bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing Homogeneity in a Semiparametric Two-Sample Problem
Authors: Liu Yukun , Li Pengfei , Fu Yuejiao
Published: April 2012

We study a two-sample homogeneity testing problem, in which one sample comes from a population with densityf(x)and the other is from a mixture population with mixture density(1−λ)f(x)+λg(x). This problem arises naturally from many statistical applications such as test for partial differential gene expression in microarray study or genetic studies for gene mutation. Under the semiparametric assumptiong(x)=f(x)eα+βx, a penalized empirical likelihood ratio test could be constructed, but its implementation is hindered by the fact that there is neither feasible algorithm for computing the test statistic nor available research results on its theoretical properties. To circumvent these difficulties, we propose an EM test based on the penalized empirical likelihood. We prove that the EM test has a simple chi-square limiting distribution, and we also demonstrate its competitive testing performances by simulations. A real-data example is used to illustrate the proposed methodology.
Cobalamin and Folic Acid Status in Relation to the Etiopathogenesis of Pancytopenia in Adults at a Tertiary Care Centre in North India
Authors: Premkumar M. , Gupta N. , Singh T. , Velpandian T.
Published: April 2012

Background. Pancytopenia has multiple etiologies like megaloblastic anemia, aplastic anemia, leukemia, and various infections. We investigated the clinical, etiological and hematological profile including bone marrow morphology of patients with pancytopenia in relation to their vitamin B12 and folic acid status at a tertiary care referral hospital in north India.Methods. A total of 140 consecutive patients with pancytopenia were selected from June 2007 to December 2008. Bone marrow examination and other tests were carried out as warranted, including serum cobalamin and folate assays using liquid chromatography mass spectroscopy (LC MS/MS).Results. The study population consisted of 92 males and 48 females with a mean age of 32.8 years. Megaloblastic anemia 60.7%, aplastic anemia (7.8%), and leukemia (9.2%) were common causes. Infectious causes (16.4% of all cases) included leishmaniasis, HIV–AIDS, malaria and tuberculosis. Severe cobalamin deficiency (B12 < 100 pg/mL) was seen in 81% of all patients including 91.6% of patients with MA. In contrast, only 7.14% of all pancytopenic patients were folate deficient. Folate deficiency (<5 ng/mL) was seen in just 5% MA patients. Combined cobalamin and folate deficiency was seen in 5 patients (3.51%).Conclusion. Cobalamin deficiency was found to be more common in our setting and is largely underdiagnosed in the age of folate supplementation. Infectious diseases like tuberculosis, leishmaniasis, and increasingly HIV are important and treatable causes of pancytopenia. This is in contrast with the developed nations where the bulk of disease is due to malignancy or marrow aplasia.
Bovine Tuberculosis in Cattle in the Highlands of Cameroon: Seroprevalence Estimates and Rates of Tuberculin Skin Test Reactors at Modified Cut-Offs
Authors: Awah-Ndukum J. , Kudi A. C. , Bah G. S. , Bradley G. , Tebug S. F. , Dickmu P. L. , Njakoi H. N. , Agharih W. N.
Published: April 2012

The aim of this study was to obtain epidemiological estimates of bovine tuberculosis (TB) prevalence in cattle in the highlands of Cameroon using two population-based tuberculin skin test (TST) surveys in the years 2009 and 2010. However, prior to the TST survey in 2010, blood was collected from already chosen cattle for serological assay. Anti-bovine TB antibodies was detected in 37.17% of tested animals and bovine TB prevalence estimates were 3.59%–7.48%, 8.92%–13.25%, 11.77%–17.26% and 13.14%–18.35% for comparative TST at ≥4 mm, ≥3 mm and ≥2 mm cut-off points and single TST, respectively. The agreement between TST and lateral flow was generally higher in TST positive than in TST negative subjects. TheKcoefficients were 0.119, 0.234, 0.251 and 0.254 for comparative TST at ≥4 mm, ≥3 mm and ≥2 mm cut-off points and the single TST groups, respectively. Chi square statistics revealed that strong (P<0.05;χ2>48) associations existed between seroprevalence rates and TST reactors. The study suggested that using lateral flow assay and TST at severe interpretations could improve the perception of bovine TB in Cameroon. The importance of defining TST at modified cut-offs and disease status by post-mortem detection and mycobacterial culture of TB lesions in local environments cannot be overemphasised.
Exercise Intensity Modulation of Hepatic Lipid Metabolism
Authors: Lira Fábio S. , Carnevali Luiz C. , Zanchi Nelo E. , Santos Ronaldo VT. , Lavoie Jean Marc , Seelaender Marília
Published: April 2012

Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL), ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations in the liver as induced by exercise training has advanced considerably in the recent years, but much remains to be addressed. More recently, the adoption of high intensity exercise training has been put forward as a means of modulating hepatic metabolism. The purpose of the present paper is to summarise and discuss the merit of such new knowledge.
Tumor Hypoxia Predicts Biochemical Failure following Radiotherapy for Clinically Localized Prostate Cancer
Authors: Milosevic Michael , Warde Padraig , Ménard Cynthia , Chung Peter , Toi Ants , Ishkanian Adrian , McLean Michael , Pintilie Melania , Sykes Jenna , Gospodarowicz Mary , Catton Charles , Hill Richard P. , Bristow Robert
Published: April 2012

Purpose: Tumor hypoxia is an important determinant of outcome in many human malignancies and is associated with treatment resistance and metastases. The aim of this study was to determine the effect of hypoxia in patients with prostate cancer treated with radiotherapy.

Experimental Design: Tumor hypoxia was measured in 247 patients with clinically localized prostate cancer before radiotherapy, with or without hormonal therapy. The median pO2 was 6.8 mm Hg and the median hypoxic percentage less than 10 mm Hg (HP10) was 63%. The median follow-up was 6.6 years.

Results: The 5-year biochemical relapse-free rate (bRFR) was 78%. Prostrate-specific antigen and Gleason score were both associated with biochemical relapse and formed a baseline clinical model. The effect of hypoxia was found to vary with the duration of patient follow-up. HP10, when added to the clinical model, was an independent predictor of early bRFR (P = 0.019). The relationship between hypoxia and early bRFR was more pronounced when the analysis was restricted to 142 patients with bulk tumor at the site of the oxygen measurements (P = 0.004). Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during follow-up (P = 0.043), again with the effect being greatest early after completing treatment.

Conclusions: This is the largest clinical study of prostate cancer hypoxia with direct measurement of tumor oxygen levels. It shows that hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland. Clin Cancer Res; 18(7); 2108–14. ©2012 AACR.
Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer
Authors: Sadeghi Navid , Abbruzzese James L. , Yeung Sai-Ching J. , Hassan Manal , Li Donghui
Published: April 2012

Purpose: Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer.

Experimental Design: We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan–Meier plot, log-rank test, and Cox proportional hazards regression models.

Results: Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ2 test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52–0.89) in a univariate model (P = 0.004), 0.64 (0.48–0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44–0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only.

Conclusions: Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population. Clin Cancer Res; 18(10); 2905–12. ©2012 AACR.
Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing's Sarcoma Family Tumors
Authors: Naing Aung , LoRusso Patricia , Fu Siqing , Hong David S. , Anderson Pete , Benjamin Robert S. , Ludwig Joseph , Chen Helen X. , Doyle Laurence A. , Kurzrock Razelle
Published: April 2012

Purpose: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R).

Experimental Design: Patients received cixutumumab, 6 mg/kg i.v. weekly, and temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months.

Results: Twenty patients [17 with Ewing's sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT)] were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I–II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose.

Conclusion: Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors. Clin Cancer Res; 18(9); 2625–31. ©2012 AACR.
Metformin and Pancreatic Cancer: A Clue Requiring Investigation
Authors: Pollak Michael
Published: April 2012

Laboratory models show antineoplastic activity of metformin under certain conditions, and pharmacoepidemiologic studies have reported reduced cancer burden among diabetics taking metformin. Therefore, the hypothesis that metformin has antineoplastic activity is receiving increasing attention. However, gaps in knowledge must be addressed before metformin can be “repurposed” for oncologic indications. Clin Cancer Res; 18(10); 2723–5. ©2012 AACR.
Metformin Prevents Liver Tumorigenesis by Inhibiting Pathways Driving Hepatic Lipogenesis
Authors: Bhalla Kavita , Hwang Bor Jang , Dewi Ruby E. , Twaddel William , Goloubeva Olga G. , Wong Kwok-Kin , Saxena Neeraj K. , Biswal Shyam , Girnun Geoffrey D.
Published: April 2012

A number of factors have been identified that increase the risk of hepatocellular carcinoma (HCC). Recently it has become appreciated that type II diabetes increases the risk of developing HCC. This represents a patient population that can be identified and targeted for cancer prevention. The biguanide metformin is a first-line therapy for the treatment of type II diabetes in which it exerts its effects primarily on the liver. A role of metformin in HCC is suggested by studies linking metformin intake for control of diabetes with a reduced risk of HCC. Although a number of preclinical studies show the anticancer properties of metformin in a number of tissues, no studies have directly examined the effect of metformin on preventing carcinogenesis in the liver, one of its main sites of action. We show in these studies that metformin protected mice against chemically induced liver tumors. Interestingly, metformin did not increase AMPK activation, often shown to be a metformin target. Rather metformin decreased the expression of several lipogenic enzymes and lipogenesis. In addition, restoring lipogenic gene expression by ectopic expression of the lipogenic transcription factor SREBP1c rescues metformin-mediated growth inhibition. This mechanism of action suggests that metformin may also be useful for patients with other disorders associated with HCC in which increased lipid synthesis is observed. As a whole these studies show that metformin prevents HCC and that metformin should be evaluated as a preventive agent for HCC in readily identifiable at-risk patients. Cancer Prev Res; 5(4); 544–52. ©2012 AACR.
Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions
Authors: Vitale-Cross Lynn , Molinolo Alfredo A. , Martin Daniel , Younis Rania H. , Maruyama Takashi , Patel Vyomesh , Chen Wanjun , Schneider Abraham , Gutkind J. Silvio
Published: April 2012

Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mTOR complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type II diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and -independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression. Cancer Prev Res; 5(4); 562–73. ©2012 AACR.
Metformin and Hepatic Carcinogenesis
Authors: Pollak Michael , Gonzalez-Angulo Ana M.
Published: April 2012

Retrospective, hypothesis-generating population studies suggest that diabetics treated with metformin have a substantially reduced risk of several cancers, including hepatoma, relative to diabetics on other therapies. In this issue of the journal (beginning on page 544), Bhalla and colleagues contribute to the growing literature on metformin effects in experimental carcinogenesis models, showing reduced carcinogen-induced hepatoma in mice. The clinical need to develop novel prevention strategies for hepatoma is obvious, given an increasing prevalence and poor prognosis. The clues that metformin or related biguanides may have utility in this area justify accelerated laboratory research, as more data concerning mechanism, pharmacokinetics, and predictors of efficacy will help to optimize the design of clinical trials. Cancer Prev Res; 5(4); 500–2. ©2012 AACR.
Metformin Accelerates the Growth of BRAFV600E-Driven Melanoma by Upregulating VEGF-A
Authors: Martin Matthew J. , Hayward Robert , Viros Amaya , Marais Richard
Published: April 2012

The antidiabetic drug metformin has antitumor activity in a variety of cancers because it blocks cell growth by inhibiting TORC1. Here, we show that melanoma cells that are driven by oncogenic BRAF are resistant to the growth-inhibitory effects of metformin because RSK sustains TORC1 activity even when AMP-activated protein kinase (AMPK) is activated. We further show that AMPK targets the dual-specificity protein phosphatase DUSP6 for degradation and this increases ERK activity, which then upregulates the VEGF-A protein. Critically, this drives angiogenesis and accelerates the growth of BRAF-driven tumors in mice. Unexpectedly, however, when VEGF signaling is inhibited, instead of accelerating tumor growth, metformin inhibits tumor growth. Thus, we show that BRAF-driven melanoma cells are resistant to the antigrowth effects of AMPK and that AMPK mediates cell-autonomous and cell-nonautonomous effects that accelerate the growth of these cells in vivo.

Significance: Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients. Cancer Discov; 2(4); 344–55. ©2012 AACR.

This article is highlighted in the In This Issue feature, 288
Differential Sensitivity of Glioma- versus Lung Cancer–Specific EGFR Mutations to EGFR Kinase Inhibitors
Authors: Vivanco Igor , Robins H. Ian , Rohle Daniel , Campos Carl , Grommes Christian , Nghiemphu Phioanh Leia , Kubek Sara , Oldrini Barbara , Chheda Milan G. , Yannuzzi Nicolas , Tao Hui , Zhu Shaojun , Iwanami Akio , Kuga Daisuke , Dang Julie , Pedraza Alicia , Brennan Cameron W. , Heguy Adriana , Liau Linda M. , Lieberman Frank , Yung W. K. Alfred , Gilbert Mark R. , Reardon David A. , Drappatz Jan , Wen Patrick Y. , Lamborn Kathleen R. , Chang Susan M. , Prados Michael D. , Fine Howard A. , Horvath Steve , Wu Nian , Lassman Andrew B. , DeAngelis Lisa M. , Yong William H. , Kuhn John G. , Mischel Paul S. , Mehta Minesh P. , Cloughesy Timothy F. , Mellinghoff Ingo K.
Published: April 2012

Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types.

Significance: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain. Cancer Discov; 2(5); 458–71. ©2012 AACR.

Read the Commentary on this article by Park and Lemmon, p. 398.

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Kinetics of Inhibitor Cycling Underlie Therapeutic Disparities between EGFR-Driven Lung and Brain Cancers
Authors: Barkovich Krister J. , Hariono Sujatmi , Garske Adam L. , Zhang Jie , Blair Jimmy A. , Fan Qi-Wen , Shokat Kevan M. , Nicolaides Theodore , Weiss William A.
Published: April 2012

Although mutational activation of the epidermal growth factor receptor (EGFR) features prominently in glioma and non–small cell lung cancer (NSCLC), inhibitors of EGFR improve survival only in patients with NCSLC. To understand how mutations in EGFR influence response to therapy, we generated glioma cells expressing either glioma- or NSCLC-derived alleles and quantified kinase-site occupancy by clinical inhibitors with the use of a novel affinity probe and kinetic methodology. At equivalent doses, erlotinib achieved lower kinase-site occupancy in glioma-derived EGFRvIII compared with NSCLC-derived EGFR mutants. Kinase-site occupancy correlated directly with cell-cycle arrest. EGFRvIII released erlotinib rapidly compared with wild-type EGFR, whereas NSCLC-derived mutants released erlotinib slowly.

Significance: These data suggest that kinase-site occupancy is a biomarker for efficacy of EGFR inhibitors, that rapid binding and release of erlotinib in glioma-derived EGFRvIII opposes the blockade of downstream signaling, and that slower cycling of erlotinib within the active site of NSCLC-derived mutants underlies their improved clinical response. Cancer Discov; 2(5); 450–7. ©2012 AACR.

Read the Commentary on this article by Park and Lemmon, p. 398.

This article is highlighted in the In This Issue feature, p. 377.
Imaging Androgen Receptor Signaling with a Radiotracer Targeting Free Prostate-Specific Antigen
Authors: Ulmert David , Evans Michael J. , Holland Jason P. , Rice Samuel L. , Wongvipat John , Pettersson Kim , Abrahamsson Per-Anders , Scardino Peter T. , Larson Steven M. , Lilja Hans , Lewis Jason S. , Sawyers Charles L.
Published: April 2012

Despite intense efforts to develop radiotracers to detect cancers or monitor treatment response, few are widely used as a result of challenges with demonstrating clear clinical use. We reasoned that a radiotracer targeting a validated clinical biomarker could more clearly assess the advantages of imaging cancer. The virtues and shortcomings of measuring secreted prostate-specific antigen (PSA), an androgen receptor (AR) target gene, in patients with prostate cancer are well documented, making it a logical candidate for assessing whether a radiotracer can reveal new (and useful) information beyond that conferred by serum PSA. Therefore, we developed 89Zr-labeled 5A10, a novel radiotracer that targets “free” PSA. 89Zr–5A10 localizes in an AR-dependent manner in vivo to models of castration-resistant prostate cancer, a disease state in which serum PSA may not reflect clinical outcomes. Finally, we demonstrate that 89Zr–5A10 can detect osseous prostate cancer lesions, a context where bone scans fail to discriminate malignant and nonmalignant signals.

Significance: This report establishes that AR-dependent changes in PSA expression levels can be quantitatively measured at tumor lesions using a radiotracer that can be rapidly translated for human application and advances a new paradigm for radiotracer development that may more clearly highlight the unique virtues of an imaging biomarker. Cancer Discov; 2(4); 320–7. ©2012 AACR.

Read the Commentary on this article by Herschman and Czernin, p. 301

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Is There a Nonverbal Period of Development?
Authors: Vivona Jeanine M.
Published: April 2012

That the infant lives in a nonverbal sensorimotor world is widely believed. Yet this notion is being challenged by research, in a range of fields, that depicts the young infant as actively attuned to aural speech from birth and able to process and use its sounds and meanings well before the end of the first year. Following a selective review of the research on infant speech processing between birth and age twelve months, three questions are identified that highlight the theoretical and clinical implications of this research for psychoanalytic conceptualizations of infancy, the nature of language, and clinical process. The research, it is concluded, identifies the operation of linguistic and conceptual processes in early life, processes that may intersect with the experiential and emotional processes with which psychoanalysis is already concerned. Moreover, this research raises questions about the view that the nature of infancy is essentially nonverbal.
An Operational Analysis of the Clinical Goals of Psychoanalytic Technique
Authors: Levey Mark
Published: April 2012

An operational description is presented of the clinical goals of analytic technique shared by various analytic orientations. This operational schema of their similarities is then used to organize their differences. In this schema, analytic schools differ from one another in three areas: the kind of unconscious content looked for in uncovering; aspects of the process considered subject to direct intervention; and the most effective stance and interventions with which to pursue their shared analytic goals. Organizing the differences between approaches in the context of shared analytic process goals makes it possible to clarify implicit clinical assumptions and to develop empirical rather than theoretical clinical discussions between analytic orientations. Understanding the intent or purpose of an intervention is useful in comparing approaches, exploring clinical controversies, clarifying implicit clinical assumptions, and understanding approaches more deeply in their own terms.
An Atypical Case of Islet Cell Hyperplasia in a Wistar Rat
Authors: Shirai Norimitsu , Papanikolaou Alexandros , Perry Rick
Published: April 2012

The present article describes an unusual proliferative islet finding observed incidentally in a young male Wistar rat in a 2-week toxicity study. Histologically, the islet lesion was characterized by diffuse enlargement of the islets, which consisted of peripheral proliferation of non-insulin-containing islet cells surrounding normal-appearing insulin-containing cells in the center. To the authors’ knowledge, this is the first report of spontaneous proliferative islet lesion composed of non-insulin-containing cells in young rats.
Three Validity Studies of the Daily Progress Report in Relationship to the Check, Connect, and Expect Intervention
Authors: Stage Scott A. , Cheney Doug , Lynass Lori , Mielenz Christine , Flower Andrea
Published: April 2012

Elementary students ( N = 104) at risk for severe behavior problems or with special education eligibility participated in three validity studies of the daily progress report (DPR) used in a Tier 2 behavioral intervention known as Check, Connect, and Expect (CCE). In Study 1, the relationship between teachers’ ratings of students’ externalizing problem behavior and students’ DPR scores was established. In Study 2, behavior specialists’ use of the DPR to make student treatment decisions in the CCE program was partially validated. The utility of placing students with low DPR percentages into interventions based on functional behavior assessment (FBA) was validated. In Study 3, the treatment duration of 4 weeks above the 75th percentile on the DPR proved to be an efficacious treatment outcome predictor versus 8 weeks duration, which was originally recommended in the CCE protocol. Future implementation of the CCE program would suggest assigning students who meet the 4-week DPR criterion to the self-monitoring phase of the intervention, allowing behavior specialists more time to facilitate individualized FBA-based interventions for students who fail to respond to the basic intervention.
Effects of Multimedia Goal-Setting Instruction on Students’ Knowledge of the Self-Determined Learning Model of Instruction and Disruptive Behavior
Authors: Mazzotti Valerie L. , Test David W. , Wood Charles L.
Published: April 2012

Students at risk for, or with, emotional disturbance during preadolescence struggle to adjust socially, behaviorally, and academically and often make choices about relationships that support problem behaviors. Research suggests explicitly teaching self-determination skills as early as preschool may prevent referral to special education with a label of emotional disturbance. This study examined the effects of a multimedia goal-setting intervention on students’ knowledge of the self-determined learning model of instruction and disruptive behavior. Results indicated a functional relationship between the independent variable and dependent variables. Limitations, suggestions for future research, and implications for practice are provided.
The Effects of Self-Monitoring on Teachers’ Use of Specific Praise
Authors: Simonsen Brandi , MacSuga Ashley S. , Fallon Lindsay M. , Sugai George
Published: April 2012

Teachers typically enter the field with limited training in classroom management, and research demonstrates that training alone does not result in improved practice. Typically, researchers have relied on time-intensive training packages that include performance feedback to improve teachers’ use of classroom management practices; however, initial evidence suggests that self-management may be an effective and efficient alternative. In this study, the authors directly compared the effects of three different self-monitoring conditions (tally, count, and rate) and no self-monitoring on five middle school teachers’ rate of specific praise using an alternating treatments design. The authors also included baseline and follow-up phases to descriptively explore the effects of self-monitoring across time. Results indicate that noting each instance of specific praise by either tallying or using a counter resulted in optimal performance, and teachers preferred using a counter. Additional study results, limitations, and implications are discussed.
Energy Cost of Walking and Its Association With Gait Parameters, Daily Activity, and Fatigue in Persons With Mild Multiple Sclerosis
Authors: Motl Robert W , Sandroff Brian M , Suh Yoojin , Sosnoff Jacob J
Published: April 2012

Background. Energy cost of walking (Cw) is elevated in persons with multiple sclerosis (MS), perhaps because of gait impairment, and may impact daily activity and fatigue. Objective. The authors examined for associations between Cw, spatiotemporal gait parameters, daily activity, and perceived fatigue in persons with mild MS. Methods. Forty-four participants completed 4 trials of walking on a GAITRite mat and one 6-minute trial of walking on a treadmill at a constant, controlled speed of 54 m min−1 while expired gases were analyzed for oxygen consumption. Participants also completed the Fatigue Severity Scale (FSS) and wore a waist-mounted accelerometer for 7 days. Results. Cw was significantly and inversely associated with gait speed ( r = −.25) and stride length ( r = −.32) and positively associated with double limb support ( r = .27). Cw was significantly and inversely associated with daily accelerometer activity counts ( r = −.35) and positively associated with FSS scores (ρ = .31). Conclusion. The results support the development and application of rehabilitation strategies to address impaired gait parameters as an approach to improve Cw, daily activities, and fatigue.
Getting Neurorehabilitation Right
Authors: Krakauer John W. , Carmichael S. Thomas , Corbett Dale , Wittenberg George F.
Published: April 2012

Animal models suggest that a month of heightened plasticity occurs in the brain after stroke, accompanied by most of the recovery from impairment. This period of peri-infarct and remote plasticity is associated with changes in excitatory/inhibitory balance and the spatial extent and activation of cortical maps and structural remodeling. The best time for experience and training to improve outcome is unclear. In animal models, very early (<5 days from onset) and intense training may lead to increased histological damage. Conversely, late rehabilitation (>30 days) is much less effective both in terms of outcome and morphological changes associated with plasticity. In clinical practice, rehabilitation after disabling stroke involves a relatively brief period of inpatient therapy that does not come close to matching intensity levels investigated in animal models and includes the training of compensatory strategies that have minimal impact on impairment. Current rehabilitation treatments have a disappointingly modest effect on impairment early or late after stroke. Translation from animal models will require the following: (1) substantial increases in the intensity and dosage of treatments offered in the first month after stroke with an emphasis on impairment; (2) combinational approaches such as noninvasive brain stimulation with robotics, based on current understanding of motor learning and brain plasticity; and (3) research that emphasizes mechanistic phase II studies over premature phase III clinical trials.
European Union Standards for Tuberculosis Care
Authors: Migliori G.B. , Zellweger J.P. , Abubakar I. , Ibraim E. , Caminero J.A. , De Vries G. , D'Ambrosio L. , Centis R. , Sotgiu G. , Menegale O. , Kliiman K. , Aksamit T. , Cirillo D.M. , Danilovits M. , Dara M. , Dheda K. , Dinh-Xuan A.T. , Kluge H. , Lange C. , Leimane V. , Loddenkemper R. , Nicod L.P. , Raviglione M.C. , Spanevello A. , Thomsen V.Ø. , Villar M. , Wanlin M. , Wedzicha J.A. , Zumla A. , Blasi F. , Huitric E. , Sandgren A. , Manissero D.
Published: April 2012

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB).

The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting.

A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed.

These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.
Glucagon-like peptides 1 and 2 and vasoactive intestinal peptide are neuroprotective on cultured and mast cell co-cultured rat myenteric neurons
Authors: Voss Ulrikke , Sand Elin , Hellström Per M , Ekblad Eva
Published: April 2012

Background

Neuropathy is believed to be a common feature of functional and inflammatory intestinal diseases. Vasoactive intestinal peptide (VIP) is an acknowledged neuroprotective agent in peripheral, including enteric, and central neurons. The proglucagon-like hormones glucagon-like peptide 1 and 2 (GLP1 and GLP2) belong to the secretin/glucagon/VIP superfamily of peptides and GLP1 and GLP2 receptors are expressed in enteric neurons. Possible neuroprotective effects of these peptides were investigated in the present study.

Methods

GLP1, GLP2 and VIP were added to cultured myenteric neurons from rat small intestine or to co-cultures of myenteric neurons and rat peritoneal mast cells. Receptor selectivity was tested by the simultaneous presence of a GLP1 receptor antagonist (exendin (9-39) amide) or a VIP receptor antagonist (hybrid of neurotensin 6-11 and VIP 7-28). Neuronal survival was examined using immunocytochemistry and cell counting.

Results

GLP1, GLP2 and VIP significantly and concentration-dependently enhanced neuronal survival. In addition the peptides efficiently counteracted mast cell-induced neuronal cell death in a concentration-dependent manner. Exendin(9-39)amide reversed GLP1-induced neuroprotection while GLP2- and VIP-induced enhanced neuronal survival were unaffected. The VIP receptor antagonist reversed GLP1- and VIP-induced neuroprotection while the GLP2-induced effect on neuronal survival was unaffected.

Conclusions

By activating separate receptors VIP, GLP1 and GLP2 elicit neuroprotective effects on rat myenteric neurons cultured with or without mast cells. This implies a powerful therapeutic potential of these peptides in enteric neuropathies with a broad spectrum of applications from autoimmunity to functional disorders.
Enhancement of the proline and nitric oxide synthetic pathway improves fermentation ability under multiple baking-associated stress conditions in industrial baker's yeast
Authors: Sasano Yu , Haitani Yutaka , Hashida Keisuke , Ohtsu Iwao , Shima Jun , Takagi Hiroshi
Published: April 2012

Background

During the bread-making process, industrial baker's yeast, mostly Saccharomyces cerevisiae, is exposed to baking-associated stresses, such as air-drying and freeze-thaw stress. These baking-associated stresses exert severe injury to yeast cells, mainly due to the generation of reactive oxygen species (ROS), leading to cell death and reduced fermentation ability. Thus, there is a great need for a baker's yeast strain with higher tolerance to baking-associated stresses. Recently, we revealed a novel antioxidative mechanism in a laboratory yeast strain that is involved in stress-induced nitric oxide (NO) synthesis from proline via proline oxidase Put1 and N-acetyltransferase Mpr1. We also found that expression of the proline-feedback inhibition-less sensitive mutant γ-glutamyl kinase (Pro1-I150T) and the thermostable mutant Mpr1-F65L resulted in an enhanced fermentation ability of baker's yeast in bread dough after freeze-thaw stress and air-drying stress, respectively. However, baker's yeast strains with high fermentation ability under multiple baking-associated stresses have not yet been developed.

Results

We constructed a self-cloned diploid baker's yeast strain with enhanced proline and NO synthesis by expressing Pro1-I150T and Mpr1-F65L in the presence of functional Put1. The engineered strain increased the intracellular NO level in response to air-drying stress, and the strain was tolerant not only to oxidative stress but also to both air-drying and freeze-thaw stresses probably due to the reduced intracellular ROS level. We also showed that the resultant strain retained higher leavening activity in bread dough after air-drying and freeze-thaw stress than that of the wild-type strain. On the other hand, enhanced stress tolerance and fermentation ability did not occur in the put1-deficient strain. This result suggests that NO is synthesized in baker's yeast from proline in response to oxidative stresses that induce ROS generation and that increased NO plays an important role in baking-associated stress tolerance.

Conclusions

In this work, we clarified the importance of Put1- and Mpr1-mediated NO generation from proline to the baking-associated stress tolerance in industrial baker's yeast. We also demonstrated that baker's yeast that enhances the proline and NO synthetic pathway by expressing the Pro1-I150T and Mpr1-F65L variants showed improved fermentation ability under multiple baking-associated stress conditions. From a biotechnological perspective, the enhancement of proline and NO synthesis could be promising for breeding novel baker's yeast strains.
Plasmodium yoelii blood-stage primes macrophage-mediated innate immune response through modulation of toll-like receptor signalling
Authors: Fu Yong , Ding Yan , Zhou Taoli , Fu Xiaolan , Xu Wenyue
Published: April 2012

Background

Toll-like receptors (TLRs) signalling is reported to be primed by the infection of human malaria parasite,Plasmodium falciparum. However, little is known about the regulation of macrophages TLR signalling by the infection of lethal or non-lethal strain of rodent malaria parasites.

Methods

BALB/c mice were infected with non-lethal strainPlasmodium yoelii17XNL or lethal strainP. yoelii17XL. Peritoneal macrophages were isolated to study its immune response to pRBC lysate, and TLRs (TLR2, TLR4, and TLR9) agonists, and the expression of TLRs and intracellular signalling molecules were also investigated by flow cytometry and semi-quantitive RT-PCR.

Results

The reactivity of peritoneal macrophages from the mice infected with lethal strainP. y17XL or non-lethal strainP. y17XNL were enhanced to pRBC lysate, and TLR2, TLR4, and TLR9 agonists at one, three and five days post-infection. Of all the tested TLRs, only TLR2 was up-regulated on peritoneal macrophages of mice infected with either strain. However, transcription of intracellular signalling molecules MyD88, IRAK-1, and TRAF-6 was significantly up-regulated in peritoneal macrophages from mice infected either withP. yoelii17XL orP. yoelii17XNL at one, three and five days post-infection. However, the enhanced TLRs response of macrophage fromP. yoelii17XNL-infected mice persisted for a much longer time than that fromP. yoelii17XL-infected mice.

Conclusion

BothP. yoelii17XL and 17XNL strains could enhance the response of peritoneal macrophages to pRBC lysate and TLR agonists, through up-regulating the expression of TLR2 and intracellular signalling molecules MyD88, IRAK-1, and TRAF-6. In addition, prolonged high response of macrophage fromP. yoelii17XNL-infected mice might be associated with the more efficiently controlling ofP. yoelii17XNL growth in mice at early stage.
Genetic polymorphism of merozoite surface protein 2 and prevalence of K76T pfcrt mutation in Plasmodium falciparum field isolates from Congolese children with asymptomatic infections
Authors: Koukouikila-Koussounda Felix , Malonga Vladimir , Mayengue Pembe Issamou , Ndounga Mathieu , Vouvoungui Christevy Jeannhey , Ntoumi Francine
Published: April 2012

Background

In order to prepare the field site for future interventions, the prevalence of asymptomatic Plasmodium falciparum infection was evaluated in a cohort of children living in Brazzaville. Plasmodium falciparum merozoite surface protein 2 gene (msp 2) was used to characterize the genetic diversity and the multiplicity of infection. The prevalence of mutant P. falciparum chloroquine resistance transporter (pfcrt) allele in isolates was also determined.

Methods

Between April and June 2010, 313 children below 10 years of age enrolled in the cohort for malaria surveillance were screened for P. falciparum infection using microscopy and polymerase chain reaction (PCR). The children were selected on the basis of being asymptomatic. Plasmodium falciparum msp2 gene was genotyped by allele-specific nested PCR and the pfcrt K76T mutation was detected using nested PCR followed by restriction endonuclease digestion.

Results

The prevalence of asymptomatic P. falciparum infections was 8.6% and 16% by microscopy and by PCR respectively. Allele typing of the msp2 gene detected 55% and 45% of 3D7 and FC27 allelic families respectively. The overall multiplicity of infections (MOI) was 1.3. A positive correlation between parasite density and multiplicity of infection was found. The prevalence of the mutant pfcrt allele (T76) in the isolates was 92%.

Conclusion

This is the first molecular characterization of P. falciparum field isolates in Congolese children, four years after changing the malaria treatment policy from chloroquine (CQ) to artemisinin-based combination therapy (ACT). The low prevalence of asymptomatic infections and MOI is discussed in the light of similar studies conducted in Central Africa.
Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity
Authors: van Maarseveen Noortje M , Andersson Dan , Lepšík Martin , Fun Axel , Schipper Pauline J , de Jong Dorien , Boucher Charles AB , Nijhuis Monique
Published: April 2012

Background

Mutations in the substrate of HIV-1 protease, especially changes in the NC/p1 cleavage site, can directly contribute to protease inhibitor (PI) resistance and also compensate for defects in viral replicative capacity (RC) due to a drug resistant protease. These NC/p1 changes are known to enhance processing of the Gag protein. To investigate the capacity of HIV-1 to modulate Gag cleavage and its consequences for PI resistance and RC, we performed a detailed enzymatic and virological analysis using a set of PI resistant NC/p1 variants (HXB2431V, HXB2436E+437T, HXB2437T and HXB2437V).

Results

Here, we demonstrate that single NC/p1 mutants, which displayed only a slight increase in PI resistance did not show an obvious change in RC. In contrast, the double NC/p1 mutant, which displayed a clear increase in processing efficiency and PI resistance, demonstrated a clear reduction in RC. Cleavage analysis showed that a tridecameric NC/p1 peptide representing the double NC/p1 mutant was cleaved in two specific ways instead of one.

The observed decrease in RC for the double NC/p1 mutant (HXB2436E+437T) could (partially) be restored by either reversion of the 436E change or by acquisition of additional changes in the NC/p1 cleavage site at codon 435 or 438 as was revealed during in vitro evolution experiments. These changes not only restored RC but also reduced PI resistance levels. Furthermore these changes normalized Gag processing efficiency and obstructed the novel secondary cleavage site observed for the double NC/p1 mutant.

Conclusions

The results of this study clearly demonstrate that HIV-1 can modulate Gag processing and thereby PI resistance. Distinct increases in Gag cleavage and PI resistance result in a reduced RC that can only be restored by amino acid changes in NC/p1 which reduce Gag processing to an optimal rate.