in the ovarian surface epithelial cells were measured by staining paraffin-embedded ovary sections and whole ovaries with the BrdU antibody. Re-epithelialization of the ovarian surface after ovulatory rupture was visualized by immunohistochemical staining with E-cadherin and Keratin 8 in paraffin-embedded ovary sections and whole ovaries.

Results

We determined that active proliferation of ovarian epithelial surface cells primarily occurs during antral follicle formation and, to a lesser extent, in response to an ovulatory wound. We also demonstrated that ovarian surface epithelial cells exhibit a circular organization around the wound site

Conclusion

Whole ovary immunohistochemistry enables efficient and comprehensive three-dimensional visualization of ovarian surface epithelial cells without the need for laborious reconstruction from immunohistochemically-stained serial ovary sections.
Transcriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases
Authors: Vo Thi Kim Duy , Godard Patrice , de Saint-Hubert Marie , Morrhaye Gabriel , Swine Christian , Geenen Vincent , Martens Henri J , Debacq-Chainiaux Florence , Toussaint Olivier
Published: August 2010

Background

Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response in acute phase of the infectious disease is poorly understood.

Results

Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease (day 2-4 after hospitalization) or in convalescence phase (day 7-10). This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged. For instance, transcripts associated with inflammatory and anti-inflammatory reactions (TNFRSF1A, IL1R1, IL1R2, IL10RB) and with oxidative stress (HMOX1, GPX1, SOD2, PRDX6) were more abundant while those associated with T-cell functions (CD28, CD69, LCK) were less abundant in acute phase. The abundance of seven of these transcripts (CD28, CD69, LCK, CTSD, HMOX1, TNFRSF1A and PRDX6) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase, compromising an efficient response.

Conclusion

This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons.
Inferring modules from human protein interactome classes
Authors: Marras Elisabetta , Travaglione Antonella , Chaurasia Gautam , Futschik Matthias , Capobianco Enrico
Published: August 2010

Background

The integration of protein-protein interaction networks derived from high-throughput screening approaches and complementary sources is a key topic in systems biology. Although integration of protein interaction data is conventionally performed, the effects of this procedure on the result of network analyses has not been examined yet. In particular, in order to optimize the fusion of heterogeneous interaction datasets, it is crucial to consider not only their degree of coverage and accuracy, but also their mutual dependencies and additional salient features.

Results

We examined this issue based on the analysis of modules detected by network clustering methods applied to both integrated and individual (disaggregated) data sources, which we call interactome classes. Due to class diversity, we deal with variable dependencies of data features arising from structural specificities and biases, but also from possible overlaps. Since highly connected regions of the human interactome may point to potential protein complexes, we have focused on the concept of modularity, and elucidated the detection power of module extraction algorithms by independent validations based on GO, MIPS and KEGG. From the combination of protein interactions with gene expressions, a confidence scoring scheme has been proposed before proceeding via GO with further classification in permanent and transient modules.

Conclusions

Disaggregated interactomes are shown to be informative for inferring modularity, thus contributing to perform an effective integrative analysis. Validation of the extracted modules by multiple annotation allows for the assessment of confidence measures assigned to the modules in a protein pathway context. Notably, the proposed multilayer confidence scheme can be used for network calibration by enabling a transition from unweighted to weighted interactomes based on biological evidence.
NDRG2 suppresses the proliferation of clear cell renal cell carcinoma cell A-498
Authors: Ma Jian-Jun , Liao Cheng-Gong , Jiang Xue , Zhao Hua-Dong , Yao Li-Bo , Bao Ting-Yi
Published: August 2010

Background

Recently, the anti-tumor activity of N-myc downstream-regulated gene 2 (NDRG2) was shown decreased expression in clear cell renal cell carcinoma (CCRCC), but the role of the down-expression of NDRG2 has not been described.

Methods

The NDRG2 recombinant adenovirus plasmid was constructed. The proliferation rate and NDRG2 expression of cell infected with recombinant plasmid were mesured by MTT, Flow cytometry analysis and western blot.

Results

The CCRCC cell A-498 re-expressed NDRG2 when infected by NDRG2 recombinant adenovirus and significantly decreased the proliferation rate. Fluorescence activated cell sorter analysis showed that 25.00% of cells expressed NDRG2 were in S-phase compared to 40.67% of control cells, whereas 62.08% of cells expressed NDRG2 were in G1-phase compared to 54.39% of control cells (P < 0.05). In addition, there were much more apoptotic cells in NDRG2-expressing cells than in the controls (P < 0.05). Moreover, upregulation of NDRG2 protein was associated with a reduction in cyclin D1, cyclin E, whereas cyclinD2, cyclinD3 and cdk2 were not affected examined by western blot. Furthermore, we found that p53 could upregulate NDRG2 expression in A-498 cell.

Conclusions

We found that NDRG2 can inhibit the proliferation of the renal carcinoma cells and induce arrest at G1 phase. p53 can up-regulate the expression of NDRG2. Our results showed that NDRG2 may function as a tumor suppressor in CCRCC.
Idiopathic toe walking and sensory processing dysfunction
Authors: Williams Cylie M , Tinley Paul , Curtin Michael
Published: August 2010

Background

It is generally understood that toe walking involves the absence or limitation of heel strike in the contact phase of the gait cycle. Toe walking has been identified as a symptom of disease processes, trauma and/or neurogenic influences. When there is no obvious cause of the gait pattern, a diagnosis of idiopathic toe walking (ITW) is made. Although there has been limited research into the pathophysiology of ITW, there has been an increasing number of contemporary texts and practitioner debates proposing that this gait pattern is linked to a sensory processing dysfunction (SPD). The purpose of this paper is to examine the literature and provide a summary of what is known about the relationship between toe walking and SPD.

Method

Forty‐nine articles were reviewed, predominantly sourced from peer reviewed journals. Five contemporary texts were also reviewed. The literature styles consisted of author opinion pieces, letters to the editor, clinical trials, case studies, classification studies, poster/conference abstracts and narrative literature reviews. Literature was assessed and graded according to level of evidence.

Results

Only one small prospective, descriptive study without control has been conducted in relation to idiopathic toe walking and sensory processing. A cross‐sectional study into the prevalence of idiopathic toe walking proposed sensory processing as being a reason for the difference. A proposed link between ITW and sensory processing was found within four contemporary texts and one conference abstract.

Conclusion

Based on the limited conclusive evidence available, the relationship between ITW and sensory processing has not been confirmed. Given the limited number and types of studies together with the growing body of anecdotal evidence it is proposed that further investigation of this relationship would be advantageous.
Who benefits most from mild therapeutic hypothermia in coronary intervention era? A retrospective and propensity-matched study
Authors: Kagawa Eisuke , Inoue Ichiro , Kawagoe Takuji , Ishihara Masaharu , Shimatani Yuji , Kurisu Satoshi , Nakama Yasuharu , Dai Kazuoki , Otani Takayuki , Ikenaga Hiroki , Morimoto Yoshimasa , Ejiri Kentaro , Oda Nozomu
Published: August 2010

Introduction

The aim of the present study was to investigate the impact of the time interval from collapse to return of spontaneous circulation (CPA-ROSC) in cardiac arrest patients and the types of patients who will benefit from therapeutic hypothermia.

Methods

Four hundred witnessed adult comatose survivors of out-of-hospital cardiac arrest of cardiac etiology were enrolled in the study. The favorable neurological outcome was defined as category 1 or 2 on the five-point Pittsburgh cerebral performance scale at the time of hospital discharge. A matching process based on the propensity score was performed to equalize potential prognostic factors in the hypothermia and normothermia groups, and to formulate a balanced 1:1 matched cohort study.

Results

The rate of favorable neurological outcome was higher (P < 0.05) in the hypothermia group (n = 110) than in the normothermia group in patients with CPA-ROSC of 15 to 20 minutes (64% vs. 17%), 20 to 25 minutes (70% vs. 8%), 25 to 30 minutes (50% vs. 7%), 35 to 40 minutes (27% vs. 0%) and 40 to 45 minutes (29% vs. 2%). A similar association was observed in a propensity-matched cohort, but the differences were not significant. There was no significant difference in the rate of favorable neurological outcome between the hypothermia-matched group and the normothermia-matched group. In the patients whose CPA-ROSC was greater than 15 minutes, however, the rate of favorable neurological outcome was higher in the hypothermia-matched group than in the normothermia-matched group (27% vs. 4%, P < 0.001). In multivariate analysis, the CPA-ROSC was an independent predictor of favorable neurological outcome (every 1 minute: odds ratio = 0.89, 95% confidence interval = 0.85 to 0.92, P < 0.001).

Conclusions

The CPA-ROSC is an independent predictor of neurological outcome. Therapeutic hypothermia is more beneficial in comatose survivors of cardiac arrest with CPA-ROSC greater than 15 minutes.
Qualitative Assessment of the Progesterone Receptor and HER2 Improves the Nottingham Prognostic Index Up to 5 Years After Breast Cancer Diagnosis
Authors: Van Belle Vanya , Van Calster Ben , Brouckaert Olivier , Vanden Bempt Isabelle , Pintens Saskia , Harvey Vernon , Murray Paula , Naume Björn , Wiedswang Gro , Paridaens Robert , Moerman Philippe , Amant Frederic , Leunen Karin , Smeets Ann , Drijkoningen Maria , Wildiers Hans , Christiaens Marie-Rose , Vergote Ignace , Van Huffel Sabine , Neven Patrick
Published: August 2010

Purpose

To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS).

Patients and Methods

The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively.

Results

In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer–related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI − PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group.

Conclusion

The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care.
Cancer Patients' Roles in Treatment Decisions: Do Characteristics of the Decision Influence Roles?
Authors: Keating Nancy L. , Beth Landrum Mary , Arora Neeraj K. , Malin Jennifer L. , Ganz Patricia A. , van Ryn Michelle , Weeks Jane C.
Published: August 2010

Purpose

Patients with more active roles in decisions are more satisfied and may have better health outcomes. Younger and better educated patients have more active roles in decisions, but whether patients' roles in decisions differ by characteristics of the decision itself is unknown.

Patients and Methods

We surveyed a large, population-based cohort of patients with recently diagnosed lung or colorectal cancer about their roles in decisions regarding surgery, radiation therapy, and/or chemotherapy. We used multinomial logistic regression to assess whether characteristics of the decision, including evidence about the treatment's benefit, whether the decision was likely preference-sensitive (palliative therapy for metastatic cancer), and treatment modality, influenced patients' roles in that decision.

Results

Of 10,939 decisions made by 5,383 patients, 38.9% were patient controlled, 43.6% were shared, and 17.5% were physician controlled. When there was good evidence to support a treatment, shared control was greatest; when evidence was uncertain, patient control was greatest; and when there was no evidence for or evidence against a treatment, physician control was greatest (overall P < .001). Decisions about treatments for metastatic cancers tended to be more physician controlled than other decisions (P < .001).

Conclusion

Patients making decisions about treatments for which no evidence supports benefit and decisions about noncurative treatments reported more physician control, which suggests that patients may not want the responsibility of deciding on treatments that will not cure them. Better strategies for shared decision making may be needed when there is no evidence to support benefit of a treatment or when patients have terminal illnesses that cannot be cured.
Pretreatment Quality of Life As a Predictor of Distant Metastasis and Survival for Patients With Nasopharyngeal Carcinoma
Authors: Fang Fu-Min , Tsai Wen-Ling , Chien Chih-Yen , Chen Hui-Chun , Hsu Hsuan-Chih , Huang Tai-Lin , Lee Tsair-Fwu , Huang Hsuan-Ying , Lee Chien-Hung
Published: August 2010

Purpose

The purpose of this study was to examine the prognostic value of pretreatment quality of life (QoL) data on locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with nasopharyngeal carcinoma (NPC).

Patients and Methods

A total of 347 new patients with NPC, who were curatively treated by conformal radiotherapy from March 2003 to December 2007, were recruited. The Taiwan Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 was completed before treatment. Multivariate Cox's proportional hazards models were used to analyze the impact of clinical and QoL variables on the treatment results.

Results

The 5-year LRC, DMFS, and OS rates were 72.9%, 79.1%, and 68.4%, respectively. After adjusting the clinical variables, 10 QoL variables were observed to be significantly (P < .05) related to OS, and four QoL variables were related to DMFS. No QoL variable was predictive of LRC. Among the QoL variables that significantly predicted OS and DMFS, physical functioning was the most powerful predictor. A 10-point increase in the physical functioning score was associated with a 23% (95% CI, 12% to 34%) reduction in the likelihood of death and a 22% (95% CI, 9% to 36%) reduction in the likelihood of distant metastasis.

Conclusion

Our findings indicate that pretreatment QoL variables, especially physical functioning, provide easily available prognostic value for distant metastasis and survival in patients with NPC.
Early Treatment Failure in Intermediate-Risk Rhabdomyosarcoma: Results From IRS-IV and D9803—A Report From the Children's Oncology Group
Authors: Minn A. Yuriko , Lyden Elizabeth R. , Anderson James R. , Million Lynn , Arndt Carola A. , Brown Kenneth , Hawkins Douglas S. , Donaldson Sarah S.
Published: August 2010

Purpose

The goal of this study was to determine the frequency and clinical features of early treatment failure during induction chemotherapy before protocol radiation therapy for children with intermediate-risk rhabdomyosarcoma (RMS).

Patients and Methods

Patients with intermediate-risk RMS enrolled onto the Intergroup Rhabdomyosarcoma Study-IV and the Children's Oncology Group D9803 study were reviewed for an early treatment failure. Early failure was defined as failure caused by progressive disease, death as a result of progressive disease, or death as a result of other causes occurring fewer than 120 days from study entry. Patients with parameningeal site RMS with high-risk features who received radiation therapy at week 1 were excluded from analysis. Overall survival (OS) was estimated using the Kaplan-Meier method. Fisher's exact test was used to compare differences between groups. Cumulative incidence of progression was estimated.

Results

Of 916 patients, 20 (2.2%) were found to have an early disease progression and did not receive planned protocol radiotherapy. Three additional early failures resulted from treatment-related death without progression. Median time to failure was 48 days (range, 7 to 106 days). Nineteen (95%) of the 20 patients experienced progression at their primary site. Five-year OS was 32% (95% CI, 12% to 54%) for patients experiencing an early progression.

Conclusion

A small proportion of patients with intermediate-risk RMS suffer an early failure as a result of early progression (2.2%) or treatment-related mortality (0.3%). The majority of patients with early progression had a local failure. Earlier radiotherapy could potentially improve outcome by preventing early local progression.
Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial
Authors: Eich Hans Theodor , Diehl Volker , Görgen Helen , Pabst Thomas , Markova Jana , Debus Jürgen , Ho Anthony , Dörken Bernd , Rank Andreas , Grosu Anca-Ligia , Wiegel Thomas , Karstens Johann Hinrich , Greil Richard , Willich Normann , Schmidberger Heinz , Döhner Hartmut , Borchmann Peter , Müller-Hermelink Hans-Konrad , Müller Rolf-Peter , Engert Andreas
Published: August 2010

Purpose

Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied.

Patients and Methods

Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPbaseline) + 30 Gy of IFRT; or four cycles of BEACOPPbaseline + 20 Gy of IFRT.

Results

With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPPbaseline was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPPbaseline and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, −3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPPbaseline, 20 Gy was not inferior to 30 Gy (5-year FFTF difference, −0.8%; 95% CI, −5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, −4.7%; 95% CI, −10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy.

Conclusion

Moderate dose escalation using BEACOPPbaseline did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.
Randomized, Phase II Study of the Insulin-Like Growth Factor-1 Receptor Inhibitor IMC-A12, With or Without Cetuximab, in Patients With Cetuximab- or Panitumumab-Refractory Metastatic Colorectal Cancer
Authors: Reidy Diane Lauren , Vakiani Efsevia , Fakih Marwan G. , Saif Muhammad Wasif , Hecht Joel Randolph , Goodman-Davis Noah , Hollywood Ellen , Shia Jinru , Schwartz Jonathan , Chandrawansa Kumari , Dontabhaktuni Aruna , Youssoufian Hagop , Solit David B. , Saltz Leonard B.
Published: August 2010

Purpose

To evaluate the safety and efficacy of IMC-A12, a human monoclonal antibody (mAb) that blocks insulin-like growth factor receptor-1 (IGF-1R), as monotherapy or in combination with cetuximab in patients with metastatic refractory anti–epidermal growth factor receptor (EGFR) mAb colorectal cancer.

Methods

A randomized, phase II study was performed in which patients in arm A received IMC-A12 10 mg/kg intravenously (IV) every 2 weeks, while patients in arm B received this same dose of IMC-A12 plus cetuximab 500 mg/m2 IV every 2 weeks. Subsequently, arm C (same combination treatment as arm B) was added to include patients who had disease control on a prior anti-EGFR mAb and wild-type KRAS tumors. Archived pretreatment tumor tissue was obtained when possible for KRAS, PIK3CA, and BRAF genotyping, and immunohistochemistry was obtained for pAKT as well as IGF-1R.

Results

Overall, 64 patients were treated (median age, 61 years; range, 40 to 84 years): 23 patients in arm A, 21 in arm B, and 20 in arm C. No antitumor activity was seen in the 23 patients treated with IMC-A12 monotherapy. Of the 21 patients randomly assigned to IMC-A12 plus cetuximab, one patient (with KRAS wild type) achieved a partial response, with disease control lasting 6.5 months. Arm C (all patients with KRAS wild type), however, showed no additional antitumor activity. Serious adverse events thought possibly related to IMC-A12 included a grade 2 infusion-related reaction (2%; one of 64 patients), thrombocytopenia (2%; one of 64 patients), grade 3 hyperglycemia (2%; one of 64 patients), and grade 1 pyrexia (2%, one of 64 patients).

Conclusion

IMC-A12 alone or in combination with cetuximab was insufficient to warrant additional study in patients with colorectal cancer refractory to EGFR inhibitors.
Animal models of soft-tissue sarcoma
Authors: Dodd Rebecca D. , Mito Jeffery K. , Kirsch David G.
Published: August 2010

Soft-tissue sarcomas (STSs) are rare mesenchymal tumors that arise from muscle, fat and connective tissue. Currently, over 75 subtypes of STS are recognized. The rarity and heterogeneity of patient samples complicate clinical investigations into sarcoma biology. Model organisms might provide traction to our understanding and treatment of the disease. Over the past 10 years, many successful animal models of STS have been developed, primarily genetically engineered mice and zebrafish. These models are useful for studying the relevant oncogenes, signaling pathways and other cell changes involved in generating STSs. Recently, these model systems have become preclinical platforms in which to evaluate new drugs and treatment regimens. Thus, animal models are useful surrogates for understanding STS disease susceptibility and pathogenesis as well as for testing potential therapeutic strategies.
Family relationship of female breeders reduce the systematic inter-individual variation in the gut microbiota of inbred laboratory mice
Authors: Hufeldt M R , Nielsen D S , Vogensen F K , Midtvedt T , Hansen A K
Published: August 2010

The gut microbiota (GM) may influence disease expression in several animal models for inflammatory diseases. It may therefore seem reasonable to pursue reduction in the number of animals used for individual studies by reducing the variation in the GM. Previous studies have shown that the composition of the GM is related to genetics to a certain extent. We hypothesized that the GM similarity in a group of mice born by mothers not being sisters would be lower than that in a group born by mothers being sisters. The lower similarity could lead to clustering of the GM of mice born by non-sisters according to their mothers, while such clustering would not be visible if the mothers were sisters. We used 16S rRNA gene (V3 region) polymerase chain reaction-derived amplicon profiling by denaturing gradient gel electrophoresis (DGGE) to study the GM composition in caecum samples of 33 eight-week-old C57BL/6Sca mice from a breeding set-up with dam breeders that were sisters, as well as caecum samples of 35 eight-week-old C57BL/6Sca mice from a breeding set-up with dam breeders that were not sisters. Principal component analysis revealed a significant difference between the litters from the breeding set-up with dam breeders that were not sisters, whereas no significant difference between the litters based on the breeding set-up with dam breeders that were sisters was observed. The results obtained indicate that the systematic variation in the GM of inbred mice can be reduced by increasing the family relatedness of the breeding pairs.
OB-fold domain of KREPA4 mediates high-affinity interaction with guide RNA and possesses annealing activity
Authors: Kala Smriti , Salavati Reza
Published: August 2010

KREPA4, also called MP24, is an essential mitochondrial guide RNA (gRNA)-binding protein with a preference for the 3′ oligo(U) tail in trypanosomes. Structural prediction and compositional analysis of KREPA4 have identified a conserved OB (oligonucleotide/oligosaccharide-binding)-fold at the C-terminal end and two low compositional complexity regions (LCRs) at its N terminus. Concurrent with these predictions, one or both of these regions in KREPA4 protein may be involved in gRNA binding. To test this possibility, deletion mutants of KREPA4 were made and the effects on the gRNA-binding affinities were measured by quantitative electrophoretic mobility shift assays. The gRNA-binding specificities of these mutants were evaluated by competition experiments using gRNAs with U-tail deletions or stem–loop modifications and uridylated nonguide RNAs or heterologous RNA. Our results identified the predicted OB-fold as the functional domain of KREPA4 that mediates a high-affinity interaction with the gRNA oligo(U) tail. An additional contribution toward RNA-binding function was localized to LCRs that further stabilize the binding through sequence-specific interactions with the guide secondary structure. In this study we also found that the predicted OB-fold has an RNA annealing activity, representing the first report of such activity for a core component of the RNA editing complex.
Etoposide, Methotrexate, Actinomycin, Cyclophosphamide, and Vincristine (EMA/CO) Regimen for Gestational Trophoblastic Disease
Authors: Waddell J. Aubrey , Solimando Dominic A.
Published: August 2010

The increasing complexity of cancer chemotherapy heightens 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. It will also serve as a review of various agents, both commercially available and investigational, used to treat malignant diseases.
Compliance with Institutional Guidelines on the Use of Vancomycin in a Medical Intensive Care Unit
Authors: Eschenauer Gregory A. , Fedewa Karen , Collins Curtis D. , Alaniz Cesar
Published: August 2010

Purpose

The University of Michigan implemented guidelines and restrictions for the use of vancomycin in 1995, based on recommendations from the Centers for Disease Control and Prevention. This study evaluated vancomycin use in the University of Michigan's Medical Intensive Care Unit (MICU), and assessed compliance with these institutional guidelines.

Methods

The primary objective of the study was to assess compliance with institutional guidelines. All patients admitted to the MICU who received vancomycin during the period of October 2002 through January 2003 were included in the study. Patients were identified retrospectively and patient medical records were accessed to gather pertinent information. Approval of the Institutional Review Board was obtained.

Results

Fifty-one patients received a total of 71 courses of vancomycin therapy (55 empiric, 16 definitive). Fifty-five (77.5%) of the 71 total courses of vancomycin therapy met institutional criteria. All courses of definitive therapy met specific criteria. Thirty-nine (71%) of the 55 courses of empiric therapy met criteria. Of the courses of empiric therapy which did not fulfill criteria, 12 were from patients exhibiting signs of sepsis and received vancomycin for more than 72 hours, and nine involved immunocompromised patients.

Conclusions

The implementation of guidelines and restrictions is essential to limiting and preventing resistance, but are only effective if designed with the specific hospital's patient population in mind. The results of this study suggest that immunocompromised patients may require a different approach than what is allowed by existing criteria.
Tramadol: Premature Ejaculation
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 .
Expression and Localization of Angiogenic Growth Factors in Developing Porcine Mesonephric Glomeruli
Authors: Ward De Spiegelaere , Cornillie Pieter , Erkens Tim , Denis Van Loo , Casteleyn Christophe , Mario Van Poucke , Burvenich Christian , Luc Van Hoorebeke , Chris Van Ginneken , Peelman Luc , Wim Van den Broeck
Published: August 2010

The development and growth of renal glomeruli is regulated by specific angiogenic growth factors, including vascular endothelial growth factor (VEGF) and the angiopoietins (ANGPT1 and ANGPT2). The expression of these factors has already been studied during metanephric glomerulogenesis, but it remains to be elucidated during the development of the embryonic mesonephros, which can function as an interesting model for glomerular development and senescence. In this study, the presence of the angiogenic growth factors was studied in developing porcine mesonephroi, using IHC and real-time RT-qPCR on laser capture microdissected glomeruli. In addition, mesonephric glomerular growth was measured by using stereological methods. ANGPT2 remained upregulated during maturation of glomeruli, which may be explained by the continuous growth of the glomeruli, as observed by stereological examination. The mRNA for VEGFA was expressed in early developing and in maturing glomeruli. The VEGF receptor VEGFR1 was stably expressed during the whole lifespan of mesonephric glomeruli, whereas VEGFR2 mRNA was only upregulated in early glomerulogenesis, suggesting that VEGFR2 is important for the vascular growth but that VEGFR1 is important for the maintenance of endothelial fenestrations. (J Histochem Cytochem 58:1045–1056, 2010)
Immunohistochemical Analysis of the Effects of Cross-innervation of Murine Thyroarytenoid and Sternohyoid Muscles
Authors: Rhee Hannah S. , Joseph F.Y. Hoh
Published: August 2010

This work uses cross-innervation of respiratory muscles of different developmental origins to probe myogenic and neurogenic mechanisms regulating their fiber types. The thyroarytenoid (TA) originates from the sixth branchial arch, whereas the sternohyoid (SH) is derived from somitic mesoderm. Immunohistochemical analysis using highly specific monoclonal antibodies to myosin heavy chain (MyHC) isoforms reveals that normal rat SH comprises slow, 2a, 2x, and 2b fibers, as in limb fast muscles, whereas the external division of the TA has only 2b/eo fibers coexpressing 2B and extraocular (EO) MyHCs. Twelve weeks after cross-innervation with the recurrent laryngeal nerve, the SH retained slow and 2a fibers, greatly increased the proportion of 2x fibers, and their 2b fibers failed to express EO MyHC. In the cross-innervated TA, the SH nerve failed to induce slow and 2A MyHC expression and failed to suppress EO MyHC expression in 2b/eo fibers. However, 2x fibers amounting to 4.2% appeared de novo in the external division of the TA. We conclude that although MyHC gene expression in these muscles can be modulated by neural activity, the patterns of response to altered innervation are largely myogenically determined, thus supporting the idea that SH and TA differ in muscle allotype. (J Histochem Cytochem 58:1057–1065, 2010)
Distance Treatment of Obsessive–Compulsive Disorder
Authors: Wootton Bethany M. , Titov Nickolai
Published: August 2010

Obsessive–compulsive disorder (OCD) is an important mental health problem. The Australian National Survey of Mental Health and Wellbeing estimates the 12-month prevalence of OCD is 1.9% (Australian Bureau of Statistics, 2007). Individuals with OCD experience considerable impairment in daily functioning. Cognitive and behavioural therapy for OCD has been shown to be effective, however, accessibility to evidence based treatments is limited in Australia, especially for those living in rural and remote communities. Treatment delivered in a remote fashion may improve accessibility to such treatments. The present review aimed to evaluate the current status of evidence based treatments for OCD delivered remotely.
Yin and Yang of Histone H2B Roles in Silencing and Longevity: A Tale of Two Arginines
Authors: Dai Junbiao , Hyland Edel M , Norris Anne , Boeke Jef D
Published: August 2010

In budding yeast, silent chromatin is defined at the region of telomeres, rDNA loci, and silent mating loci. Although the silent chromatin at different loci shows structural similarity, the underlying mechanism to establish, maintain, and inherit these structures may be fundamentally different. In this study, we found two arginine residues within histone H2B, which are specifically required to maintain either the telomeric or the rDNA silenct chromatin. Arginine 95 (R95) plays a specific role at telomeres, whereas arginine 102 (R102) is required to maintain the silent chromatin at rDNA and to ensure the integrity of rDNA loci by suppressing recombination between rDNA repeats. R95 mutants show enhanced rDNA silencing but a paradoxically low Sir2 protein abundance. Furthermore weakened silencing at telomeres in R95 mutants can be suppressed by a specific SIR3 allele, SIR3–D205N, which increases the affinity of Sir proteins to telomeres, suggesting H2B–R95 may directly mediate telomeric Sir protein–nucleosome interactions. Double mutations of R95 and R102 lead to desilencing of both rDNA and telomeres, indicating both arginines are necessary to ensure integrity of silent chromatin at these loci. Furthermore, mutations of R102 cause accumulation of extrachromosomal rDNA circles and reduce life span, suggesting that histone H2B contributes to longevity.
Prediction of Death for Extremely Premature Infants in a Population-Based Cohort
Authors: Lee Henry Chong , Green Charles , Hintz Susan R. , Tyson Jon E. , Parikh Nehal A. , Langer John , Gould Jeffrey B.
Published: August 2010

OBJECTIVE:

Although gestational age (GA) is often used as the primary basis for counseling and decision-making for extremely premature infants, a study of tertiary care centers showed that additional factors could improve prediction of outcomes. Our objective was to determine how such a model could improve predictions for a population-based cohort.

METHODS:

From 2005 to 2008, data were collected prospectively for the California Perinatal Quality Care Collaborative, which encompasses 90% of NICUs in California. For infants born at GAs of 22 to 25 weeks, we assessed the ability of the Eunice Kennedy Shriver National Institute of Child Health and Human Development 5-factor model to predict survival rates, compared with a model using GA alone.

RESULTS:

In the study cohort of 4527 infants, 3647 received intensive care. Survival rates were 53% for the whole cohort and 66% for infants who received intensive care. In multivariate analyses of data for infants who received intensive care, prenatal steroid exposure, female sex, singleton birth, and higher birth weight (per 100-g increment) were each associated with a reduction in the risk of death before discharge similar to that for a 1-week increase in GA. The multivariate model increased the ability to group infants in the highest and lowest risk categories (mortality rates of >80% and <20%, respectively).

CONCLUSIONS:

In a population-based cohort, the addition of prenatal steroid exposure, sex, singleton or multiple birth, and birth weight to GA allowed for improved prediction of rates of survival to discharge for extremely premature infants.
Bicalutamide and Third-Generation Aromatase Inhibitors in Testotoxicosis
Authors: Lenz Anne M. , Shulman Dorothy , Eugster Erica A. , Rahhal Samar , Fuqua John S. , Pescovitz Ora H. , Lewis Katherine A.
Published: August 2010

Testotoxicosis, a form of gonadotropin-independent precocious puberty, results from an activating mutation of the luteinizing hormone receptor expressed in testicular Leydig cells. Affected males experience early testosterone secretion, virilization, advancing bone age, and resultant short stature. Recently, the use of combination therapy with a potent antiandrogen agent (bicalutamide) and a third-generation aromatase inhibitor (anastrozole or letrozole) was reported to yield encouraging short-term results. We present here the results of longer-term treatment (4.5 and 5 years) with this combination therapy in 2 boys who demonstrated that it is well tolerated, slows bone-age advancement in the face of continued linear growth, and prevents progression of virilization.
Effects of feeding diets contaminated with Fusarium mycotoxins on blood biochemical parameters of broiler chickens
Authors: Faixová Zita , Faix Štefan , Bořutová Radka , Leng Ľubomír
Published: August 2010

This study was conducted to investigate the effects of deoxynivalenol (DON) and zearalenone (ZEA) on some biochemical indices of broiler chickens. Twenty-four Ross 308 hybrid broiler chickens of both sexes were fed diets containing maize contaminated with
Fusarium
mycotoxins. The diets included a control diet (DON 0.60 mg/kg feed; ZEA 0.07 mg/kg feed), an experimental 1 diet (DON 3.4 mg kg
−1
feed; ZEA 3.4 mg kg
−1
feed), and an experimental 2 diet (DON 8.2 mg kg
−1
feed; ZEA 8.3 mg kg
−1
feed). Contaminated diets were fed from 14 days of age for 14 days. Blood samples were collected from 4-week-old birds. Chicks fed a diet containing a low level of contaminated maize (experimental 1) had decreased plasma potassium, magnesium, phosphorus, total protein, albumin, triglycerides, free glycerol concentrations and increased cholesterol and calcium levels as well as alkaline phosphatase (ALP) and aspartate aminotransferase (AST) enzyme activities as compared to the control. Feeding a diet contaminated with high levels of mycotoxins (experimental 2) resulted in decreased plasma potassium, magnesium, total protein, albumin, triglycerides, free glycerol concentrations and increased plasma ALP, alanine aminotransferase (ALT) and AST enzyme activities. The effect of mycotoxin-contaminated diets on ALP activity was dose dependent. Chloride concentration was not affected by the diets. It can be concluded that feeding diets contaminated with both levels of
Fusarium
mycotoxins significantly affected protein, lipid and mineral metabolism as well as AST and ALP enzyme activities in broiler chickens.