bluuebunny/crossref_metadata_2025 huggingface dataset:
The State of the Economy: Neo-logicism and Inflation
Authors: Cook Rov T.
Published: February 2012

In this paper I examine the prospects for a successful neo–logicist reconstruction of the real numbers, focusing on Bob Hale's use of a cut-abstraction principle. There is a serious problem plaguing Hale's project. Natural generalizations of this principle imply that there are far more objects than one would expect from a position that stresses its epistemological conservativeness. In other words, the sort of abstraction needed to obtain a theory of the reals is rampantly inflationary. I also indicate briefly why this problem is likely to reappear in any neo–logicist reconstruction of real analysis.
Choice Principles and Constructive Logics
Authors: DEVIDI DAVID
Published: February 2012

That choice principles ‘change the logic’ when added to constructive systems is significant for contemporary metaphysics. However, many are surprised by these results, having learned that the Axiom of Choice (AC) is constructively valid. Indeed, even among specialists there were, until recently, reasons for puzzlement-rival versions of Intuitionistic Type Theory, one where (AC) is valid, another where it implies classical logic. This paper accessibly explains the situation, puts the issues in a broader setting by considering other choice principles, and draws philosophical morals for the understanding of quantification, choice principles, and the prospects for constructivism.
Inflammatory Bowel Disease Manifesting After Surgical Treatment for Hirschsprung Disease
Authors: Levin David N. , Marcon Margaret A. , Rintala Risto J. , Jacobson Dustin , Langer Jacob C.
Published: February 2012

Eight children developed chronic inflammatory bowel disease (IBD) 4 to 21 years after surgery for Hirschsprung disease. Three had trisomy 21 and 6 experienced chronic or recurrent enterocolitis. Four had a family history of IBD. Clinical presentation included chronic diarrhea, hematochezia, abscess, and fistula formation. Three required surgery for fistula, stricture, and small bowel obstruction and the other 5 were managed medically. Recognition of this condition may be important in the long‐term follow‐up of children with Hirschsprung disease, and patients who have carried a diagnosis of chronic enterocolitis may warrant further investigation looking for evidence of IBD.
Incidence of Peptic Ulcer Bleeding in the US Pediatric Population
Authors: Brown Kurt , Lundborg Per , Levinson Jeremy , Yang Huiying
Published: February 2012

Objectives:

The aim of the present study was to determine the incidence of peptic ulcer bleeding (PUB) in pediatric patients.

Methods:

A hospital inpatient database, Premier Perspective, and an insurance claims database, MarketScan, were analyzed to estimate upper and lower limits for the annual incidence of PUB in the US pediatric population.

Results:

Using data from the Premier Perspective database and database‐specific projection methodology, the total number of cases of hospitalization of pediatric patients for PUB in the United States in 2008 was estimated to be between 378 and 652. This translated to an incidence of 0.5 to 0.9/100,000 individuals in the pediatric population. Using data from the MarketScan database, the incidence of PUB in the insured pediatric population was estimated to be 4.4/100,000 individuals. Overall, 17.4% of insured pediatric patients diagnosed as having any upper gastrointestinal ulcer in 2008 were reported to have developed PUB.

Conclusions:

The estimated incidence of PUB in the US pediatric population in 2008 ranged from 0.5 to 4.4/100,000 individuals. The total number of cases of PUB in pediatric patients in the United States each year was thus estimated to be between 378 and 3250. Such estimates provide a likely lower and upper limit for the total number of cases of the condition annually.
Variability of perceptual multistability: from brain state to individual trait
Authors: Kleinschmidt Andreas , Sterzer Philipp , Rees Geraint
Published: February 2012

Few phenomena are as suitable as perceptual multistability to demonstrate that the brain constructively interprets sensory input. Several studies have outlined the neural circuitry involved in generating perceptual inference but only more recently has the individual variability of this inferential process been appreciated. Studies of the interaction of evoked and ongoing neural activity show that inference itself is not merely a stimulus-triggered process but is related to the context of the current brain state into which the processing of external stimulation is embedded. As brain states fluctuate, so does perception of a given sensory input. In multistability, perceptual fluctuation rates are consistent for a given individual but vary considerably between individuals. There has been some evidence for a genetic basis for these individual differences and recent morphometric studies of parietal lobe regions have identified neuroanatomical substrates for individual variability in spontaneous switching behaviour. Moreover, disrupting the function of these latter regions by transcranial magnetic stimulation yields systematic interference effects on switching behaviour, further arguing for a causal role of these regions in perceptual inference. Together, these studies have advanced our understanding of the biological mechanisms by which the brain constructs the contents of consciousness from sensory input.
Functional brain networks underlying perceptual switching: auditory streaming and verbal transformations
Authors: Kashino Makio , Kondo Hirohito M.
Published: February 2012

Recent studies have shown that auditory scene analysis involves distributed neural sites below, in, and beyond the auditory cortex (AC). However, it remains unclear what role each site plays and how they interact in the formation and selection of auditory percepts. We addressed this issue through perceptual multistability phenomena, namely, spontaneous perceptual switching in auditory streaming (AS) for a sequence of repeated triplet tones, and perceptual changes for a repeated word, known as verbal transformations (VTs). An event-related fMRI analysis revealed brain activity timelocked to perceptual switching in the cerebellum for AS, in frontal areas for VT, and the AC and thalamus for both. The results suggest that motor-based prediction, produced by neural networks outside the auditory system, plays essential roles in the segmentation of acoustic sequences both in AS and VT. The frequency of perceptual switching was determined by a balance between the activation of two sites, which are proposed to be involved in exploring novel perceptual organization and stabilizing current perceptual organization. The effect of the gene polymorphism of catechol-
O
-methyltransferase (COMT) on individual variations in switching frequency suggests that the balance of exploration and stabilization is modulated by catecholamines such as dopamine and noradrenalin. These mechanisms would support the noteworthy flexibility of auditory scene analysis.
Joint genotyping on the fly: Identifying variation among a sequenced panel of inbred lines
Authors: Stone Eric A.
Published: February 2012

High-throughput sequencing is enabling remarkably deep surveys of genomic variation. It is now possible to completely sequence multiple individuals from a single species, yet the identification of variation among them remains an evolving computational challenge. This challenge is compounded for experimental organisms when strains are studied instead of individuals. In response, we present the Joint Genotyper for Inbred Lines (JGIL) as a method for obtaining genotypes and identifying variation among a large panel of inbred strains or lines. JGIL inputs the sequence reads from each line after their alignment to a common reference. Its probabilistic model includes site-specific parameters common to all lines that describe the frequency of nucleotides segregating in the population from which the inbred panel was derived. The distribution of line genotypes is conditional on these parameters and reflects the experimental design. Site-specific error probabilities, also common to all lines, parameterize the distribution of reads conditional on line genotype and realized coverage. Both sets of parameters are estimated per site from the aggregate read data, and posterior probabilities are calculated to decode the genotype of each line. We present an application of JGIL to 162 inbredDrosophila melanogasterlines from theDrosophilaGenetic Reference Panel. We explore by simulation the effect of varying coverage, sequencing error, mapping error, and the number of lines. In doing so, we illustrate how JGIL is robust to moderate levels of error. Supported by these analyses, we advocate the importance of modeling the data and the experimental design when possible.
Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance
Authors: Li Jingfeng , Akagi Keiko , Hu Yongjun , Trivett Anna L. , Hlynialuk Christopher J.W. , Swing Deborah A. , Volfovsky Natalia , Morgan Tamara C. , Golubeva Yelena , Stephens Robert M. , Smith David E. , Symer David E.
Published: February 2012

Endogenous retrotransposons have caused extensive genomic variation within mammalian species, but the functional implications of such mobilization are mostly unknown. We mapped thousands of endogenous retrovirus (ERV) germline integrants in highly divergent, previously unsequenced mouse lineages, facilitating a comparison of gene expression in the presence or absence of local insertions. Polymorphic ERVs occur relatively infrequently in gene introns and are particularly depleted from genes involved in embryogenesis or that are highly expressed in embryonic stem cells. Their genomic distribution implies ongoing negative selection due to deleterious effects on gene expression and function. A polymorphic, intronic ERV at Slc15a2 triggers up to 49-fold increases in premature transcriptional termination and up to 39-fold reductions in full-length transcripts in adult mouse tissues, thereby disrupting protein expression and functional activity. Prematurely truncated transcripts also occur at Polr1a, Spon1, and up to ∼5% of other genes when intronic ERV polymorphisms are present. Analysis of expression quantitative trait loci (eQTLs) in recombinant BxD mouse strains demonstrated very strong genetic associations between the polymorphic ERV in cis and disrupted transcript levels. Premature polyadenylation is triggered at genomic distances up to >12.5 kb upstream of the ERV, both in cis and between alleles. The parent of origin of the ERV is associated with variable expression of nonterminated transcripts and differential DNA methylation at its 5′-long terminal repeat. This study defines an unexpectedly strong functional impact of ERVs in disrupting gene transcription at a distance and demonstrates that ongoing retrotransposition can contribute significantly to natural phenotypic diversity.
A model for calculating diffraction elastic constants
Authors: Gnäupel-Herold Thomas , Creuziger Adam A. , Iadicola Mark
Published: February 2012

A model, dubbed the inverse Kröner model, is proposed to calculate the diffraction elastic constants from the elastic constants of a single crystal. It is related to the classic Kröner model, and both are identified as bounds on the diffraction elastic constants. Through the grain shape as controlling parameter, the classic Kröner model is bound by thehkl-independent mechanical limit given by the bulk elastic constants of the matrix, while the inverse Kröner model approaches the Reuss limit.
Combined phylogenetic analyses reveal interfamilial relationships and patterns of floral evolution in the eudicot order Fabales
Authors: Bello M. Angélica , Rudall Paula J. , Hawkins Julie A.
Published: February 2012

Relationships between the four families placed in the angiosperm order Fabales (Leguminosae, Polygalaceae, Quillajaceae, Surianaceae) were hitherto poorly resolved. We combine published molecular data for the chloroplast regions matK and rbcL with 66 morphological characters surveyed for 73 ingroup and two outgroup species, and use Parsimony and Bayesian approaches to explore matrices with different missing data. All combined analyses using Parsimony recovered the topology Polygalaceae (Leguminosae (Quillajaceae + Surianaceae)). Bayesian analyses with matched morphological and molecular sampling recover the same topology, but analyses based on other data recover a different Bayesian topology: ((Polygalaceae + Leguminosae) (Quillajaceae + Surianaceae)). We explore the evolution of floral characters in the context of the more consistent topology: Polygalaceae (Leguminosae (Quillajaceae + Surianaceae)). This reveals synapomorphies for (Leguminosae (Quillajaceae + Surianaceae)) as the presence of free filaments and marginal/ventral placentation, for (Quillajaceae + Surianaceae) as pentamery and apocarpy, and for Leguminosae the presence of an abaxial median sepal and unicarpellate gynoecium. An octamerous androecium is synapomorphic for Polygalaceae. The development of papilionate flowers, and the evolutionary context in which these phenotypes appeared in Leguminosae and Polygalaceae, shows that the morphologies are convergent rather than synapomorphic within Fabales.
Microsatellite DNA markers indicate three genetic lineages in East Asian indigenous goat populations
Authors: Nomura K. , Ishii K. , Dadi H. , Takahashi Y. , Minezawa M. , Cho C. Y. , Sutopo  , Faruque M. O. , Nyamsamba D. , Amano T.
Published: February 2012

The genetic differentiation and phylogenetic relationships of 18 indigenous goat populations from seven East Asian countries were analysed based on data obtained from 26 microsatellite DNA markers. The mean number of alleles (MNA) per population ranged from 2.5 to 7.6, with an average of 5.8. Genetic variability estimated from MNA and heterozygosity (HE and HO) were relatively low in coastal and island populations. A heterozygous deficiency within populations (FIS = 0.054, P < 0.001) and total inbreeding (FIT = 0.181, P < 0.01) were observed, and genetic differentiation in the populations (FST) was 13.4%. The results of Bayesian model‐based clustering and a neighbour‐joining tree based on Nei's genetic distance showed that Asian goat populations could be subdivided into at least the following three genetic clusters: East Asian, Southeast Asian and Mongolian. These results are in close accordance with conventional morphological and geographical classifications and migration history.
Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte‐predominantHodgkin lymphoma
Authors: Porrata Luis F. , Ristow Kay , Habermann Thomas M. , Witzig Thomas E. , Colgan Joseph P. , Inwards David J. , Ansell Stephen M. , Micallef Ivana N. , Johnston Patrick B. , Nowakowski Grzegorz S. , Thompson Carrie , Markovic Svetomir N.
Published: February 2012

The pathological background in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consists of lymphocytes and histocytes. This study analysed the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis (ALC/AMC‐DX) on the impact of survival inNLPHL. One hundred and three consecutiveNLPHLpatients that were followed atMayoClinic from 1974 to 2010 were included in the study. Receiver operating characteristic and area under the curve were used forALC/AMC‐DXcut‐off value analysis and proportional‐hazards models were used to compare survival based on theALC/AMC‐DXratio. With a median follow‐up of 8·9 years (range: 0·3–31 years), anALC/AMC‐DX≥2·1 was the best cut‐off value for survival with an area under the curve of 0·82, a sensitivity of 70% and specificity of 84%. After adjusting for theInternationalPrognosticScore (IPS),ALC/AMC‐DXremained an independent prognostic factor for overall survival [HazardRatio (HR), 0·33, 95% confidence interval (CI), 0·15–0·71%,P < 0·004]; lymphoma‐specific survival (HR, 0·05; 95%CI, 0·01–0·68%,P < 0·002); progression‐free survival (HR, 0·30; 95%CI, 0·14–0·60%,P < 0·006), and time to progression (HR, 0·06, 95%CI, 0·04–0·30%,P < 0·004).ALC/AMC‐DXis a low cost, already standarized, biomarker to predict clinical outcomes inNLPHL.
PAI‐1, progress in understanding the clinical problem and its aetiology
Authors: Iwaki Takayuki , Urano Tetsumei , Umemura Kazuo
Published: February 2012

Plasminogen activator inhibitor‐1 (PAI‐1, also known as SERPINE1) is a member of the serine protease inhibitor (SERPIN) superfamily and is the primary physiological regulator of urokinase‐type plasminogen activator (uPA) and tissue‐type plasminogen activator (tPA) activity. Although the principal function of PAI‐1 is the inhibition of fibrinolysis, PAI‐1 possesses pleiotropic functions besides haemostasis. In the quarter century since its discovery, a number of studies have focused on improving our understanding of PAI‐1 functions in vivo and in vitro. The use of Serpine1‐deficient mice has particularly enhanced our understanding of the functions of PAI‐1 in various physiological and pathophysiological conditions. In this review, the results of recent studies on PAI‐1 and its role in clinical conditions are discussed.
Effects of experimental osteoporosis and low calcium intake on postextraction sockets of rats
Authors: d. Prado Renata F. , Silveira Vanessa Á. S. , d. Rocha Rosilene F. , d. Vasconcellos Luana M. R. , Carvalho Yasmin R.
Published: February 2012

This study analysed the initial effects of the combination of oestrogen deficiency with a calcium‐deficient diet on alveolar bone repair. Sixty‐three 3‐month‐old female rats were either ovariectomized (OVX, n = 42) or sham‐operated (SHAM, n = 21). Among the 42 ovariectomized rats, 21 received standard commercial food (OVX) and 21 received food with low calcium content (ESP). The mandibular first molars were extracted bilaterally 15 days after ovariectomy or sham surgery. The rats were weighed and killed at 7, 21 and 45 days after tooth extraction. The results were evaluated by descriptive microscopic analysis, histomorphometry of the trabecular and osteoid volume and mast cell counts. Analysis of the results indicated that trabecular volume and mast cell counts increased significantly over time, while osteoid volume decreased over time. Comparisons between the SHAM and OVX groups demonstrated no statistical differences, while comparison between the OVX and ESP groups indicated differences in trabecular volume and the number of mast cells. The data suggest that hormonal deficiency does not delay alveolar bone repair in OVX rats; however, oestrogen deficiency associated with calcium deficiency can lead to bone resorption through the activation of mast cells.
The pyrodiversity–biodiversity hypothesis: a test with savanna termite assemblages
Authors: Davies Andrew B. , Eggleton Paul , van Rensburg Berndt J. , Parr Catherine L.
Published: February 2012

1. Fire is an important disturbance in African savannas where it is generally assumed that high levels of pyrodiversity (variation in aspects of the fire regime) are necessary to maintain high levels of biodiversity. There is, however, little empirical evidence in support of this hypothesis for animals. Furthermore, the relationship between pyrodiversity and biodiversity may vary with different savanna types, shaped by mean annual precipitation.

2. We made use of a long‐term burning experiment to investigate the effect of interactions between precipitation and pyrodiversity on biodiversity. We sampled termites (major ecosystem engineers in savannas) within experimental plots involving a range of fire seasons and frequencies. Sampling was conducted in three distinct savanna types along a rainfall gradient in South Africa. We explored how termite diversity varied with mean annual precipitation and whether faunal responses to fire regimes varied with rainfall. Termites were sampled comprehensively during the wet season using cellulose baits and active searching in order to sample a variety of functional groups.

3. Assemblages differed significantly across savanna types with higher levels of diversity in the wetter site using the active searching method. Diversity was lowest at the most arid site but certain feeding groups (FGs) peaked in the savanna with intermediate rainfall. Differences between these savannas are attributed to broad underlying changes in net primary productivity and temperature, with mammalian herbivores thought to generate a peak in diversity of some faunal groups at the intermediate savanna through their role in facilitating nutrient cycling.

4. Overall, termites were highly resistant to fire in all savanna types with little difference between fire regimes (season and frequency), but assemblage composition and some FGs were affected by burning. Differences between fire regimes were more pronounced with increasing rainfall. These differences are likely to be linked to changes in vegetation structure caused by fire, which are more significant in wet savannas.

5. Synthesis and applications. Our findings, along with those for other insect taxa, indicate limited support for the pyrodiversity–biodiversity hypothesis; this suggests that, at least for invertebrates, management regimes can be flexible, although more caution is advisable in wetter savannas.
Interspecific differences in determinants of plant species distribution and the relationships with functional traits
Authors: Aiba Masahiro , Takafumi Hino , Hiura Tsutom
Published: February 2012

1. Environmental control and dispersal limitation are both essential processes in plant community assembly and species distribution. Although numerous studies in the past decade have examined their importance as determinants of community composition, remarkably little is known about interspecific differences in the importance of these two processes.

2. To quantify these interspecific differences, we compared the importance of environmental factors and space as correlates of species distribution among 24 understorey plant species in a Japanese cool–temperate forest by performing variation partitioning at the species level. Specifically, we hypothesized that the importance of environment and space differs among species, and these differences can be partly predicted from the functional traits and/or phylogenetic identity of each species.

3. The unique contributions of both environment and space were significant in the community‐level analysis. However, at the species level, the relative and absolute sizes of the unique contributions of environment and space differed considerably among the 24 species. Environment and space were not necessarily significant variables explaining the distribution of many species.

4. No significant relationships were found between the unique contribution of environment and the four functional traits tested, that is, dispersal mode, seed mass, plant height and specific leaf area among the 24 species. In contrast, the unique contribution of space was significantly larger in species with no dispersal mechanisms than in animal‐dispersed species. No significant phylogenetic signal was detected for the unique contribution of environment or space, suggesting that importance of environmental control and dispersal limitation as determinants of species distribution is evolutionarily labile.

5.
Synthesis. Our results suggest that the relative and absolute importance of different processes of community assembly (i.e. environmental control and dispersal limitation) differs remarkably among species even within a single community. These interspecific differences may be explained in part by interspecific differences in dispersal mode.
Evaluating care pathways for community psychiatry in England: a qualitative study
Authors: Khandaker Golam M. , Gandamaneni Praveen K. , Dibben Claire R. M. , Cherukuru Srinivasarao , Cairns Paul , Ray Manaan K.
Published: February 2012

Objectives  In view of forthcoming ‘payment by results’ (PbR) for mental health, increasing number of National Health Service (NHS) Trusts are reorganizing their community services for working age adults to create care pathways. However, research base for the care pathways model in mental health is limited. Our NHS Foundation Trust was one of the first to introduce care pathways for community psychiatry in the UK. We have carried out a qualitative study to evaluate how this model works out in practice, including its impact on quality of patient care, mental health professionals and primary care.

Methods  We interviewed doctors, multidisciplinary staff and Trusts managers (19 in total). Transcripts of recorded interviews were coded and analysed thematically using a grounded theory approach.

Results  Overall, despite teething problems, working in pathways was generally seen as a positive change. It led to more focused interventions being offered, and practitioners being held to account over clear standards of care. It is more cost‐effective and allows for active case management and clear clinical leadership. It is recovery focused and encourages social inclusion. The arbitrary time frame, strict criteria and thresholds for different teams can create issues. Improved communication, flexible and patient‐centred approach, staff supervision, and increasing support to primary care were felt to be central to this model working efficiently and effectively.

Conclusions  Introduction of care pathways is an important step towards effective implementation of PbR for mental health. Our study would inform future research into care pathways, facilitate organizational learning and help to improve effectiveness of services.
Participation in population‐based case–control studies: does the observed decline vary by socio‐economic status?
Authors: Mazloum Marie , Bailey Helen D. , Heiden Tamika , Armstrong Bruce K. , de Klerk Nicholas , Milne Elizabeth
Published: February 2012

Mazloum M, Bailey HD, Heiden T, Armstrong BK, de Klerk N, Milne E. Participation in population‐based case–control studies: does the observed decline vary by socio‐economic status? Paediatric and Perinatal Epidemiology 2012; 26: 276–279.

An Australian study of childhood leukaemia (Aus‐ALL) previously reported that control participation was positively associated with socio‐economic status (SES). A similar study of childhood brain tumours (Aus‐CBT) was carried out 4 years later, and this paper compares control participation and its relationship with SES in the two studies. To assess the representativeness of controls in terms of SES, the addresses of controls were linked to Australian Bureau of Statistics Census 2006 Collection Districts (CDs), and hence to area‐based indices of SES. Independent sample t‐tests and chi‐squared tests were used to compare the SES indices of CDs where Aus‐CBT controls lived with those where Aus‐ALL controls lived and with those of all CDs where Australian families lived. The overall percentage of eligible families who agreed to participate was lower in Aus‐CBT (53.9%) than in Aus‐ALL (70.3%). Control families in both studies were of higher SES than the general population, while the distribution of SES among recruited controls was similar in both studies. These findings provide some reassurance that the observed decline in research participation over time may not be associated with an increasingly unrepresentative participant population.
Comparison of the effects of loratadine and astemizole in the treatment of children with seasonal allergic rhinoconjunctivitis
Authors: Boner A. L. , Richeili C. , Castellani C. , Marchesi E. , Andreoli A.
Published: February 2012

The efficacy and safety of a once‐daily dose of loratadine 10 mg (5 mg in patients whose body weight was ≤ 30 kg) and astemizole 2 mg/10 kg body weight o.d. were compared in a 14‐day third‐party blind study. Forty‐one children (30 boys and 11 girls, aged 6–14 years) with seasonal allergic rhinoconjunctivitis entered the study. The pollen count was monitored throughout the study. A significant improvement (p < 0.01) in allergy symptoms was observed from the third day for both drugs; there was no significant difference between drugs, although loratadine led to a greater reduction in symptoms. In the astemizole group, the apparently rapid onset of drug action might by explained by reduced pollen exposure. Therapeutic response was excellent/good in 83.3% and 58.8% of the loratadine and astemizole groups, respectively. The results reported by the patients/parents were similar. Nine of the children on astemizole and four children on loratadine complained of side effects; three patients in the astemizole group were withdrawn from treatment because of adverse effects. No abnormal changes in lab values were observed in either group.
A clinical index: A new method to assess efficacy of allergen immunotherapy
Authors: McHugh S. M. , Ewan P. W.
Published: February 2012

Assessment of efficacy in immunotherapy trials is difficult: a number of parameters can be measured; these may give conflicting results and it is not clear which best represents the clinical state. We therefore derived a Clinical Index (CI), by combining five individual parameters‐diary card symptom score, visual analogue symptom score, drug score, nasal challenge and skin prick test‐by rank analysis. The CI has been used to express the results in a trial of house dust mite (D. pteronyssinus) immunotherapy for allergic rhinitis, comparing two active treatments, Pharmalgen® and Allpyral®, with placebo. The derived index correlated well with all parameters measured. Correlations between the five individual parameters were variable: with the exception of the skin test, good correlations were seen, each parameter correlating with two or three of the others, but the visual analogue showed the closest association with other parameters. Results from a single parameter taken alone could be misleading, e.g. in the Allpyral group, nasal challenge improved significantly, but symptoms assessed either by visual analogue or diary card score did not. The CI showed significant improvement in the Pharmalgen group but not in the Allpyral group. The CI gave a more reliable measure of outcome than individual parameters.
Anaphylactic shock after skin test with phytohaemoagglutinin
Authors: Schiavino D. , Nucera E. , Murzilli F. , Schinco G. , Papa G. , Fais G. , Patriarca G.
Published: February 2012

A young woman (26 years old), with gastrointestinal candidosis of 8 months duration, was hospitalized in our department to study her cell immunity. Five minutes after an id injection of PHA (bactophytohaemoagglutinin M, Difco, 1 mg), mix monilieae, mix tricophyton and PPD Berna, she showed an extensive wheal and flare reaction in the PHA injection area, eyelid oedema and respiratory distress. In spite of adrenaline, corticosteroid and antihistamine drug administration, the patient collapsed and was admitted to the resuscitation department, where she quickly recovered. In the following days, the patient underwent immune and allergy testing: 1) total Ige immuno‐enzymatic assay: 72 KU/l; 2) specific IgE and IgE immuno‐enzymatic assay for Candida: negative; 3) in vitro lymphocyte transformation test (thymidine 2‐C14) with PHA Difco was positive. This finding and the positivity of the id injection with PHA could indicate an allergic type I immunoreaction, the description of which we have not found in the international literature (the presence of IgG STS cannot be totally excluded).
Transjugular intrahepatic portosystemic shunt for hepatitis C virus‐related portal hypertension after liver transplantation
Authors: Ghinolfi Davide , De Simone Paolo , Catalano Gabriele , Petruccelli Stefania , Coletti Laura , Carrai Paola , Marti Josep , Tincani Giovanni , Cicorelli Antonio , Cioni Roberto , Filipponi Franco
Published: February 2012

Ghinolfi D, De Simone P, Catalano G, Petruccelli S, Coletti L, Carrai P, Marti J, Tincani G, Cicorelli A, Cioni R, Filipponi F. Transjugular intrahepatic portosystemic shunt for hepatitis C virus‐related portal hypertension after liver transplantation.

Abstract:  This is a single center retrospective review of 19 consecutive liver transplant (LT) patients with hepatitis C virus (HCV)‐related graft recurrent hepatitis who underwent transjugular intrahepatic portosystemic shunt (TIPS) at a median interval of 21 months (range: 5–50) from LT. Indications were refractory ascites in 11 patients (57.9%), hydrothorax in six (31.6%), and both in two (10.5%). TIPS was successful in 94.7% of cases (18/19) with only one procedure‐related mortality (5.3%) owing to sepsis on day 35. At a median follow‐up of 23 months (range: one month–nine yr), TIPS allowed for symptoms resolution in 16 patients (84.2%), with ascites resolving in all cases and hydrothorax persisting in 2. Post‐TIPS patient survival at six months, one yr, and three yr was 84.2%, 73.7%, and 56.8%, respectively. We compared these results with a control group of 29 patients with HCV recurrence but without unresponsive ascites or hydrothorax. Patients in the control group had better survival than patients undergoing TIPS placement. However, survival of TIPS patients with a MELD score lower than or equal to 12 was similar to that of the control group. We conclude that TIPS may be used to treat complications secondary to HCV.
Pediatric liver transplantation for fibropolycystic liver disease
Authors: Ko Jae Sung , Yi Nam‐Joon , Suh Kyung Suk , Seo Jeong Kee
Published: February 2012

Ko JS, Yi N‐J, Suh KS, Seo JK. Pediatric liver transplantation for fibropolycystic liver disease. Pediatr Transplantation 2012: 16: 195–200. © 2012 John Wiley & Sons A/S.

Abstract:  Fibropolycystic liver disease includes CHF, Caroli’s syndrome, and Caroli’s disease. Patients with Caroli’s disease and Caroli’s syndrome have an increased risk of recurrent cholangitis, intrahepatic calculi, biliary cirrhosis, and cholangiocarcinoma. The aim of this study was to examine the post‐transplantation outcomes of children with fibropolycystic liver disease. Of the 158 children transplanted at Seoul National University Hospital, there were four patients with Caroli’s syndrome, two patients with CHF, and one patient with Caroli’s disease. One patient underwent combined liver/kidney transplantation. Associated renal manifestations included ARPKD in three children and nephronophthisis in one child. The indications for LT were recurrent cholangitis, decompensated cirrhosis, and refractory complications of portal hypertension. Both graft and patient survival rates were 100% at a median follow‐up period of two yr after LT. Three children with growth failure achieved catch‐up growth after LT. In three patients with ARPKD, mean serum creatinine levels increased from 0.53 mg/dL at the time of LT to 0.91 mg/dL at the last follow‐up (p = 0.01). LT is an excellent option for children with complications from fibropolycystic liver disease. Renal function should be monitored cautiously after LT in the patients with ARPKD.
Gilbert’s syndrome – a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation
Authors: Kathemann Simone , Lainka Elke , Baba Hideo A. , Hoyer Peter F. , Gerner Patrick
Published: February 2012

Kathemann S, Lainka E, Baba HA, Hoyer PF, Gerner P. Gilbert’s syndrome – a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation.  Pediatr Transplantation 2012: 16: 201–204. © 2012 John Wiley & Sons A/S.

Abstract:  Gilbert’s syndrome is one major cause for unconjugated hyperbilirubinemia in healthy individuals with the prevalence being approximately 3.2–8.6%. It is caused by a mutation in the promoter region of the UGT1A1‐gene with a prolonged TAA‐repeat coding for the enzyme bilirubin UDP‐glucuronosyltransferase (A(TA)7TAA allele). After OLT, Gilbert’s disease of the transplanted liver can cause unconjugated hyperbilirubinemia. Therefore, we looked for the presence of A(TA)7TAA alleles in pediatric liver transplant recipients with unconjugated hyperbilirubinemia. Laboratory results of 106 pediatric liver transplant recipients (aged 0–17 yr) were evaluated for elevated total bilirubin over 2.0 mg/dL (conjugated bilirubin <30%). In these patients, DNA of the liver graft was extracted from paraffin‐embedded liver biopsy samples formerly taken for diagnostic reasons. The DNA was analyzed for A(TA)7TAA alleles in the promoter region of the UGT1A1‐gene. In 4 of 106 pediatric liver transplant recipients we found unconjugated hyperbilirubinemia with total bilirubin above 2.0 mg/dL (conjugated bilirubin <30%). The analysis of the promoter region of the UGT1A1‐gene of the liver grafts showed three homozygous A(TA)7TAA alleles (homozygous Gilbert’s syndrome) and one heterozygous A(TA)7TAA allele (heterozygous Gilbert’s syndrome). This study shows that pediatric liver transplant recipients with unconjugated hyperbilirubinemia are very likely to have received a liver graft from a donor with Gilbert’s syndrome.
Systematic design, production and breeding of multi‐transgenic donor pigs
Authors: Klymiuk Nikolai , Baehr Andrea , Kessler Barbara , Kurome Mayuko , Wuensch Anne , Richter Anne , Wolf Eckhard
Published: February 2012

The continuously increasing shortage of donor organs for allotransplantation demands the development of alternative treatments. The implementation of xenotransplantation suffers from various pathways of rejection and incompatibilities between recipient and donor tissues. Usage of transgenic donor pigs might overcome these problems, but the generation of transgenic animals by nuclear transfer is costly and teadious, the combination of several transgenes represents considerable efforts and the permanent production of donor pigs requires optimization between the conflicting issues of transgene segregation and high inbreeding coefficient.

The establishment of novel transgenes is normally biased, which means that with increasing knowledge on the diverse mechanisms of xenograft failure, novel transgene variants arise. In addition, the poor knowledge about the porcine genome and site‐specific regulation in pigs requires concise planning and pre‐evaluation of bio‐informatic data.

The generation of transgenic pig follows the conventional and well established strategies in mouse, with the exception that no embryonic stem cells are available in the pig. But the establishment of transgenic primary cells, their usage as donors for somatic cell nuclear transfer and the transfer of cloned embryos into synchronized gilts represent a reasonable alternative, conventionally resulting in suitable founder animals within a few litters. The characterization of the founders depends on the site of expression and, thus, influences the strategy of founder reproduction.

The lateron combination with other transgenes is challenging and normally requires implementation of the transgene into an existing breeding herd. Thus, the breeding concept has to be designed to (i) to establish a core herd, (ii) to allow the addition of novel transgenes to the herd and (iii) to support the maintainence of the breeding herd by continuous re‐juvenation. The latter is of certain importance, as transgenes normally segregate according to the Mendelian pattern of inheritance. This aspect would favour a homozygous transgene status for all breeding animals. However, such a strategy will result in dramatically increasing inbreeding coefficients and, consequently, reduce fertility and litter sizes.

Taken together, both, the permanent production of multi‐transgenic donor animals as well as the development of novel transgenes and their integration into a breeding herd is a logistic challenge that requires long‐term planning but also flexibility regarding the transgene combination which depend is governed by the increasing insight in the diverse mechanisms of xenograft failure.
Antigen‐specific regulatory T cells can induce tolerance to immunogenic grafts without the need for chronic immunosuppression
Authors: Seltrecht Nadja , Mpofu Nonsikelelo , Hardtke‐Wolenski Matthias , Noyan Fatih , Manns Michael P. , Jaeckel Elmar
Published: February 2012

Regulatory CD4+CD25+Foxp3+ T cells (Tregs) play an important role in the induction of allospecific tolerance. However tolerance in solid organ transplantation by mere transfer of Tregs has been difficult. Besides this the stability of the differentiation phenotype of Tregs has recently been questioned.

We therefore aimed in generating large numbers of stable allospecific Tregs from naïve T cells by retroviral transduction with Foxp3. These were tested in an immunogenic skin transplantation model (C57BL/6→BALB/c).

We established a system of transduction of mouse T cells with ecotropic retroviruses expressing Foxp3 and Thy1.1 as a surface marker to follow up transduced T cells. Alloantigen‐specific Tregs were generated by stimulating naïve recipient CD4+ T cells with irradiated donor splenocytes. CD25+ and/or CD69+ allospecific recipient CD4+ T cells were isolated and transduced with Foxp3. Alloantigen‐specific Foxp3 T cells (iTregs) showed high expression for the Treg markers Foxp3, CTLA4 and GITR. They could suppress a MLR in an alloantigen‐specific manner. Furthermore, they could be expanded up to 18 fold in vitro while maintaining their Treg phenotype and expression of lymph node homing markers like CCR7 and CD62L. iTregs prevented skin graft rejection without the need for chronic immunosuppression and recipients showed systemic allospecific allotolerance. Alloantigen‐specific Tregs were far more potent than polyspecific Tregs. Mechanisms of tolerance were graft specific homing, expansion and long‐term persistence of Tregs within the graft (>100 days, 90% of intragraft Tregs were alloantigen‐specific). In fact, tolerance could be transferred with re‐transplantation of the tolerant graft onto secondary recipients. Third party grafts were readily rejected demonstrating specificity of tolerance. Due to the Foxp3 transduction, iTregs did not lose their Treg phenotype.

The results prove that large numbers of stable alloantigen‐specific Tregs can be generated from a polyclonal repertoire of naïve T cells. This is the first time that allotolerance was achieved in a non‐lymphopenic transplant model using skin grafts in an immunogenic strain combination. Therefore, antigen‐specific Tregs might have a huge therapeutic potential after solid organ transplantation.
Transplantation of neonatal islets from LEA29Y‐transgenic pigs restores normoglycemia in streptozotocin‐diabetic NSG‐mice
Authors: van Bürck Lelia , Klymiuk Nikolai , Kessler Barbara , Thormann Michael , Postrach Johannes , Wolf Eckhard , Seissler Jochen
Published: February 2012

Beta cell replacement therapy represents the only way towards complete restoration of the physiological glucose homeostasis in patients with Type 1 diabetes. Xenotransplantation of transgenic pig islets expressing immunomodulatory molecules might represent a promising approach to overcome the problems of lacking organ donors, adverse effects of the required systemic immunosuppression, and disappointing transplantation outcomes. LEA29Y, a second generation CTLA‐4‐Ig fusion protein exerts potent immunosuppressive effects by selective blockade of the B7 costimulatory pathway. To assess the impact of high local LEA29Y concentrations on xenogeneic islet graft rejection, a transgenic pig model with islet‐specific LEA29Y transgene expression was generated.

Islet‐like clusters from neonatal pigs expressing LEA29Y under the control of the porcine insulin promoter and from wild‐type pigs were isolated by collagenase digestion and subsequent in vitro culture. After 6 days 2500 clusters/mouse were transplanted under the kidney capsule of streptozotocin‐diabetic NOD‐scidIL2Rgammanull (NSG) mice. After an initial period of insulin dependency, mice developed stable normoglycemia within 8 weeks after transplantation. Transplanted mice of both groups (Tx, wt; Tx, LEA29Y) exhibited normal and as compared to non‐transplanted normoglycemic NSG mice even improved fasting glucose and glucose tolerance resulting from glucose‐responsive graft‐derived porcine insulin secretion. Beta cell‐specific expression of LEA29Y was detectable in neonatal porcine pancreas, in the grafts of transplanted mice, and was also measurable in the plasma of normoglycemic mice. Furthermore, mice with LEA29Y transgenic grafts exhibited a glucose‐dependent LEA29Y release during glucose tolerance testing.

The present study demonstrates that LEA29Y transgenic islet‐like clusters display normal beta cell function and have the same potential as wild‐type islet clusters to restore normoglycemia in streptozotocin‐diabetic NSG mice after an in vivo maturation period towards a functional endocrine tissue. NSG mice with LEA29Y islet grafts may therefore represent a promising model to study the modulation of human‐anti‐pig xenograft rejection in detail. In ongoing experiments xenograft rejection is analyzed in “humanized” mice after the transfer of human PBMCs or isolated CD34+ stem cells.
Porcine alanine transaminase after liver allo‐and xenotransplantation
Authors: Ekser Burcin , Gridelli Bruno , Cooper David K.C.
Published: February 2012

Ekser B, Gridelli B, Cooper DKC. Porcine alanine transaminase after liver allo‐ and xenotransplantation. Xenotransplantation 2012; 19: 52–55. © 2012 John Wiley & Sons A/S.

Abstract:  Aspartate transaminase (AST) and alanine transaminase (ALT) are measured following liver transplantation as indicators of hepatocellular injury. During a series of orthotopic liver allo‐and xenotransplants, we observed that there was an increase in AST in all cases. The anticipated concomitant rise in ALT did not occur when a wild‐type (WT) pig was the source of the liver graft, but did occur when a baboon or a genetically engineered (α1,3‐galactosyltransferase gene‐knockout [GTKO]) pig was the source of the graft. We hypothesized that the cience of Galα1,3Gal in GTKO pig livers may render pig hepatocytes similar to human and baboon hepatocytes in their response to hepatocellular injury. Reviewing the literature, after WT pig liver allotransplantation or xenotransplantation, in the majority of reports, although changes in AST were reported, no mention was made of changes in ALT, suggesting that there was no change in ALT. However, Ramirez et al. reported two cases of liver xenotransplants from hCD55 pigs, following which there were increases in both AST and ALT, suggesting that it is not simply the cience of expression of Galα1,3Gal that is the cause. We acknowledge that our observation is based on a small number of experiments, but we believe it is worth recording.
Larval development rate of the mosquitoes Culex quinquefasciatus and Aedes aegypti (Diptera: Culicidae) varies between clutches: implications for population ecology
Authors: Kokkinn Michael J , Roberts Derek M , Williams Craig R
Published: February 2012

Egg clutches from two mosquito species were incubated under controlled conditions and the larval development time was recorded. Both the egg raft‐laying mosquito Culex quinquefasciatus and the individual egg layer Aedes aegypti displayed significant intraspecific variation between clutches when it came to larval development at the same temperature. Furthermore, embryonic incubation temperature was found to influence subsequent larval growth rate in some cases. These hitherto undocumented phenomena are indicative of development rate plasticity that appears to be conserved across mosquito genera. The derived development rate data were used to calculate the minimum number of egg clutches required to give a representative mean day‐degrees value for a population of each species. These values were six and five clutches, respectively. A simple population simulation was given to illustrate the impact of different larval development rates when overlapping generations of problem mosquitoes breed. The implication of this work for mosquito population modelling is that the extent of developmental rate variation needs to be taken into account. Furthermore, such conserved variation in larval development rate illustrates the extent of selective pressures on this life history trait.