bluuebunny/crossref_metadata_2025 huggingface dataset:
David Pocock’s Contributions and the legacy of Leavis
Authors: Parry Jonathan , Simpson Edward
Published: February 2011

David Pocock (1928–2007) co-founded this journal with Louis Dumont, and it is easy to assume that they were intellectually more ‘like-minded’ than we believe was really the case. In the first part of this appreciation, we offer some biographical and intellectual context for Pocock’s career. In the second, we identify the principal ways in which his sociological project did converge with Dumont’s and the respects in which it seems fundamentally different. Both were deeply influenced by Evans-Pritchard; but much of their difference is explained, we suggest, by Pocock’s prior loyalty to the teachings of the literary critic, F.R. Leavis. For good or ill, Pocock’s more reflexive preoccupations and his concern with the moral complexity of social life chime better with, and indeed anticipate, subsequent theoretical trends in the discipline.
The bases of political trust in six Asian societies: Institutional and cultural explanations compared
Authors: Wong Timothy Ka-ying , Wan Po-san , Hsiao Hsin-Huang Michael
Published: February 2011

Political trust reflects people’s evaluative orientation toward the polity and is thus vital to regime stability. Based on data drawn from a cross-national social survey, this article examines the level of political trust in six Asian societies and the possible effects of a series of institutional and cultural factors on political trust. It finds that institutional factors, particularly the economic and political performance of government, are powerful determinants of political trust, whereas the effects of such cultural factors as post-materialism, traditionalism, and authoritarianism are either insignificant or weak. The superiority of the institutional approach over the cultural approach is reconfirmed.
Acid Mucopolysaccharides in Mammary Tumors of Dogs
Authors: Palmer T. E. , Monlux A. W.
Published: February 2011

The predominant acid mucopolysaccharides found in selected epithelial mammary tumors of dogs stained with alcian blue and were labile to hyaluronidase digestion. These histochemical characteristics identified them as hyaluronic acid, chondroitin-4- and chondroitin-6-sulfate. The intensity of the staining of these acid mucopolysaccharides varied in a transitionary process from a precartilaginous to a pseudocartilaginous intercellular matrix to mature hyaline cartilage.

The tumor acid mucopolysaccharides were indistinguishable from those associated with formation of cartilage in developing mammals; such cartilage is reported to be produced only by cells of mesodermal origin. There was no evidence to suggest transitional changes in myoepithelial cells, neoplastic epithelial cells or their components that could contribute to the formation of the acid mucopolysaccharides. It was concluded that the heterotopic tissues (cartilage, bone and fibrous connective tissue) in the epithelial mammary tumors were derived from cells of mesodermal orgin and formed the adjacent stroma in areas of neoplasia.
Hematologic Abnormalities Preceding Myeloid Leukemia in Three Cats
Authors: Madeweix B. R. , Jain N. C. , Weller R. E.
Published: February 2011

Cytopenia were recognized in three cats infected with feline leukemia virus. In one cat, marrow blast cells were increased in number, and a diagnosis of aleukemic leukemia was made. The disease progressed slowly for 31/2 months before terminating in acute myelomonocytic leukemia, recognized as a blast crisis in blood. In the other two cats, neutropenia and altered granulopoiesis in bone marrow preceded development of myeloid leukemia.
Niemann-Pick Disease in a Poodle Dog
Authors: Bundza A. , Lowden J. A. , Charlton K. M.
Published: February 2011

A 5-month-old minature Poodle dog had widespread cytoplasmic vacuolation of neurons in the central nervous system and foamy macrophages in the lung, spleen, renal lymph node, liver, adrenal gland and intestine. Concentric membranous cytoplasmic inclusions were seen in the neurons of the central nervous system by electron microscopy. There was no sphingomyelinase in the brain tissue. Sphingomyelin and cholesterol were increased in brain, kidney and liver. A diagnosis of Niemann-Pick Disease was based on absence of sphingomyelinase activity, as well as on histologic, histochemical and chemical findings.
Intraocular Melanoma in a Horse
Authors: Murphy J. , Young S.
Published: February 2011

Sudden unilateral blindness occurred in a 7-year-old grey gelding Quarterhorse. Ophthalmoscopy revealed a pigmented mass arising from the nasal ciliary body of the right eye and extending around the posterior surface of the lens, and there were pigmented particles in the vitreous. Examination of the enucleated globe showed a circumscribed, black, dense and symmetrically ovoid mass with sessile attachment to the nasal ciliary region and extension to posterior lens capsule, vitreous and along the vitreal face of the detached retina to the optic papilla. The mass was composed of heavily pigmented, plump, polyhedral cells that invaded the vitreous and the inner limiting membrane of peripapillary retina and optic papilla. It was considered to be a primary, malignant, intraocular melanoma arising from a large uveal nevus.
Acinar Cell Carcinoma of the Pancreas in a Cat
Authors: Banner B. F. , Alroy J. , Kipnis R. M.
Published: February 2011

A feline pancreatic acinar cell carcinoma studied by light and electron microscopy was characterized by three growth patterns: acinar formation, colloid production and sheets of neoplastic cells. Ultrastructurally, the acinar origin of the tumor was determined by the presence of zymogen granules, some of which contained and released microfibrillar material.
Spontaneous Aortic Atherosclerosis in Sheep
Authors: Gupta P. P. , Nagpal S. K.
Published: February 2011

Aortas of 334 sheep 6 months to 6 years old were stained with Sudan IV. Sudanophilic lesions resembling early fatty streaks of man were detected in 50% of these aortas. Metastatic calcification was seen in eight (2.3%) aortas.
Mesotheliomas and Proliferative Lesions of the Testicular Mesothelium Produced in Fischer, Sprague-Dawley and Buffalo Rats by Methyl(acetoxymethyl)nitrosamine (DMN-OAc)
Authors: Berman J. J. , Rice J. M.
Published: February 2011

A single intraperitoneal dose of methyl(acetoxymethyl)nitrosamine (13 mg/kg body weight) given to 78 5-week-old male rats induced 25 mesotheliomas; two mesotheliomas were found in 67 control rats. All mesotheliomas arose from the peritesticular mesothelium and had a typical microscopic appearance of branching papillary fronds with a collagenous core covered by one or many layers of plump tumor cells. Cytoplasm of tumor cells contained material that reacted positively to a colloidal iron stain and was labile to hyaluronidase. In addition to frank mesotheliomas, 16 lesions, which we called atypical mesothelial proliferations. were found. These consisted of a single focus of plump mesothelial cells overlying an area of thick stroma. Often these foci included short, non-branched papillary projections above the surface of adjacent normal mesothelium. Twelve of the 16 lesions occurred in methyl(acetoxymethyl)nitrosamine-treated rats.
New pollen, sedimentary, and radiocarbon records from the Marquesas Islands, East Polynesia: Implications for archaeological and palaeoclimate studies
Authors: Allen Melinda S. , Butler Kevin , Flenley John , Horrocks Mark
Published: February 2011

Three sediment cores, from one upland and two lowland sites on Nuku Hiva, Marquesas Islands, provide a c. 750-year record of palaeo-environmental change on the island. Accelerator mass spectrometry (AMS) dating of pollen concentrates from the base of each core indicates that the three widely separated marshes developed c. AD 1200 and 1350, after the known period of human colonisation and establishment. Detailed analyses (pollen, sediments, and charcoal) and additional dating of the upland core from Tōvi’i Plateau (810 m) allow for identification of four chronozones. The core sediment data and age-depth curve suggest an alternation of wet-dry-wet conditions over the c. 750-year period. The pollen spectra, in contrast, are fairly stable, with ferns dominating but arborescent species also present. The micro-charcoal evidence points to regional burning and long-distance transport until c. AD 1640, after which localised burning may be indicated. Among the more notable changes is a major increase in pollen and spore deposition after c. AD 1640, a trend most evident in the pollen concentration diagram. Overall, the data suggest rapid sedimentation in the fourteenth century AD, followed by drier and/or more settled conditions until the mid-seventeenth century, and finally wetter conditions after c. AD 1640. The latter in particular is consistent with emerging regional evidence for warm-wet conditions in the central eastern Pacific during the seventeenth century, the height of the Northern Hemisphere ‘Little Ice Age’. The charcoal record also provides insights into human activities on the island, suggesting burning in the lowlands from the fourteenth century AD, probably in conjunction with forest clearance preparatory to tree and root crop cultivation.
Comparison of modeled and reconstructed changes in forest cover through the past 8000 years
Authors: Kleinen Thomas , Tarasov Pavel , Brovkin Victor , Andreev Andrei , Stebich Martina
Published: February 2011

Reproducing the tree cover changes throughout the Holocene is a challenge for land surface–atmosphere models. Here, results of a transient Holocene simulation of the coupled climate–carbon cycle model, CLIMBER2-LPJ, driven by changes in orbital forcing, are compared with pollen data and pollen-based reconstructions for several regions of Eurasia in terms of changes in tree fraction. The decline in tree fraction in the high latitudes suggested by data and model simulations is driven by a decrease in summer temperature over the Holocene. The cooler and drier trend at the eastern side of the Eurasian continent, in Mongolia and China, also led to a decrease in tree cover in both model and data. In contrast, the Holocene trend towards a cooler climate in the continental interior (Kazakhstan) is accompanied by an increase in woody cover. There a relatively small reduction in precipitation was likely compensated by lower evapotranspiration in comparison to the monsoon-affected regions. In general the model-data comparison demonstrates that climate-driven changes during the Holocene result in a non-homogeneous pattern of tree cover change across the Eurasian continent. For the Eifel region in Germany, the model suggests a relatively moist and cool climate and dense tree cover. The Holzmaar pollen record agrees with the model for the intervals 8–3 ka and 1.7–1.3 ka BP, but suggests great reduction of the tree cover 3–2 ka and after 1.3 ka BP, when highly developed settlements and agriculture spread in the region.
Modelling prehistoric land use and carbon budgets
Authors: Boyle John F. , Gaillard Marie-José , Kaplan Jed O. , Dearing John A.
Published: February 2011

An evaluation of modelled estimates for C release following early land clearance at the global level based on new model assumptions suggests that earlier studies may have underestimated its magnitude, chiefly because of underestimation of the mid-Holocene global population. Alternative information sources for population and land utilisation support both a greater total CO2 release and a greater Neolithic contribution. Indeed, we show that the quantity of terrestrial C release due to early farming, even using the most conservative assumptions, greatly exceeds the net terrestrial C release estimated by inverse modelling of ice core data by Elsig et al. (Elsig J, Schmitt J, Leuenberger D, Schneider R, Eyer M, Leuenberger M et al. (2009) Stable isotope constraints on Holocene carbon cycle changes from an Antarctic ice core. Nature 461: 507–510), though uncertainty about past global population estimates precludes calculation of a precise value.
Text World Theory, real readers and emotional responses to The Remains of the Day
Authors: Whiteley Sara
Published: February 2011

Recent investigations into emotion and discourse processing using the Text World Theory framework (Werth, 1999) regard psychological projection as a key factor in readers’ emotional responses to discourse (Gavins, 2007; Lahey, 2005; Stockwell, 2009). The present article examines psychological projection in relation to an extract from Kazuo Ishiguro’s The Remains of the Day (1989) and the comments made by a group of readers discussing the novel. As a result, a more nuanced account of psychological projection is proposed, which highlights the multiple perspectives which readers are able to monitor and adopt during text-world construction. Whilst previous work in Text World Theory has focused upon psychological projection in relation to a single text-world role (such as the addressee, for example), here it is argued that multiple projections in relation to a range of text-world enactors are of fundamental significance in our emotional responses to narrative. Such multiple projections, it is proposed, should receive greater consideration in accounts of our emotional experience of literary discourse.
Evolution, science and the study of literature: A critical response
Authors: Cameron Deborah
Published: February 2011

This article offers a critical response to the proposal made by Jonathan Gottschall (2008), and discussed sympathetically in a review article for this journal (Francis 2010), for a more ‘scientific’ approach to the study of literature. A critical examination of evolutionary psychology, the particular scientific approach which underpins Gottschall’s own work on folk tales, is followed by a broader consideration of what ‘scientific’ might mean in relation to literature, asking how far it is either possible or desirable to apply the methods and evaluative metrics of science in other areas of scholarly endeavour. It is argued that there are good reasons for linguists and literary scholars to maintain the theoretical and methodological pluralism that has characterized their fields in the past
Competition, Agricultural Trade Reform and Developing Countries
Authors: McCorriston Steve
Published: February 2011

In this paper, we consider the potential impact of market power on the likely effects of trade reform and how this may impact on developing country exporters. The emphasis is on trade reform in agricultural markets, one of the principal features of the Doha Round negotiations, and we discuss the mechanisms via which market power will matter for agricultural markets even if those markets themselves are competitive. Using results from a calibrated theoretical model, we show that the existence of downstream market power in vertical chains is likely to dissipate the potential benefits that would accrue to developing country agricultural exporters following trade reform.
Deeper Integration between Canada and India?
Authors: Dobson Wendy
Published: February 2011

Relative to their economic sizes, structures and linkages, the bilateral relationship between Canada and India is too small. Trade and foreign direct investment (FDI) flows are gradually increasing within such sectors as finance, energy, power and environmental services, agriculture and information technology (IT) services. Two channels are identified to expand this economic footprint: deeper linkages among bilateral business groups to reduce Canadians’ transactions costs relative to those in the United States (US) market; and improved market access for India’s competitive low-cost producers. Governments, which focus primarily on incremental improvements, should elevate the bilateral relationship to a strategic level with the negotiation of a free trade agreement (FTA). Although each government prefers the World Trade Organization (WTO) as the venue for liberalising agricultural trade, it is argued that a services-only FTA would yield mutual gains by removing many of the restrictions affecting both domestic markets and foreign entrants in the two countries revealed by the comparative analysis in this paper.
Sink Hypothesis and Therapeutic Strategies for Attenuating Aβ Levels
Authors: Zhang Yan , Lee Daniel H. S.
Published: February 2011

Amyloid β (Aβ) plaque, comprised mainly by Aβ peptides, is an important pathology of Alzheimer’s brains. Major efforts have been devoted to targeting this neurotoxic Aβ peptide for discovering disease-modifying treatments for Alzheimer’s disease. Inasmuch as Aβ is found in both the brain and the periphery, it is hypothesized that there is some form of equilibrium for the Aβ in the brain and the periphery such that Aβ can be transported across the blood-brain barrier. By modulating the periphery Aβ levels, it is predicted that the brain Aβ levels will undergo concomitant changes, forming the basis of the “sink hypothesis” for Aβ lowering strategies. In this review, the significance and implication of this sink hypothesis as well as how the sink hypothesis may contribute to the recent Aβ-based drug discovery in AD are discussed. Ultimately, the validity of the sink hypothesis will be resolved when the appropriate Aβ agents are being tested in the clinic.
The first encounter: Observations on the chronology of encounter with some adaptations of Lewis Carroll’s Alice books
Authors: Bonner Frances , Jacobs Jason
Published: February 2011

The article argues for the necessity of taking into account not only the chronology of adaptation but also the chronology of encounter, using as a starting point an instance of an adaptation student who had seen the 1951 Disney film Alice in Wonderland as a child many times, long before her subsequent encounter with Lewis Carroll’s Alice’s Adventures in Wonderland. It considers a selection of adaptations of Carroll’s work, including the 1950 Disney television promotion of its 1951 film and the 1966 Jonathan Miller’s BBC adaptation, to explore the probable consequences of different sequences of encounter.
Transmedia teens: Affect, immaterial labor, and user-generated content
Authors: Martens Marianne
Published: February 2011

The internet offers teens (especially girls, who have embraced social aspects of the web) a voice in the books they read, from reviewing, blogging, and creating fan sites, to actually collaborating on books-in-progress — such as The Amanda Project — by writing portions of the book or suggesting storylines. But while these new means of participation are seemingly empowering for teenage girls, is this participation a form of empowerment, or is it merely a way for publishers to exploit teens’ labor to create commodified cultural products which they in turn can sell back to the teens who helped shape them? In an era of user-generated content, this article examines how teens’ affective labor as peer-to-peer-marketers and content creators is changing the transmedia cultural products created for them.
Higher levels of prorenin predict development of diabetic retinopathy in patients with type 2 diabetes
Authors: Yokota Harumasa , Nagaoka Taiji , Tani Tomofumi , Takahashi Atsushi , Sato Eiichi , Kato Yuji , Yoshida Akitoshi
Published: February 2011

The aim was to determine whether serum prorenin levels affect the development of diabetic retinopathy (DR) in type 2 diabetes. Baseline serum prorenin levels were measured in 196 patients (85 males, 111 females) with type 2 diabetes without DR using the antibody-activating direct prorenin assay. The fundi were checked regularly. The participants were divided into two groups based on the serum prorenin levels (high and low). We used Kaplan—Meyer analysis to detect differences in the development of DR between the two groups within the same gender. Kaplan—Meyer analysis showed that males with a high serum prorenin level tended to develop DR earlier and more frequently than males with a low prorenin level ( p = 0.004 by the log rank test). However, there was no difference in the development of DR between high and low groups in females ( p = 0.58). Serum prorenin levels in males with type 2 diabetes could be a new prognostic indicator of the development of DR.
Is the ACE I/D polymorphism associated with extreme longevity? A study on a Spanish cohort
Authors: Fiuza-Luces Carmen , Ruiz Jonatan R , Rodríguez-Romo Gabriel , Santiago Catalina , Gómez-Gallego Félix , Cano-Nieto Amalia , Garatachea Nuria , Rodríguez-Moreno Inmaculada , Morán María , Lucia Alejandro
Published: February 2011

The 287 bp Ins(I)/Del(D) polymorphism [rs1799752] in intron 16 of the angiotensin-converting enzyme ( ACE) gene has been associated with extreme longevity (≥ 100 years) in some Caucasian and Asian cohorts, but this finding was not corroborated in other reports. We compared the allelic/genotypic frequency of the ACE I/D polymorphism among centenarians ( N = 64, 100—108 years, 89.1% female) and nonagenarians ( N = 47, 90—97 years, 76.6% female), and a control group of healthy young adults ( n = 434, age 20—40 years, 50% female). All participants were of the same Caucasian (Spanish) descent. The ACE I/D genotype met Hardy—Weinberg expectations in all the cohorts. Allelic and genotypic frequencies did not differ by sex in any of the study groups (all p > 0.2). There were no differences in allelic or genotypic frequencies between groups, for example the frequency of the D allele was 62.3% in controls vs. 65.3% in the elderly (64.8% in centenarians). In summary, the ACE I/D polymorphism is not significantly associated with extreme longevity in the Spanish population. Further research is, however, necessary using other approaches. It also remains to be determined if the interaction of ACE genotypes with some other genetic variants exerts a potential effect on longevity.
25-Hydroxyvitamin D is associated with plasma renin activity and the pressor response to dietary sodium intake in Caucasians
Authors: Vaidya Anand , Forman John P , Hopkins Paul N , Seely Ellen W , Williams Jonathan S
Published: February 2011

Introduction: Concentrations of 1,25-hydroxyvitamin D have been positively associated with dietary sodium and salt sensitivity (SS) of blood pressure (BP), and inversely with plasma renin activity (PRA). We investigated the association between PRA and 25-hydroxyvitamin D (25OHD), the most clinically relevant vitamin D metabolite, and whether 25OHD associates with SS of BP in renin phenotypes of hypertension.

Methods: We performed cross-sectional analyses on 223 Caucasian subjects with hypertension maintained in high and low dietary sodium balance. Subjects were distinguished as having low-renin (LR) or normal-renin (NR) hypertension. Multivariable linear regression was used to evaluate adjusted relationships.

Results: Increasing 25OHD concentrations were inversely associated with PRA ( p < 0.05) on both salt diets. Furthermore, 25OHD was associated with SS of BP in LR hypertension (b = 0.62, p = 0.04), but not in NR hypertension (b = 0.06, p = 0.59). In an adjusted multivariable interaction model, renin status (LR vs . NR) was a significant effect modifier of the relationship between 25OHD and SS of BP ( p = 0.04).

Conclusions: Our findings suggest that 25OHD is inversely associated with PRA and positively associated with SS of BP in LR hypertension subjects. These results extend and support prior evidence indicating an interaction between dietary sodium, the RAS, and vitamin D that influences BP in hypertension.
Insertion/deletion polymorphism of angiotensin-1 converting enzyme is associated with metabolic syndrome in Hungarian adults
Authors: Fiatal Szilvia , Szigethy Endre , Széles György , Tóth Réka , Ádány Róza
Published: February 2011

The aim of our study was to evaluate whether any association exists between metabolic syndrome (MS) and ACE I/D and AGT M235T gene polymorphisms in Hungarians as an example of European Caucasian population. Study subjects of our cross-sectional study were recruited from the Hungarian General Practitioners’ Morbidity Sentinel Stations Program. The study population ( n = 1762) approximates very well the age and sex distribution of the general Hungarian population. MS was defined according to the latest diagnostic criteria proposed by the International Diabetes Federation. The frequency of DD genotype (31.36% vs. 25.42%, p = 0.006) and the frequency of D allele (0.56 vs. 0.51, p = 0.006) were significantly higher in the metabolic group than in the non-metabolic group. The distribution of the AGT M235T polymorphism was similar in each group investigated. Association was shown in the case of patients in whom central obesity was combined with elevated TG and low HDL cholesterol level ( p = 0.024 and p = 0.022). It suggests that ACE I/D polymorphism is likely to be involved in lipid metabolism.
Treatment Options and Outcomes for Celiac Artery Compression Syndrome
Authors: Kohn Geoffrey P. , Bitar Raghid S. , Farber Mark A. , Marston William A. , Overby D. Wayne , Farrell Timothy M.
Published: February 2011

Background. Abdominal pain attributed to compression of the celiac artery at the level of the median arcuate ligament (MAL) of the diaphragm is an uncommon disorder. Although ultrasound investigation and arteriography can be suggestive of the diagnosis, no definitive criteria exist with only cases reports in the literature. This study presents the only known reported case series in which a combination of open and laparoscopic access techniques of MAL decompression are reported. Methods. A retrospective review of prospectively collected electronic databases of the University of North Carolina at Chapel Hill was performed for the period February 1999 until February 2009. Patients having undergone operation for celiac artery compression syndrome were identified and participated in a telephone interview. Questions were asked about the success of the operation, the recovery period, and patient satisfaction. Results. Six patients were identified, 3 were male; mean age was 37.7 years. Four underwent open MAL division and celiac ganglion neurolysis, and 2 underwent a laparoscopic approach. Mean follow-up was 48.6 months. All patients experienced symptomatic improvement and were satisfied with their outcome. No patient had symptoms recurrence. Conclusion. In this limited experience, MAL division with celiac ganglion neurolysis appears to be an effective treatment for celiac artery compression syndrome in appropriately selected patients. Both the open and laparoscopic approaches are safe with durable midterm follow-up results.
Comparison of dynamic block randomization and minimization in randomized trials: a simulation study
Authors: Xiao Lan , Lavori Phillip W , Wilson Sandra R , Ma Jun
Published: February 2011

Background Minimizing the imbalance of key baseline covariates between treatments is known to be very important to the precision of the estimate of treatment effect in clinical research. Dynamic randomization allocation techniques have been used to achieve balance across multiple baseline characteristics. However, empirical data are limited on how these techniques compare in terms of balance and efficiency. We are motivated by a newly funded randomized controlled trial, in which we have the option of choosing between two methods of randomization at the subject level: (1) randomizing individual subjects consecutively as they are enrolled, using Pocock and Simon’s minimization method, and (2) simultaneously randomizing blocks of subjects once all subjects in a block have been enrolled, using a balance algorithm originally developed for cluster randomized trials.

Purpose To compare dynamic block randomization and minimization in terms of balance on baseline covariates and statistical efficiency. Simple randomization was included as a reference.

Methods A simulation study using data from a previous randomized controlled trial was conducted to compare balance statistics and the accuracy and power of hypothesis testing among the randomization methods.

Results Dynamic block randomization consistently produced the best balance and highest power for various sample and treatment effect sizes, even after post-adjustment of the pre-specified baseline covariates in all three methods. Consistent with previous reports, minimization performed better in balance and power than simple randomization; however, the differences were noticeably smaller compared to those between dynamic block randomization and simple randomization.

Limitations In this simulation study, we considered three sample sizes and two block sizes for a two-arm randomized trial. We assumed no interactions among the multiple baseline covariates. It is necessary to evaluate how the results may vary when the simulation conditions are changed before drawing broader conclusions regarding comparisons between the randomization methods.

Conclusions This study demonstrates that dynamic block randomization outperforms minimization with regard to achieving balance and maximizing efficiency. Nevertheless, the differences across the three randomization strategies are modest. The statistical advantages associated with dynamic block randomization need to be considered in relation to the planned sample size and the practical issues for its implementation in deciding the preferred method of randomization for a given trial (e.g., the time required to accrue blocks of subjects of adequate size as balanced against the need to commence intervention/treatment immediately in those randomized to that experimental condition).
Likelihood inference on the relative risk in split-cluster designs
Authors: Shoukri Mohamed M , Colak Dilek , Donner Allan
Published: February 2011

Background Split-cluster experiments are being used by investigators in health sciences when naturally occurring aggregate of individuals with nested sub-groups may be assigned to different treatments. Cited examples include the split-mouth trials, in which a subject’s mouth is divided into two segments that are randomly assigned to different treatment groups. In other situation, randomization to treatment conditions may be possible at the person level within the cluster. In this case, when the treatment conditions are available within each cluster, the design is referred to as a multisite or split-cluster design (SCD). The major attractiveness of this design is that it removes a large portion of the inter-subject variation from the estimates of the treatment effect; hence, it has the potential to require lesser number of measurements than a parallel arm design with the same power. When the response variable of interest is binary, statistical methods developed to evaluate the effect of interventions depended on nonparametric methods. Though these methods are simple to apply, they are known to be less efficient.

Methods Taking the relative risk (RR) as an effect measure, we construct a bivariate-correlated model under which a score test is applied to test H0: RR = 1.0. Moreover, we construct Wald- and Fieller-based confidence intervals on RR. Since the efficiency of SCD increases when the interclass correlation coefficient (ρ12) is high, we present a goodness-of-fit procedure for testing H0:ρ12=0,  which may be helpful in choosing a design for a future study.

Results For illustrating the proposed methodology, we consider two application data from the published literature; the first from a split-mouth trial on 23 patients evaluating the effect of chlorhexidine in the treatment of gingivitis, and second from study of mental health (depression and anxiety) as outcome measure obtained on 173 patients evaluated by two screening instruments. Moreover, we discussed the efficiency gained using our approach in these design settings.

Limitations The likelihood approach makes more assumptions as compared to previous approaches that have been described.

Conclusions We have developed a bivariate beta-binomial model, from which we can conduct a full likelihood statistical inference. Based on this model, we may construct Wald’s confidence intervals and score tests, which are known to possess optimal statistical properties. For the purpose of comparison with nonparametric methods, we constructed the Fieller’s confidence interval.
A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease
Authors: Zhang Richard Y , Leon Andrew C , Chuang-Stein Christy , Romano Steven J
Published: February 2011

Background The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges.

Purpose To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies.

Methods Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies.

Results The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial.

Limitations A regulatory claim of disease modification for any compound will likely require additional verification of a drug’s effect on a validated biomarker of Alzheimer’s pathology.

Conclusions Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.
Adjusted intraclass correlation coefficients for binary data: methods and estimates from a cluster-randomized trial in primary care
Authors: Yelland Lisa N , Salter Amy B , Ryan Philip , Laurence Caroline O
Published: February 2011

Background Accurate estimates of the intraclass correlation coefficient (ICC) are important for calculating appropriate sample sizes for cluster-randomized trials. The ICC and hence the sample size may be reduced through adjustment for baseline covariates. A method exists for calculating adjusted ICCs for binary outcomes based on the logit link, used to calculate odds ratios. Recent interest in presenting relative risks rather than odds ratios indicates that a method based on the log link is needed.

Purpose To determine and evaluate a method for calculating adjusted ICCs based on the log link, and to provide and compare unadjusted and adjusted ICCs from a cluster-randomized trial in primary care based on the logit and log link.

Methods Two methods are proposed for calculating adjusted ICCs for the log link based on a first-order Taylor series expansion and properties of the lognormal distribution. The methods are evaluated by simulation. Unadjusted and adjusted ICCs are calculated for binary outcomes from the Point of Care Testing (PoCT) Trial using the logit and log link.

Results The methods for calculating adjusted ICCs for the log link produced similar results unless the between cluster variance was large. Unadjusted ICCs for the PoCT Trial ranged from 0.001 to 0.048. The impact of adjustment on the ICC varied between outcomes and link functions, ranging from a 59% reduction to an 89% increase.

Limitations The true ICC was unknown for the simulation study. Adjustment was made for age and gender only for the PoCT Trial.

Conclusions The method for calculating adjusted ICCs for binary outcomes depends on the link function. For the log link, the method based on the lognormal distribution is recommended. This method will be useful for cluster-randomized trials where the relative risk, rather than the odds ratio, is the effect measure of interest.
Differing Uses of YouTube During the 2008 U.S. Presidential Primary Election
Authors: Hanson Gary L. , Haridakis Paul M. , Sharma Rekha
Published: February 2011

In this uses and effects study, we explored YouTube use during the 2008 U.S. presidential primaries. Survey results suggested that traditional news sources (i.e., network television) were the source of content most often accessed on YouTube for political information. Participants used YouTube predominantly for habitual entertainment and information-seeking purposes. But there was a strong relationship between political surveillance motivation and watching news, political ads, direct-to-camera videos, and campaign ads, suggesting YouTube could be a significant medium in future elections.
cpsf1 is required for definitive HSC survival in zebrafish
Authors: Bolli Niccolò , Payne Elspeth M. , Rhodes Jennifer , Gjini Evisa , Johnston Adam B. , Guo Feng , Lee Jeong-Soo , Stewart Rodney A. , Kanki John P. , Chen Aye T. , Zhou Yi , Zon Leonard I. , Look A. Thomas
Published: February 2011

A comprehensive understanding of the genes and pathways regulating hematopoiesis is needed to identify genes causally related to bone marrow failure syndromes, myelodysplastic syndromes, and hematopoietic neoplasms. To identify novel genes involved in hematopoiesis, we performed an ethyl-nitrosourea mutagenesis screen in zebrafish (Danio rerio) to search for mutants with defective definitive hematopoiesis. We report the recovery and analysis of the grechetto mutant, which harbors an inactivating mutation in cleavage and polyadenylation specificity factor 1 (cpsf1), a gene ubiquitously expressed and required for 3′ untranslated region processing of a subset of pre-mRNAs. grechetto mutants undergo normal primitive hematopoiesis and specify appropriate numbers of definitive HSCs at 36 hours postfertilization. However, when HSCs migrate to the caudal hematopoietic tissue at 3 days postfertilization, their numbers start decreasing as a result of apoptotic cell death. Consistent with Cpsf1 function, c-myb:EGFP+ cells in grechetto mutants also show defective polyadenylation of snrnp70, a gene required for HSC development. By 5 days postfertilization, definitive hematopoiesis is compromised and severely decreased blood cell numbers are observed across the myeloid, erythroid, and lymphoid cell lineages. These studies show that cpsf1 is essential for HSC survival and differentiation in caudal hematopoietic tissue.
Overexpression of IL-3Rα on CD34+CD38− stem cells defines leukemia-initiating cells in Fanconi anemia AML
Authors: Du Wei , Li Xu-E , Sipple Jared , Pang Qishen
Published: February 2011

Patients with Fanconi anemia (FA) have a high risk of developing acute myeloid leukemia (AML). In this study, we attempted to identify cell-surface markers for leukemia-initiating cells in FA-AML patients. We found that the IL-3 receptor-α (IL-3Rα) is a promising candidate as an leukemia-initiating cell-specific antigen for FA-AML. Whereas IL-3Rα expression is undetectable on normal CD34+CD38− HSCs, it is overexpressed on CD34+CD38− cells from FA patients with AML. We examined the leukemia-initiating cell activity of IL-3Rα–positive FA-AML cells in a “humanized” FA xenotransplant model in which we separated AML cells into IL-3Rα–positive and IL-3Rα–negative CD34 fractions and transplanted them into irradiated recipient mice. In all 3 FA-AML samples, only IL-3Rα–positive cells showed significant levels of engraftment and developed leukemia in the recipient mice. The FA CD34+IL-3Rα+ blasts isolated from leukemic mice exhibited hypersensitivity to IL-3 deprivation and JAK2-STAT5 overactivation after IL-3 treatment. Finally, treatment of FA CD34+IL-3Rα+ blasts with an IL-3Rα–neutralizing antibody inhibited IL-3–mediated proliferation and STAT5 activation. These results demonstrate that IL-3Rα is a cell-surface marker present on FA-AML leukemia-initiating cells and may be a valuable therapeutic target.
Toll-like receptor 2 mediates the activation of human monocytes and endothelial cells by antiphospholipid antibodies
Authors: Satta Nathalie , Kruithof Egbert K. O. , Fickentscher Céline , Dunoyer-Geindre Sylvie , Boehlen Françoise , Reber Guido , Burger Danielle , de Moerloose Philippe
Published: February 2011

The presence of antiphospholipid antibodies (aPLAs) is associated with arterial or venous thrombosis and/or recurrent fetal loss. The proposed pathogenic mechanisms for aPLA effects include the inflammatory activation of monocytes and endothelial cells. Toll-like receptors (TLRs) are candidate signaling intermediates. The aim of this study was to investigate the relative contribution of TLR2 and TLR4 in cell activation by aPLAs. Of 32 patient-derived aPLAs, 19 induced an inflammatory activation of human monocytes and umbilical vein endothelial cells (HUVECs). In HUVECs, inflammatory responses to these aPLAs were increased by TNF pretreatment, which increases the expression of TLR2 but not TLR4. Anti-TLR2 but not anti-TLR4 antibodies reduced the aPLA-induced activation of monocytes and HUVECs. aPLAs activated TLR2-expressing human embryonic kidney 293 (HEK293) cells but not TLR4-expressing cells. Binding studies demonstrated an interaction between aPLAs and TLR2 but not TLR4. A role for CD14, a coreceptor for TLR2 and TLR4, can be inferred by observations that anti-CD14 antibodies reduced responses to aPLAs in monocytes, and that responses in HEK293 cells expressing TLR2 and CD14 were greater than in HEK293 cells expressing TLR2 alone. Our results demonstrate a role for TLR2 and CD14 in human endothelial cell and monocyte activation by aPLAs.
An efficient algorithmic approach for mass spectrometry-based disulfide connectivity determination using multi-ion analysis
Authors: Murad William , Singh Rahul , Yen Ten-Yang
Published: February 2011

Background

Determining the disulfide (S-S) bond pattern in a protein is often crucial for understanding its structure and function. In recent research, mass spectrometry (MS) based analysis has been applied to this problem following protein digestion under both partial reduction and non-reduction conditions. However, this paradigm still awaits solutions to certain algorithmic problems fundamental amongst which is the efficient matching of an exponentially growing set of putative S-S bonded structural alternatives to the large amounts of experimental spectrometric data. Current methods circumvent this challenge primarily through simplifications, such as by assuming only the occurrence of certain ion-types (b-ions and y-ions) that predominate in the more popular dissociation methods, such as collision-induced dissociation (CID). Unfortunately, this can adversely impact the quality of results.

Method

We present an algorithmic approach to this problem that can, with high computational efficiency, analyze multiple ions types (a, b, b

o

, b

*

, c, x, y, y

o

, y

*

, and z) and deal with complex bonding topologies, such as inter/intra bonding involving more than two peptides. The proposed approach combines an approximation algorithm-based search formulation with data driven parameter estimation. This formulation considers only those regions of the search space where the correct solution resides with a high likelihood. Putative disulfide bonds thus obtained are finally combined in a globally consistent pattern to yield the overall disulfide bonding topology of the molecule. Additionally, each bond is associated with a confidence score, which aids in interpretation and assimilation of the results.

Results

The method was tested on nine different eukaryotic Glycosyltransferases possessing disulfide bonding topologies of varying complexity. Its performance was found to be characterized by high efficiency (in terms of time and the fraction of search space considered), sensitivity, specificity, and accuracy. The method was also compared with other techniques at the state-of-the-art. It was found to perform as well or better than the competing techniques. An implementation is available at: http://tintin.sfsu.edu/~whemurad/disulfidebond.

Conclusions

This research addresses some of the significant challenges in MS-based disulfide bond determination. To the best of our knowledge, this is the first algorithmic work that can consider multiple ion types in this problem setting while simultaneously ensuring polynomial time complexity and high accuracy of results.
A genetic algorithm-based boolean delay model of intracellular signal transduction in inflammation
Authors: Kang Chu Chun , Chuang Yung Jen , Tung Kai Che , Chao Chun Cheih , Tang Chuan Yi , Peng Shih Chi , Wong David Shan Hill
Published: February 2011

Background

Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Understanding relationship between external stimuli and corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach to integrate experimental data and qualitative knowledge to identify the physiological consequences of environmental stimuli is needed.

Results

In present study, we employed a genetic algorithm-based Boolean model to represent NF-κB signaling pathway. We were able to capture feedback and crosstalk characteristics to enhance our understanding on the acute and chronic inflammatory response. Key network components affecting the response dynamics were identified.

Conclusions

We designed an effective algorithm to elucidate the process of immune response using comprehensive knowledge about network structure and limited experimental data on dynamic responses. This approach can potentially be implemented for large-scale analysis on cellular processes and organism behaviors.