bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure–function relationships of the N‐terminus of receptor activity‐modifying proteins
Authors: Qi Tao , Hay Debbie L
Published: December 2009

The receptor activity‐modifying proteins (RAMPs) are a family of three single transmembrane proteins that have been identified as accessory proteins to some G‐protein‐coupled receptors (GPCRs). They can regulate their pharmacology, forward trafficking and recycling, depending on the GPCR. The best characterized receptor complexes formed by RAMPs and GPCRs are the calcitonin peptide family receptors. The association of RAMP1 with the calcitonin receptor‐like receptor (CL) constitutes the calcitonin gene‐related peptide receptor, whereas RAMP2 or 3 with CL generates adrenomedullin receptors. In this case, the RAMPs substantially alter the pharmacology and trafficking properties of this GPCR. Amylin receptor subtypes are formed from calcitonin receptor (CTR) interactions with RAMPs. Although the RAMPs themselves are not responsive to calcitonin peptide family ligands, there is clear evidence that they participate in ligand binding, although it is still unclear whether this is by directly participating in binding or through allosteric modulation of CL or CTR. A considerable amount of mutagenesis data have now been generated on RAMPs to try and identify the residues that play a role in ligand interactions, and to also identify which residues in RAMPs interact with CL and CTR. This review will focus on RAMP mutagenesis studies with CL, summarizing and discussing the available data in association with current RAMP models and structures. The data reveal key regions in RAMPs that are important for ligand binding and receptor interactions.

This article is part of a themed section on Molecular Pharmacology of GPCR. To view the editorial for this themed section visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00695.x
The accumulation and metabolism of zidovudine in 3T3‐F442A pre‐adipocytes
Authors: Janneh Omar , Owen Andrew , Bray Patrick G. , Back David J. , Pirmohamed Munir
Published: December 2009

Background and purpose: Cultured pre‐adipocytes accumulate and metabolize zidovudine (ZDV), but its mode of accumulation into these cells is unclear. We investigated the mode of accumulation of [3H]‐ZDV, and the impact of changes in external pH and modulators of drug transporters on its accumulation and metabolism.

Experimental approach: The initial rate and steady‐state accumulation of [3H]‐ZDV were measured in 3T3‐F442A cells. P‐glycoprotein (P‐gp) expression was detected by Western blotting. External pH was varied, and modulators of intracellular pH and drug transporters were used to study the mode of accumulation of ZDV. Phosphorylated ZDV metabolites were detected by high‐performance liquid chromatography.

Key results: Intracellular accumulation of ZDV was rapid, reaching equilibrium within 20 min; nigericin increased accumulation by 1.9‐fold, but this did not alter the generation of ZDV mono‐, di‐ and triphosphate. The accumulation and metabolism were pH dependent, being maximal at pH 7.4 and least at pH 5.1. Monensin, carbonyl cyanidep‐trifluoromethoxy) phenyl hydrazone, brefeldin A, bafilomycin A1 and concanamycin A increased accumulation; 2‐deoxyglucose, dipyridamole, thymidine and tetraphenylphosphonium inhibited accumulation. The accumulation was saturable; the derivedKdand capacity of binding were 250 nmol per 106cells and 265 nM respectively. 3T3‐F442A cells express P‐gp; inhibitors of P‐gp (XR9576 and verapamil), P‐gp/BCRP (GF120918), multidrug resistance protein (MRP) (MK571) and MRP/OATP (probenecid) increased the accumulation of ZDV. Saquinavir, ritonavir, amprenavir and lopinavir increased accumulation.

Conclusions and implications: The accumulation of ZDV in 3T3‐F442A cells was rapid, energy dependent, saturable and pH sensitive. Western blot analysis showed that 3T3‐F442A cells express P‐gp, and direct inhibition assays suggest that ZDV is a substrate of P‐gp and MRP.
Genetic Structure of Herpetofauna on Halmahera Island, Indonesia: Implications for Aketajawe‐Lolobata National Park
Authors: SETIADI MOHAMMAD IQBAL , HAMIDY AMIR , ABIDIN ZAINAL , SUSANTO DWI , BROWN RAFE M. , PETERSON A. TOWNSEND , LI XINGONG , EVANS BEN J.
Published: December 2009

Abstract: Genetic variation within species—a priority for biodiversity conservation—is influenced by natural selection, demography, and stochastic events such as genetic drift. We evaluated the role of these factors in 14 codistributed species of reptiles and amphibians on the Indonesian island of Halmahera by testing whether their molecular variation was correlated with geographic distance, ecology, riverine barriers, or Halmahera's paleoisland precursors. We found support for isolation by distance effects in four species. Two of these four were also significantly affected either by rivers or by ecology. A fifth species was significantly affected by ecology and a sixth was significantly affected by Halmahera's paleoislands. [Correction added after publication 9 December 2009: the previous sentence was edited for clarity.] These findings—the most comprehensive survey of multispecies genetic variation on Halmahera to date—bode well for the efficacy of the recently established Aketajawe‐Lolobata National Park in conserving a substantial component of vertebrate genetic variation on this island. Future success of conservation efforts will depend crucially, of course, on funding for and enforcement of conservation management of this park.
Measuring and Monitoring Illegal Use of Natural Resources
Authors: GAVIN MICHAEL C. , SOLOMON JENNIFER N. , BLANK SARA G.
Published: December 2009

Abstract:  Illegal use of natural resources is a threat to biodiversity globally, but research on illegal activities has methodological challenges. We examined 100 studies that empirically identify targeted resources, techniques used to procure resources illegally, locations of illegal activities, characteristics of typical violators, incentives driving illegal use of resources, magnitude of the problem of illegal use (e.g., quantities used), or frequency of illegal activity. We based our evaluation of the methods used in these studies on their ability to provide these empirical data, relative labor demands, training and technology requirements, and levels of uncontrollable bias. We evaluated eight different methods: law‐enforcement records, indirect observation, self‐reporting, direct observation, direct questioning, randomized response technique (a survey method designed to improve accuracy of responses to sensitive questions), forensics, and modeling. Different situations favored different methods, each with distinct advantages and limitations. Six context‐specific factors—location of resource use (in situ vs. ex situ), budget, technology and training capacity, ease of detection of illegal activity, scope of illegal activity (limited vs. widespread), and researchers’ willingness to accept bias in results—help narrow the choice of methods. Several methodological concerns applied to any study of illegal resource use: regular monitoring can detect trends; modeling can incorporate sampling error and data uncertainties; researchers must manage levels of bias that vary between methods; triangulation of results from multiple methods can improve accuracy. No method is a panacea, but a combination of techniques can help address the lack of data on illegal activity. Researchers empirically compared results from different methods in only four studies, and no one has compared more than two methods simultaneously. Conservation would benefit from more research focused on: methods comparisons that include cost effectiveness, time efficiency, and statistical rigor; unique applications of the eight techniques currently in use; and testing of new methods.
Prevalence and Severity of Gait Disorders in Alzheimer's and Non‐Alzheimer's Dementias
Authors: Allan Louise M. , Ballard Clive G. , Burn David J. , Kenny Rose Anne
Published: December 2009

Objectives: To compare the prevalence, severity, and type of gait and balance disorders in Alzheimer's disease (AD), vascular dementia (VaD), Parkinson's disease with dementia (PDD), dementia with Lewy bodies (DLB), Parkinson's disease without dementia (PD), and age‐matched controls.

Design: Cross‐sectional.

Setting: Secondary care clinics in geriatric psychiatry, neurology, and geriatrics.

Participants: Two hundred forty‐five participants aged 65 and older (AD, n=40; VaD, n=39; PDD, n=46; DLB, n=32; PD, n=46; and controls, n=42).

Measurements: Prevalence and severity of gait and balance disorders were assessed using the Tinetti gait and balance scale. The types of gait disorders in each diagnostic group were classified using the Nutt et al. classification.

Results: Gait and balance disorders were more common with PDD (93%), VaD (79%), and DLB (75%) than with PD (43%) and AD (25%) and in controls (7%). The risk of gait and balance disorder was higher in the non‐Alzheimer's dementia groups (VaD, PDD, and DLB) than in the AD group (odds ratio=15 (95% confidence interval=6–37). If a gait disorder was present in mild dementia (Cambridge Examination for Mental Disorders of the Elderly cognitive subsection score >65), this was diagnostic of non‐Alzheimer's dementia, with sensitivity of 78% and specificity of 100%. Non‐Alzheimer's dementia groups had worse Tinetti gait and balance scores than the AD group (all P<.001). The types of gait disorders discriminated between non‐Alzheimer's dementias.

Conclusion: The findings support the idea that gait and balance assessment may augment the diagnostic evaluation of dementia.
Effect of Arthritis in Middle Age on Older‐Age Functioning
Authors: Covinsky Kenneth E. , Lindquist Karla , Dunlop Dorothy D. , Gill Thomas M. , Yelin Edward
Published: December 2009

OBJECTIVES: To examine whether symptomatic arthritis in middle age predicts the earlier onset of functional difficulties (difficulty with activities of daily living (ADLs) and walking) that are associated with loss of independence in older persons.

DESIGN: Prospective longitudinal study.

SETTING: The Health and Retirement Study, a nationally representative sample of persons aged 50 to 62 at baseline who were followed for 10 years.

PARTICIPANTS: Seven thousand five hundred forty‐three subjects with no difficulty in mobility or ADL function at baseline.

MEASUREMENTS: Arthritis was measured at baseline according to self‐report. The primary outcome was time to persistent difficulty in one of five ADLs or mobility (walking several blocks or up a flight of stairs). Difficulty with ADLs or mobility was assessed according to subject interview every 2 years. Analyses were adjusted for other comorbid conditions, body mass index, exercise, and demographic characteristics.

RESULTS: Twenty‐nine percent of subjects reported arthritis at baseline. Subjects with arthritis were more likely to develop persistent difficulty in mobility or ADL function over 10 years of follow‐up (34% vs 18%, adjusted hazard ratio (HR)=1.63, 95% confidence interval (CI)=1.43–1.86). When each component of the primary outcome was assessed separately, arthritis was also associated with persistent difficulty in mobility (30% vs 16%, adjusted HR=1.55, 95% CI=1.41–1.71) and persistent difficulty in ADL function (13% vs 5%, adjusted HR=1.85, 95% CI=1.58–2.16).

CONCLUSION: Middle‐aged persons who report a history of arthritis are more likely to develop mobility and ADL difficulties as they enter old age. This finding highlights the need to develop interventions and treatments that take a life‐course approach to preventing the disabling effect of arthritis.
Hearing Handicap Predicts the Development of Depressive Symptoms After 3 Years in Older Community‐Dwelling Japanese
Authors: Saito Hideyuki , Nishiwaki Yuji , Michikawa Takehiro , Kikuchi Yuriko , Mizutari Kunio , Takebayashi Toru , Ogawa Kaoru
Published: December 2009

OBJECTIVES: To examine the association between hearing handicap and depressive symptoms in older community‐dwelling Japanese.

DESIGN: Community‐based cohort study.

SETTING: Kurabuchi Town, Gunma Prefecture, Japan.

PARTICIPANTS: Five hundred eighty residents (261 men, 319 women) aged 65 and older without depressive symptoms.

MEASUREMENTS: In a baseline examination performed in 2005/06, participants answered the 10‐item screening version of the Hearing Handicap Inventory for Elderly (HHIE‐S). They were divided into two groups according to their scores: a group with no hearing handicap (HHIE‐S scores of ≤8) and a hearing handicap group (HHIE‐S scores of ≥10). The Geriatric Depression Scale was used to identify depressive symptoms in face‐to‐face home visit interviews conducted in 2008, and the association between hearing handicap and depressive symptoms was assessed using logistic regression.

RESULTS: The incidence of depressive symptoms was 19.6% in the group with a hearing handicap and 8.0% in the group without a hearing handicap. When compared with the subjects without hearing handicap, subjects with a hearing handicap had a multiadjusted odds ratio of depressive symptoms of 2.45 (95% confidence interval=1.26–4.77). The association remained significant even when hearing impairment measured with pure‐tone audiometry was added to the multiadjusted model.

CONCLUSION: A hearing handicap can predict future depressive symptoms in older community‐dwelling people.
Training Nursing Staff to Recognize Depression in Home Healthcare
Authors: Brown Ellen L. , Raue Patrick J. , Roos Bernard A. , Sheeran Thomas , Bruce Martha L.
Published: December 2009

OBJECTIVES: To describe the implementation and acceptability of the TRaining In the Assessment of Depression (TRIAD) intervention, which has been tested in a randomized trial. The primary aim of TRIAD is to improve the ability of homecare nurses to detect depression in medically ill, older adult homecare patients.

DESIGN: Description of the important components of TRIAD, its implementation, and evaluation results from nurse surveys.

SETTING: Three certified home healthcare agencies in Westchester County, New York.

PARTICIPANTS: Thirty‐six homecare nurses.

INTERVENTION: Participants randomly assigned to TRIAD (n=17) were provided with the opportunity to observe and practice patient interviewing. The approach focused on clinically meaningful identification of the two “gateway” symptoms of depression and is consistent with the newly revised Medicare mandatory Outcome and Assessment Information Set (OASIS‐C). Control group participants (n=19) received no training beyond that which agencies may have provided routinely.

MEASUREMENTS: Baseline and 1‐year nurse confidence in depression detection, and postintervention acceptability ratings of the TRIAD intervention.

RESULTS: Participants randomized to the TRIAD intervention reported a statistically significant increase in confidence in assessing for depression mood (P<.001), whereas the usual care group's confidence remained unchanged (P=.34) 1 year later.

CONCLUSION: An educational program designed to improve depression detection by giving nurses the skills and confidence to integrate depression assessment into the context of routine care can be successfully implemented with homecare agency support. The authors discuss the intervention in terms of OASIS‐C and the “real world” realities of intervention implementation.
Effect of a Statewide Fall Prevention Program on Incidence of Femoral Fractures in Residents of Long‐Term Care Facilities
Authors: Rapp Kilian , Lamb Sarah E. , Erhardt‐Beer Luzia , Lindemann Ulrich , Rissmann Ulrich , Klenk Jochen , Becker Clemens
Published: December 2009

OBJECTIVES: To evaluate the effect of a statewide dissemination of a modified evidence‐based fall prevention program on incidence of femoral fractures in nursing homes.

DESIGN: Observational study of a staged implementation of a successful fall prevention program.

SETTING: One thousand three hundred fifty‐nine nursing homes in two federal states in the south of Germany.

PARTICIPANTS: Nine thousand seventy‐seven residents in the intervention homes and 43,583 residents in control homes from the same and a different federal state.

INTERVENTION: Staff education on fall prevention, advice on environmental adaptations, and progressive strength and balance training over at least 1 year.

MEASUREMENTS: Incident femoral fractures.

RESULTS: One thousand five hundred eighteen femoral fractures occurred in the total study population during the intervention period. The crude incidence rate of femoral fractures was 39.5/1,000 person‐years in residents from the intervention homes and 40.9 and 39.7/1,000 person‐years in residents from two sets of control homes. In a multivariate model, there was no evidence of an effect of the fall prevention program on incidence of femoral fracture when compared with control homes from the same federal state (adjusted hazard ratio (AHR)=0.96, 95% confidence interval (CI)=0.83–1.11) or from a different federal state (AHR=1.00, 95% CI=0.86–1.16).

CONCLUSION: The statewide dissemination of a multifactorial fall prevention program did not appear to reduce the burden of femoral fractures in residents of nursing homes.
Evaluating maturation and genetic modification of human dendritic cells in a new polyolefin cell culture bag system
Authors: Macke Lars , Garritsen Henk S.P. , Meyring Wilhelm , Hannig Horst , Pägelow Ute , Wörmann Bernhard , Piechaczek Christoph , Geffers Robert , Rohde Manfred , Lindenmaier Werner , Dittmar Kurt E.J.
Published: December 2009

BACKGROUND: Dendritic cells (DCs) are applied worldwide in several clinical studies of immune therapy of malignancies, autoimmune diseases, and transplantations. Most legislative bodies are demanding high standards for cultivation and transduction of cells. Closed‐cell cultivating systems like cell culture bags would simplify and greatly improve the ability to reach these cultivation standards. We investigated if a new polyolefin cell culture bag enables maturation and adenoviral modification of human DCs in a closed system and compare the results with standard polystyrene flasks.

STUDY DESIGN AND METHODS: Mononuclear cells were isolated from HLA‐A*0201–positive blood donors by leukapheresis. A commercially available separation system (CliniMACS, Miltenyi Biotec) was used to isolate monocytes by positive selection using CD14‐specific immunomagnetic beads. The essentially homogenous starting cell population was cultivated in the presence of granulocyte‐macrophage–colony‐stimulating factor and interleukin‐4 in a closed‐bag system in parallel to the standard flask cultivation system. Genetic modification was performed on Day 4. After induction of maturation on Day 5, mature DCs could be harvested and cryopreserved on Day 7. During the cultivation period comparative quality control was performed using flow cytometry, gene expression profiling, and functional assays.

RESULTS: Both flasks and bags generated mature genetically modified DCs in similar yields. Surface membrane markers, expression profiles, and functional testing results were comparable. The use of a closed‐bag system facilitated clinical applicability of genetically modified DCs.

CONCLUSIONS: The polyolefin bag–based culture system yields DCs qualitatively and quantitatively comparable to the standard flask preparation. All steps including cryopreservation can be performed in a closed system facilitating standardized, safe, and reproducible preparation of therapeutic cells.
Considerations on the use of adjunct red blood cell exchange transfusion in the treatment of severe Plasmodium falciparum malaria
Authors: Shelat Suresh G. , Lott Jason P. , Braga Matthew S.
Published: December 2009

BACKGROUND: Travelers returning to the United States from malaria‐endemic areas are at increased risk of a potentially fatal infection from Plasmodium falciparum, which requires prompt and aggressive treatment.

STUDY DESIGN AND METHODS: Described is a case of a 7‐year‐old boy who was infected by P. falciparum while in Africa and developed features of severe infection, including hyperparasitemia, altered neurologic status, and malarial hepatitis.

RESULTS: A single automated erythrocytapheresis procedure reduced parasitemia from 14% to less than 1%. Along with intravenous quinidine, this reduced parasite level was maintained throughout the hospitalization and the patient recovered.

CONCLUSION: Exchange transfusion (ET) is an effective adjunct therapy to reduce the parasite load in cases of severe P. falciparum malaria. When performed in certain defined settings, the benefits can outweigh the risks of the procedure. Discussed are the medical and technical considerations on the use of adjunctive ET for severe P. falciparum infection and a review of the literature of the use of adjunct ET in the treatment of severe P. falciparum malaria.
A dual antiglobulin test for the detection of weak or nonagglutinating immunoglobulin M warm autoantibodies
Authors: Bartolmäs Thilo , Salama Abdulgabar
Published: December 2009

BACKGROUND: Immunoglobulin (Ig)M warm autoantibodies (AABs) usually cause severe autoimmune hemolytic anemia (AIHA) and, in some cases, red blood cell (RBC)‐bound IgM cannot be detected. We describe a simple dual antiglobulin test (DDAT) for diagnosing such cases.

STUDY DESIGN AND METHODS: A patient with erroneously suspected cold agglutinin syndrome was investigated. The direct antiglobulin test (DAT) was performed using standard techniques and dual (two stages) antiglobulin reagents (IgG rabbit anti‐human IgM, IgG goat anti‐rabbit IgG).

RESULTS: A cold agglutinin syndrome was diagnosed initially, as the patient's serum was reactive with RBCs at a temperature of 28°C or less, and the DAT was strongly positive with anti‐C3d. Six months later, the patient was reexamined at this hospital due to progressive hemolysis. His RBCs were found to be coated with IgM warm AABs that only became detectable using a DDAT, and his serum contained only a weak cold agglutinin. The hemolysis remained refractory to treatment with prednisolone and also prednisolone plus azathioprine, but gradually improved after treatment with prednisolone plus cyclophosphamide.

CONCLUSION: Weak or nonagglutinating RBC‐bound IgM warm antibodies can be identified by the presented DDAT.
Entrepreneurship in Russia and China: The Impact of Formal Institutional Voids
Authors: Puffer Sheila M. , McCarthy Daniel J. , Boisot Max
Published: December 2009

Transition economies are often characterized by underdeveloped formal institutions, often resulting in an unstable environment and creating a void usually filled by informal ones. Entrepreneurs in transition environments thus face more uncertainty and risk than those in more developed economies. This article examines the relationship of institutions and entrepreneurship in Russia and China in the context of institutional theory by analyzing private property as a formal institution, as well as trust and blat/ guanxi as informal institutions. This article thus contributes to the literature on entrepreneurship and institutional theory by focusing on these topics in transition economies, and by emphasizing how their relationship differs from that in developed economies. We conclude that full convergence toward entrepreneurs‘ reliance on formal institutions may not readily occur in countries like Russia and China due to the embeddedness of informal institutions. Instead, such countries and their entrepreneurs may develop unique balances between informal and formal institutions that better fit their circumstances. Implications for the theory and practice of entrepreneurship in such environments are also offered.
Syndication of Venture Capital Investment: The Art of Resource Pooling
Authors: Ferrary Michel
Published: December 2009

This article explores the rationale of syndications of institutional venture capital investors when they fund start–ups. There is an implicit labor division between institutional venture capital investors in which pure venture capital firms are in charge of converting investment uncertainty into risk by funding the seed stage of start–ups. The other investors invest in the following stages to sustain the start–ups‘ development. Relationships between investors are also handled following informal rules. Exchanges between institutional venture capital investors are based on a reciprocity that follows the informal principles of the gift exchange theory.
Emotions and Entrepreneurial Opportunity Evaluation
Authors: Foo Maw–Der
Published: December 2009

Emotions may affect opportunity evaluation yet emotions’ influence in entrepreneurship research has been neglected. Findings from the two studies in this paper indicate that appraisal dimensions of emotions influence risk perceptions and preferences. In Study 1 (n = 187), the participants’ scores on risk perception for a venture scenario were significantly lower for anger and happiness–induced participants (emotions associated with outcome certainty and control) than for fear– and hope–induced participants (emotions associated with outcome uncertainty and a lack of outcome control). In Study 2 (n = 66), the entrepreneurs’ preference for the higher value but uncertain outcome related positively to their scores on trait anger and trait happiness.
Post–Entry Speed of International New Ventures
Authors: Prashantham Shameen , Young Stephen
Published: December 2009

We conceptualize a learning–based model of international new ventures (INVs)’ post–entry internationalization speed focusing upon two measures: country scope speed and international commitment speed. We contribute to a deeper understanding of the pace of international expansion of the new venture once it has become an INV by articulating the role of (1) the speed of learning, influenced by social capital and absorptive capacity, and (2) the content of learning represented by knowledge accumulation. We also offer a more refined perspective on organizational learning, which indicates that different stages in the process of exploitative learning require different forms of social capital.
Building Perceived Quality of Founder–Involved IPO Firms: Founders’ Effects on Board Selection and Stock Market Performance
Authors: Chahine Salim , Filatotchev Igor , Zahra Shaker A.
Published: December 2009

Research on governance has focused on large corporations, giving far less attention to smaller and younger companies especially those moving from founder–controlled start–ups to professionally managed public companies. Emphasizing founder–involved firms (i.e., firms that are floated by their original founders), this article examines interlinks between founders’ prestige and selection of inside and outside directors, and short–term performance measured in terms of IPO “underpricing.” The results provide evidence of positive association between founders’ and directors’ prestige, but there is substitution between inside and outside directors’ prestige. Top management team's external board experiences reduce IPO underpricing.
Sequential Analysis of Longitudinal Data in a Prospective Nested Case–Control Study
Authors: Park Eunsik , Chang Yuan‐chin I.
Published: December 2009

Summary The nested case–control design is a relatively new type of observational study whereby a case–control approach is employed within an established cohort. In this design, we observe cases and controls longitudinally by sampling all cases whenever they occur but controls at certain time points. Controls can be obtained at time points randomly scheduled or prefixed for operational convenience. This design with longitudinal observations is efficient in terms of cost and duration, especially when the disease is rare and the assessment of exposure levels is difficult. In our design, we propose sequential sampling methods and study both (group) sequential testing and estimation methods so that the study can be stopped as soon as the stopping rule is satisfied. To make such a longitudinal sampling more efficient in terms of both numbers of subjects and replications, we propose applying sequential sampling methods to subjects and replications, simultaneously, until the information criterion is fulfilled. This simultaneous sequential sampling on subjects and replicates is more flexible for practitioners designing their sampling schemes, and is different from the classical approaches used in longitudinal studies. We newly define the σ‐field to accommodate our proposed sampling scheme, which contains mixtures of independent and correlated observations, and prove the asymptotic optimality of sequential estimation based on the martingale theories. We also prove that the independent increment structure is retained so that the group sequential method is applicable. Finally, we present results by employing sequential estimation and group sequential testing on both simulated data and real data on children's diarrhea.
Modeling Familial Association of Ages at Onset of Disease in the Presence of Competing Risk
Authors: Shih Joanna H. , Albert Paul S.
Published: December 2009

SummaryIn genetic family studies, ages at onset of diseases are routinely collected. Often one is interested in assessing the familial association of ages at the onset of a certain disease type. However, when a competing risk is present and is related to the disease of interest, the usual measure of association by treating the competing event as an independent censoring event is biased. We propose a bivariate model that incorporates two types of association: one is between the first event time of paired members, and the other is between the failure types given the first event time. We consider flexible measures for both types of association, and estimate the corresponding association parameters by adopting the two‐stage estimation ofShih and Louis(1995, Biometrics 51,1384–1399) andNan et al.(2006, Journal of the American Statistical Association 101,65–77). The proposed method is illustrated using the kinship data from the Washington Ashkenazi Study.
Conserved Meiotic Genes Point to Sex in the Choanoflagellates
Authors: CARR MARTIN , LEADBEATER BARRY S. C. , BALDAUF SANDRA L.
Published: December 2009

ABSTRACT. The choanoflagellates are a widespread group of heterotrophic aquatic nanoflagellates, which have recently been confirmed as the sister‐group to Metazoa. Asexual reproduction is the only mode of cell division that has been observed within the group; at present the range of reproductive modes, as well as the ploidy level, within choanoflagellates are unknown. The recent discovery of long terminal repeat retrotransposons within the genome of Monosiga brevicollis suggests that this species also has sexual stages in its life cycle because asexual organisms cannot tolerate retrotransposons due to the rapid accumulation of deleterious mutations caused by their transposition. We screened the M. brevicollis genome for known eukaryotic meiotic genes, using a recently established “meiosis detection toolkit” of 19 genes. Eighteen of these genes were identified, none of which appears to be a pseudogene. Four of the genes were also identified in expressed sequence tag data from the distantly related Monosiga ovata. The presence of these meiosis‐specific genes provides evidence for meiosis, and by implication sex, within this important group of protists.
Hydrogenosomes of Laboratory‐Induced Metronidazole‐Resistant Trichomonas vaginalis Lines are Downsized While Those from Clinically Metronidazole‐Resistant Isolates Are Not
Authors: WRIGHT JANELLE M. , WEBB RICHARD I. , O'DONOGHUE PETER , UPCROFT PETER , UPCROFT JACQUELINE A.
Published: December 2009

ABSTRACT. Trichomonas vaginalis is the most common sexually transmitted protozoan in the world and its resistance to metronidazole is increasing. The purpose of this study was to demonstrate that clinical metronidazole resistance in T. vaginalis does not occur via the same mechanism as laboratory‐induced metronidazole resistance—that is, via hydrogenosome down sizing. Ultrathin sections of this parasite were examined using transmission electron microscopy and the size and area of the cell and hydrogenosomes were compared between drug‐resistant laboratory lines and clinically resistant isolates. Clinical metronidazole‐resistant T. vaginalis had similar‐sized hydrogenosomes as a metronidazole‐sensitive isolate. Inducing metronidazole resistance in both of these isolates caused down sizing of hydrogenosomes. Inducing toyocamycin resistance did not cause any ultrastructural changes to the cell or to the hydrogenosome. No correlation between hydrogenosome number and the drug‐resistant status of T. vaginalis isolates and lines was observed. This report demonstrates that clinical metronidazole resistance is not associated with down‐sized hydrogenosomes, thus indicating that an alternative resistance mechanism is used by T. vaginalis.
A Study of PCR Inhibition Mechanisms Using Real Time PCR*,†
Authors: Opel Kerry L. , Chung Denise , McCord Bruce R.
Published: December 2009

Abstract: In this project, real time polymerase chain reaction (PCR) was utilized to study the mechanism of PCR inhibition through examination of the effect of amplicon length, melting temperature, and sequence. Specifically designed primers with three different amplicon lengths and three different melting temperatures were used to target a single homozygous allele in the HUMTH01 locus. The effect on amplification efficiency for each primer pair was determined by adding different concentrations of various PCR inhibitors to the reaction mixture. The results show that a variety of inhibition mechanisms can occur during the PCR process depending on the type of co‐extracted inhibitor. These include Taq inhibition, DNA template binding, and effects on reaction efficiency. In addition, some inhibitors appear to affect the reaction in more than one manner. Overall we find that amplicon size and melting temperature are important in some inhibition mechanisms and not in others and the key issue in understanding PCR inhibition is determining the identity of the interfering substance.
Latin America and the Social Contract: Patterns of Social Spending and Taxation
Authors: Breceda Karla , Rigolini Jamele , Saavedra Jaime
Published: December 2009

This article analyzes the incidence of social spending and taxation by income quintile for seven Latin American countries, the United Kingdom, and the United States. Absolute levels of social spending in Latin America are fairly flat across income quintiles, a pattern similar to that in the United States and differing from the more progressive pattern of spending in the United Kingdom. The structure of taxation in Latin America is also similar to that of the United States. Because of high income inequality in Latin America and the US, the rich bear of most the burden, whereas the United Kingdom taxes the middle class to a greater extent. The analysis suggests that many Latin American countries are trapped in a vicious cycle in which the rich resist the expansion of the welfare state (because they bear most of its tax burden without receiving commensurate benefits), and their opposition to its expansion in turn maintains long‐term inequalities.
MANAGING EDUCATIONAL TRANSFORMATION IN THE GLOBALIZED WORLD: A DEWEYAN PERSPECTIVE
Authors: Striano Maura
Published: December 2009

In the globalization scenarios we currently face, educational systems are challenged by different and sometimes competing pressures and requests. These call for a deep transformation of the organization, role, and social function of educational systems. Within this context, the very concept of education has come to be understood in different ways, which sometimes distort its moral and social value. In this essay, Maura Striano contends that from a Deweyan perspective, educational transformation must be seen as strictly connected to social change, and education should be understood as a process that facilitates and supports social growth and development. In order to be effective and fruitful, Striano suggests, this transformation must occur from the inside of educational systems and can only be brought about by reflective and inquiry‐based inner processes if it is to have a sound moral and social impact within the changing framework of the globalized world.

That education shares in the confusion of transition, and in the demand for reorganization, is a source of encouragement and not of despair. It proves how integrally the school is bound up with the entire movement of modern life. —John Dewey, The Educational Situation
Mammalian Densities in a Neotropical Wetland Subject to Extreme Climatic Events
Authors: Desbiez Arnaud Léonard Jean , Bodmer Richard Ernest , Tomas Walfrido Moraes
Published: December 2009

Effective management and conservation of an ecosystem requires information on species assemblages as well as reliable estimates of population sizes to plan, implement and evaluate management strategies. The Brazilian Pantanal is one of the world's largest freshwater wetlands and considered a priority landscape for wildlife conservation. It is subject to pluri‐annual extreme dry and wet periods, which cause extreme flood and drought events, which strongly affect wildlife. Using the line‐transect method, this study examined the distribution of densities and metabolic biomass of medium‐ to large‐sized nonvolant mammals in forest, cerrado and floodplain landscapes, in an area with low anthropogenic influence, in the central area of the Brazilian Pantanal during a prolonged drought. Comparisons with a previous survey conducted during years of average rainfall in part of the study area suggest that population fluctuations of certain species are closely associated with water due to the drought. Results from this study showed that mammal assemblages varied between landscapes. Forested landscapes have the highest densities of mammals and are the most important in terms of relative energy consumption. In addition, at the time of the study, frugivores were found to have higher energy consumption than browser/grazers across the three landscapes; most fruits are produced in forested areas stressing their importance. By converting forested landscapes into grasslands, the intensification of ranching practices seriously threatens biodiversity and ecological processes in the region.
What is New in Protectionism? Consumers, Cranks, and Captives
Authors: Kerr William A.
Published: December 2009

The most contentious international trade issues currently arise not from traditional producer requests for protection, but as a result of consumers and other economic agents asking governments to erect trade barriers. The economic model that underpins multilateral trade policy—as manifest in World Trade Organization (WTO) agreements—only predicts that firms will lobby for protection, with no provisions for how governments faced with requests for protection from other groups can respond. Consequently, governments have been forced to defend the imposition of trade barriers using spurious justifications; the WTO dispute mechanism has largely dismissed these justifications, and consumers (and others) feel disenfranchised. The result has been a loss of credibility for the WTO and sometimes its demonization. The WTO needs to change but a new economic model must also be developed to deal with a broader spectrum of protectionist interests.

À l'heure actuelle, les questions de commerce international les plus litigieuses ne sont pas alimentées par des producteurs traditionnels qui demandent des mesures protectionnistes, mais plutôt par des consommateurs et d'autres agents économiques qui demandent que les États érigent des barrières commerciales. Le modèle économique à la base de la politique commerciale multilatérale – manifeste dans les accords de l'Organisation mondiale du commerce (OMC) – prévoit seulement que les entreprises exerceront des pressions protectionnistes, sans disposition sur la réaction possible des États qui sont confrontés à des demandes de protectionnisme provenant d'autres groupes. En conséquence, les États ont été forcés de défendre l'imposition de barrières commerciales en utilisant de fausses justifications. Le mécanisme de règlement des différends de l'OMC a en grande partie rejeté ces justifications, et les consommateurs (et autres agents économiques) se sentent privés de leurs droits. L'OMC a ainsi perdu de sa crédibilité et est parfois diabolisée. L'OMC doit être revue, mais il faut également élaborer un nouveau modèle économique pour tenir compte d'un large éventail d'intérêts protectionnistes.
Ambiguous Hydraulic Heads and 14C Activities in Transient Regional Flow
Authors: Schwartz Franklin W. , Sudicky Edward A. , McLaren Robert G. , Park Young‐Jin , Huber Matthew , Apted Mick
Published: December 2009

A regional flow and transport model is used to explore the implications of significant variability in Pleistocene and Holocene climates on hydraulic heads and 14C activity. Simulations involve a 39 km slice of the Death Valley Flow System through Yucca Mountain toward the Amargosa Desert. The long‐time scale over which infiltration has changed (tens‐of‐thousands of years) is matched by the large physical extent of the flow system (many tens‐of‐kilometers). Estimated paleo‐infiltration rates were estimated using a juniper pollen percentage that extends from the last interglacial (LIG) period (approximately 120 kyrbp) to present. Flow and 14C transport simulations show that groundwater flow changes markedly as a function of paleoclimate. At the last glacial maximum (LGM, 21 kyrbp), the recharge to the flow system was about an order‐of‐magnitude higher than present, and water table was more than 100 m higher. With large basin time constants, flow is complicated because hydraulic heads at a given location reflect conditions of the past, but at another location the flow may reflect present conditions. This complexity is also manifested by processes that depend on flow, for example 14C transport. Without a model that accounts for the historical transients in recharge for at least the last 20,000 years, there is no simple way to deconvolve the 14C dates to explain patterns of flow.
Ustekinumab: Lessons Learned from Targeting Interleukin‐12/23p40 in Immune‐Mediated Diseases
Authors: Elliott Michael , Benson Jacqueline , Blank Marion , Brodmerkel Carrie , Baker Daniel , Sharples Kristin Ruley , Szapary Philippe
Published: December 2009

Interleukin (IL)‐12 and IL‐23 are related cytokines that have been implicated in the pathogenesis of several immune‐mediated disorders. IL‐12 and IL‐23 are heterodimers made up of a common p40 subunit complexed to unique p35 (IL‐12) or p19 (IL‐23) subunits. Ustekinumab is a human monoclonal antibody that specifically binds the p40 subunit of IL‐12/23. Ustekinumab prevents IL‐12 and IL‐23 from binding their cell surface receptor complexes, thereby blocking the T helper (Th) 1 (IL‐12) and Th17 (IL‐23) inflammatory pathways. Here, we discuss the preclinical and human translational data supporting a role for IL‐12/23 in the pathogenesis of immune‐mediated disorders, and how that rationale was challenged in the clinic during the course of the ustekinumab development program in several indications including psoriasis, psoriatic arthritis, Crohn's disease, and multiple sclerosis. We review the key efficacy and safety data in each of these immune‐mediated diseases and compare and contrast the safety lessons learned from IL‐12/23 genetically‐deficient mice and humans in context of the overall clinical trial experience with ustekinumab.
Immune Modulation with Interleukin‐21
Authors: Bhave Neela S. , Carson III William E.
Published: December 2009

Interleukin 21 (IL‐21) is produced by activated CD4+ T cells. The IL‐21R shares the common receptor gamma‐chain with IL‐2, IL‐4, IL‐7, IL‐9, and IL‐15, is widely expressed on immune cells, and mediates a variety of effects on the immune system. IL‐21 enhances the proliferation, antigen‐induced activation, clonal expansion, IFN‐γ production, and cytotoxicity of NK cells and T cells. The antitumor actions of IL‐21 have been variously attributed to NK cell and CD8+ T cell cytotoxicity, CD4+ T cell help, NKT cells, and the antiangiogenic properties induced by IFN‐γ secretion. In clinical trials IL‐21 has been well tolerated and induces a unique pattern of immune activation. IL‐21 is therefore an excellent candidate for use in immune therapy.
Clinical and Immunologic Basis of Interferon Therapy in Melanoma
Authors: Tarhini Ahmad A. , Kirkwood John M.
Published: December 2009

Interferon α2b (IFN‐α2b) at high dosage is critical to the reversal of signaling defects in T cells of melanoma patients, and to the durable effector (α DC1) polarization of dendritic cells. These immunoregulatory effects appear to be uniquely achieved with levels of IFN‐α only attainable in vivo using the high‐dose regimen of IFN‐α2b (HDI). Three US cooperative group studies have evaluated the benefit of HDI as an adjuvant therapy for high‐risk melanoma. All have demonstrated significant and durable reduction in the frequency of relapse, while the first and third trials have demonstrated significant improvements in the fractions of patients surviving compared with observation (E1684) or with a ganglioside vaccine (GMK, E1694). A meta‐analysis of 13 randomized trials evaluating adjuvant IFN therapy has now also demonstrated significant benefits for IFN in terms of RFS and OS. Research of IFN‐α in melanoma is now focused on identifying prognostic markers of outcome and predictors of therapeutic response.
Hurdles and Leaps for Protein Therapeutics
Authors: Kozlowski Steven , Cherney Barry , Donnelly Raymond P.
Published: December 2009

Cytokines encompass a wide variety of proteins that can trigger many cellular activities. An important set of cytokines modulate inflammatory responses (inflammatory cytokines). These molecules have potent biological activities and have been a major focus for protein drug development. There have been both successes and failures in this area. Initial hurdles, such as limited manufacturing capacity, have now been largely overcome. However clinical development remains a challenge. On the basis of the history of cytokine therapeutics, a number of strategies for future drug development are considered.
An Overview of Cytokines and Cytokine Antagonists as Therapeutic Agents
Authors: Donnelly Raymond P. , Young Howard A. , Rosenberg Amy S.
Published: December 2009

Cytokine‐based therapies have the potential to provide novel treatments for cancer, autoimmune diseases, and many types of infectious disease. However, to date, the full clinical potential of cytokines as drugs has been limited by a number of factors. To discuss these limitations and explore ways to overcome them, the FDA partnered with the New York Academy of Sciences in March 2009 to host a two‐day forum to discuss more effective ways to harness the clinical potential of cytokines and cytokine antagonists as therapeutic agents. The first day was focused primarily on the use of recombinant cytokines as therapeutic agents for treatment of human diseases. The second day focused largely on the use of cytokine antagonists as therapeutic agents for treatment of human diseases. This issue of the Annals includes more than a dozen papers that summarize much of the information that was presented during this very informative two‐day conference.