bluuebunny/crossref_metadata_2025 huggingface dataset:
PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets
Authors: Hou Xu , Kumar Anil , Lee Chunsik , Wang Bin , Arjunan Pachiappan , Dong Lijin , Maminishkis Arvydas , Tang Zhongshu , Li Yang , Zhang Fan , Zhang Shi-Zhuang , Wardega Piotr , Chakrabarty Sagarika , Liu Baoying , Wu Zhijian , Colosi Peter , Fariss Robert N. , Lennartsson Johan , Nussenblatt Robert , Gutkind J. Silvio , Cao Yihai , Li Xuri
Published: June 2010

The importance of identifying VEGF-independent pathways in pathological angiogenesis is increasingly recognized as a result of the emerging drug resistance to anti-VEGF therapies. PDGF-CC is the third member of the PDGF family discovered after more than two decades of studies on PDGF-AA and PDGF-BB. The biological function of PDGF-CC and the underlying cellular and molecular mechanisms remain largely unexplored. Here, using different animal models, we report that PDGF-CC inhibition by neutralizing antibody, shRNA, or genetic deletion suppressed both choroidal and retinal neovascularization. Importantly, we revealed that PDGF-CC targeting acted not only on multiple cell types important for pathological angiogenesis, such as vascular mural and endothelial cells, macrophages, choroidal fibroblasts and retinal pigment epithelial cells, but also on the expression of other important angiogenic genes, such as PDGF-BB and PDGF receptors. At a molecular level, we found that PDGF-CC regulated glycogen synthase kinase (GSK)–3β phosphorylation and expression both in vitro and in vivo. Activation of GSK3β impaired PDGF-CC–induced angiogenesis, and inhibition of GSK3β abolished the antiangiogenic effect of PDGF-CC blockade. Thus, we identified PDGF-CC as an important candidate target gene for antiangiogenic therapy, and PDGF-CC inhibition may be of therapeutic value in treating neovascular diseases.
Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts
Authors: Wang Hsiang-Tsui , Choi Bongkun , Tang Moon-shong
Published: June 2010

Melanomas occur mainly in sunlight-exposed skin. Xeroderma pigmentosum (XP) patients have 1,000-fold higher incidence of melanoma, suggesting that sunlight-induced “bulky” photoproducts are responsible for melanomagenesis. Sunlight induces a high level of reactive oxygen species in melanocytes (MCs); oxidative DNA damage (ODD) may thus also contribute to melanomagenesis, and XP gene products may participate in the repair of ODD. We examined the effects of melanin on UVA (320–400 nm) irradiation-induced ODD and UV photoproducts and the repair capacity in MC and XP cells for ODD and UV-induced photoproducts. Our findings indicate that UVA irradiation induces a significantly higher amount of formamidopyrimidine glycosylase-sensitive ODD in MCs than in normal human skin fibroblasts (NHSFs). In contrast, UVA irradiation induces an insignificant amount of UvrABC-sensitive sites in either of these two types of cells. We also found that, compared to NHSFs, MCs have a reduced repair capacity for ODD and photoproducts; H
2
O
2
modified- and UVC-irradiated DNAs induce a higher mutation frequency in MCs than in NHSFs; and, XP complementation group A (XPA), XP complementation group C, and XP complementation group G cells are deficient in ODD repair and ODD induces a higher mutation frequency in XPA cells than in NHSFs. These results suggest that: (
i
) melanin sensitizes UVA in the induction of ODD but not bulky UV photoproducts; (
ii
) the high susceptibility to UVA-induced ODD and the reduced DNA repair capacity in MCs contribute to carcinogenesis; and (
iii
) the reduced repair capacity for ODD contributes to the high melanoma incidence in XP patients.
Mammalian target of rapamycin regulates miRNA-1 and follistatin in skeletal myogenesis
Authors: Sun Yuting , Ge Yejing , Drnevich Jenny , Zhao Yong , Band Mark , Chen Jie
Published: June 2010

Mammalian target of rapamycin (mTOR) has emerged as a key regulator of skeletal muscle development by governing distinct stages of myogenesis, but the molecular pathways downstream of mTOR are not fully understood. In this study, we report that expression of the muscle-specific micro-RNA (miRNA) miR-1 is regulated by mTOR both in differentiating myoblasts and in mouse regenerating skeletal muscle. We have found that mTOR controls MyoD-dependent transcription of miR-1 through its upstream enhancer, most likely by regulating MyoD protein stability. Moreover, a functional pathway downstream of mTOR and miR-1 is delineated, in which miR-1 suppression of histone deacetylase 4 (HDAC4) results in production of follistatin and subsequent myocyte fusion. Collective evidence strongly suggests that follistatin is the long-sought mTOR-regulated fusion factor. In summary, our findings unravel for the first time a link between mTOR and miRNA biogenesis and identify an mTOR–miR-1–HDAC4–follistatin pathway that regulates myocyte fusion during myoblast differentiation in vitro and skeletal muscle regeneration in vivo.
Allelic polymorphism in the T cell receptor and its impact on immune responses
Authors: Gras Stephanie , Chen Zhenjun , Miles John J. , Liu Yu Chih , Bell Melissa J. , Sullivan Lucy C. , Kjer-Nielsen Lars , Brennan Rebekah M. , Burrows Jacqueline M. , Neller Michelle A. , Khanna Rajiv , Purcell Anthony W. , Brooks Andrew G. , McCluskey James , Rossjohn Jamie , Burrows Scott R.
Published: June 2010

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501–restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01+ public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501HPVGEADYFEY revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR–peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.
A Quantitative Approach to Defining “High-Touch” Surfaces in Hospitals
Authors: Huslage Kirk , Rutala William A. , Sickbert-Bennett Emily , Weber David J.
Published: June 2010

Fifty interactions between healthcare workers and patients were observed to obtain a quantifiable definition of “high-touch” (ie, frequently touched) surfaces based on frequency of contact. Five surfaces were defined as high-touch surfaces: the bed rails, the bed surface, the supply cart, the over-bed table, and the intravenous pump.
Outbreak of Influenza A (2009) H1N1 among Thai Healthcare Workers: Is It Time to Integrate a Vaccination Program?
Authors: Apisarnthanarak Anucha , Mundy Linda M.
Published: June 2010

We report an outbreak of influenza A (2009) H1N1 among healthcare workers in a coronary care unit in Thailand. The attack rate was 32% (7 of 32 healthcare workers) after detection of influenza A (2009) H1N1 pneumonia in the index patient. Estimated costs for the outbreak investigation and control plan were 12-fold higher than estimated costs of vaccination for healthcare workers.
Nonlinear wave propagations over a Boltzmann shock profile
Authors: Yu Shih-Hsien
Published: June 2010

In this paper we study the wave propagation over a Boltzmann shock profile and obtain pointwise time-asymptotic stability of Boltzmann shocks. We design a

T

{\mathbb T}

-

C

{\mathbb C}

scheme to study the coupling of the transverse and compression waves. The pointwise information of the Green’s functions of the Boltzmann equation linearized around the end Maxwellian states of the shock wave provides the basic estimates for the transient waves. The compression of the Boltzmann shock profile together with a low order damping allows for an accurate energy estimate by a localized scalar equation. These two methods are combined to construct an exponentially sharp pointwise linear wave propagation structure around a Boltzmann shock profile. The pointwise estimates thus obtained are strong enough to study the pointwise nonlinear wave coupling and to conclude the convergence with an optimal convergent rate

O
(
1
)
[
(
1
+
t
)
(
1
+
ε
t
)

]

−
1

/

2

O(1)[(1+t)(1+\varepsilon t)]^{-1/2}

around the Boltzmann shock front, where

ε
\varepsilon

is the strength of a shock wave.
The complex Monge-Ampère equation on compact Hermitian manifolds
Authors: Tosatti Valentino , Weinkove Ben
Published: June 2010

We show that, up to scaling, the complex Monge-Ampère equation on compact Hermitian manifolds always admits a smooth solution.
Latitudinal and interannual distribution of the European anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) in the western Mediterranean, and sampling uncertainty in abundance estimates
Authors: Tugores M. Pilar , Iglesias Magdalena , Díaz Núria , Oñate Dolores , Miquel Joan , Giráldez Ana
Published: June 2010

Tugores, M. P., Iglesias, M., Díaz, N., Oñate, D., Miquel, J., and Giráldez, A. 2010. Latitudinal and interannual distribution of the European anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) in the western Mediterranean, and sampling uncertainty in abundance estimates. – ICES Journal of Marine Science, 67: 1574–1586. On the Spanish Mediterranean continental shelf, late-autumn echo-integration acoustic surveys have been performed annually since the 1990s. The surveys coincide with the recruitment season of anchovy (Engraulis encrasicolus) and the start of the spawning season of sardine (Sardina pilchardus), and they provide estimates of stock size for the main fisheries in the area. Latitudinal distribution of the abundance of the two species from 2003 till 2006 is evaluated, and transitive geostatistical techniques applied to estimate the sampling uncertainty of the overall abundance estimate. The anchovy stock was found mainly in areas influenced by river run-off, in well-known anchovy spawning areas, suggesting that anchovy remained on their spawning grounds until late autumn or that survival was higher in these regions of enhanced productivity. By the time of the surveys, sardine were already occupying their spawning grounds over the continental shelf. The precision of the abundance estimates was generally high. The few cases of low precision were re-examined and found to stem most probably from processing errors, so the re-examination has contributed to an improvement in the accuracy of the estimates. The greater precision obtained in the southern subarea suggested a greater homogeneity in the spatial distribution of both species.
Species richness, taxonomic diversity, and taxonomic distinctness of the deep-water demersal fish community on the Northeast Atlantic continental slope (ICES Subdivision VIa)
Authors: Campbell Neil , Neat Francis , Burns Finlay , Kunzlik Phil
Published: June 2010

Campbell, N., Neat, F., Burns, F., and Kunzlik, P. 2011. Species richness, taxonomic diversity, and taxonomic distinctness of the deep-water demersal fish community on the Northeast Atlantic continental slope (ICES Subdivision VIa). – ICES Journal of Marine Science, 68: 365–376. The fish community on the Atlantic deep continental shelf and upper slope to the northwest of Scotland has been the subject of biological studies for more than a century, and subject to bottom-trawl fishing for around 25 years. In this work, we examine trends in biodiversity of the deep-water demersal fish community revealed by a decade of trawl surveys by Marine Scotland—Science. The composition and structure of the fish assemblage was described using species richness as well as the descriptors of community interrelatedness: taxonomic diversity (Δ) and taxonomic distinctness (Δ*). Results revealed no temporal trends in community composition. The most significant factor in determining richness and taxonomic diversity of the demersal fish fauna was depth, and to a lesser extent latitude. Diversity and distinctness decreased with increasing depth and showed a complex relationship with latitude, while richness peaked at depths around 1400 m. This study shows taxonomic measures of diversity and distinctness to be sensitive indicators of ecological conditions in the deep-water fish community, with respect to depth and latitude, and the fact that no temporal trends were detected suggests that the structure of the fish community at exploitable depths on the Scottish slope has remained stable over the period 1998–2008. These findings imply that care should be taken when planning spatial measures designed to safeguard deep-water fish biodiversity because the optimal area recommended for protection is strongly dependent on the choice of metric used.
Aggregate Poverty Measures
Authors: Zheng Buhong
Published: June 2010

The way poverty is measured is important for an understanding of what has happened to poverty as well as for anti‐poverty policy evaluation. Sen's (1976) pathfinding work has motivated many researchers to focus on the way poverty should be measured. A poverty measure, argued by Sen, should satisfy certain properties or axioms and the desirability of a poverty measure should be evaluated by these axioms. During the last two decades, many researchers have adopted the axiomatic approach pioneered by Sen to propose additional axioms and develop alternative poverty measures. The objective of this survey is to provide a clarification on the extensive literature of aggregate poverty measures. In this survey, we first examine the desirability of each axiom, the properties of each poverty measure, and the interrelationships among axioms. The desirability of an axiom cannot be evaluated in isolation, and some combination of axioms may make it impossible to devise a satisfactory poverty measure; some axioms can be implied by other axioms combined and so are not independent; some others are ad hoc and are disqualified as axioms for poverty measurement. Based on the interactions among axioms, we identify the ‘core’ axioms which together have a strong implication on the functional form of a poverty measure. We then review poverty measures that have appeared in the literature, evaluating the interrelationships among different measures, and examining the properties of each measure. The axioms each measure satisfies/violates are also summarized in a tabular form. Several ‘good’ poverty measures, which have not been documented by previous surveys, are also included.
The Game Form Approach to Redistribution
Authors: Schroyen Fred
Published: June 2010

This paper reviews the game form approach to redistributive policies. This approach provides a justification for studying tax systems as good institutional arrangements for reallocating resources in a heterogeneous society. After situating the problem of asymmetric information for public policy, the paper provides a short overview of the main concepts and results in implementation theory. Next, these tools are used to inquire about the possibility to decentralise the reallocation of resources in a production economy with the help of tax/transfer systems. Finally, the paper deals with some recent extensions of the theory. A simple example is used throughout to illustrate the different results.
The Central Government‐Private Sector Wage Differential
Authors: Bender Keith A.
Published: June 2010

Since Ehrenberg and Schwarz (1986) there has been a plethora of articles investigating the relationship between public and private sector wages. This article examines part of this post 1986 literature by reviewing articles that examine central government‐private sector wage differentials. In sum, most articles find that there is a premium paid to central government workers, although the premium has declined in recent years. In developing countries, however, the differential is usually negative. Women and minorities tend to do better in the public sector relative to their private sector counterparts. The evidence on union premiums between sectors is mixed, although the premium tends to be higher in the private sector. However public sector union workers do not do much better than private sector union members. The magnitude of all of the wage differentials discussed are sensitive to the estimation technique and data source used. The most common explanation for the public sector wage premium is economic rent accruing to government workers, although the public sector wage determination literature suggests that the differential is due to returns to political and ‘vote producing’ activities not relevant in the private sector.
CASE REPORT: The unrecognised difficult extubation: a call for vigilance
Authors: Antoine J. , Hussain Z. , El‐Sayed I. , Apfel C. C.
Published: June 2010

Tracheal extubation remains a critical and often overlooked period of difficult airway management. A 66‐year‐old man, scheduled for C5–C7 anterior fusion, with an easy view of the vocal cords, presented with a sublaryngeal obstruction that required a reduced tracheal tube size. Despite correct tube placement, intra‐operative ventilation remained difficult. At the end of surgery a pulsatile tracheal compression was fibreopticially observed above the carina. After discussion with the attending otolaryngologist, neuromuscular blockade was antagonised and the patient was able to maintain normal minute volumes while spontaneously ventilating. With the otolaryngologist present, and with the patient conscious, the trachea was successfully extubated over an airway exchange catheter. A subsequent CT scan revealed an impingement of the trachea by the innominate artery and a mildly ectatic ascending and descending aorta that, in conjunction with tracheomalacia and neuromuscular blockade, could explain the observed signs and symptoms.
Great auricular nerve blockade using high resolution ultrasound: a volunteer study
Authors: Thallaj A. , Marhofer P. , Moriggl B. , Delvi B. M. , Kettner S. C. , Almajed M.
Published: June 2010

This prospective, observational volunteer study aimed to describe the appearance of the great auricular nerve using ultrasound and its blockade under ultrasound guidance. An in‐plane needle guidance technique was used for blockade of the great auricular nerve with 0.1 ml mepivacaine 1%. Sensory block was evaluated by pinprick testing in comparison with the contralateral area propriae. The great auricular nerve was successfully seen in all volunteers and the tail of the helix, antitragus, lobula and mandibular angle were blocked in all cases whereas the antihelix and concha were never blocked. Ultrasound imaging of the great auricular nerve can be reliably achieved and successful blockade with minimal volumes of local anaesthetic is another example of the benefits of ultrasound‐guided peripheral nerve blocks.
Evaluation of a QT nomogram for risk assessment after antidepressant overdose
Authors: Waring W. Stephen , Graham Ann , Gray Julie , Wilson Allen D. , Howell Catherine , Bateman D. Nicholas
Published: June 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Overdose with citalopram is associated with QT prolongation and torsades de pointes, whereas this arrhythmia has not been reported after venlafaxine or mirtazapine overdose.

• Uncertainty exists concerning the best means of identifying poisoned patients at greatest risk of arrhythmia, and a nomogram comparing QT and heart rate has recently been proposed based on published cases of torsades de pointes.

• Few data are available concerning the performance of the nomogram in patients that present to hospital after antidepressant overdose.

WHAT THIS STUDY ADDS

• After antidepressant overdose patients had a broad range of heart rate and QT values, which were below the nomogram in 98% of cases (95% confidence interval 96, 99%).

• Citalopram overdose was associated with a higher proportion of patients with QT values above the nomogram than venlafaxine and mirtazapine overdose, especially in those who had low heart rates.

• The nomogram allowed discrimination between the different antidepressant agents and may have a role in predicting arrhythmia in clinical practice.

AIMS

A QT‐heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug‐induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia.

METHODS

A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QTc (QT corrected by Bazett's formula) greater than ≥440 ms and QTc≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals.

RESULTS

There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QTc was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QTc was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QTc≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013).

CONCLUSIONS

The QT nomogram was associated with a lower false positive rate than widely accepted QTc criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QTc criteria and merits further investigation in a clinical setting.
Special lectures in haemophilia management
Authors: BATOROVA A. , HIGH K. A. , GRINGERI A.
Published: June 2010

Summary.  During the last two decades major advances have been achieved in the management of haemophilia. Modern approaches aimed at preventing the recurrent bleedings and their sequelae have been widely adopted. Major challenges of intensive treatment regimens employed today, such a short half life of haemophilia therapeutics with a need for frequent injections and the risk of inhibitor, encourage further development towards the production of factor concentrates with prolonged efficacy and reduced immunogenicity. Intensive research work on gene therapy aimed at ultimate cure of haemophilia by the restoration of missing factor FVIII (FVIII) and factor IX (FIX) production is ongoing. The current issues of gene therapy and mechanisms, modifying the host immune response to the FVIII and FIX transgene material and the coagulation factors expressed are the topic of the Arosenius lecture by Katherine High. Despite an extensive research on mechanisms leading to inhibitor development, the real reason of these serious complications of haemophilia therapy still remains unclear. Alessandro Gringeri will discuss the immunogenicity of plasma derived FVIII (pd FVIII) and recombinant FVIII (rFVIII) concentrates as one of potential, treatment related, and probably ‘modifiable’ risk factors for inhibitor development. The SIPPET study – a new prospective, randomised study aimed to reveal real incidence of inhibitors in patients treated with either pdFVIII or rFVIII will be presented.
Viral pathogens
Authors: RAGNI M. V. , SHERMAN K. E. , JORDAN J. A.
Published: June 2010

Summary.  Despite continuous improvement in safety and purity of blood products for individuals with haemophilia, transmissible agents continue to affect individuals with haemophilia. This chapter addresses three viral pathogens with significant clinical impact: HIV, hepatitis C and parvovirus B19. Hepatitis C is the leading cause of chronic hepatitis and the major co‐morbid complication of haemophilia treatment. Clinically, asymptomatic intermittent alanine aminotransferase elevation is typical, with biopsy evidence of advanced fibrosis currently in 25%. Current treatment is effective in up to 70%, and many new agents are in development. For those progressing to end‐stage liver disease, liver transplantation outcomes are similar to those in non‐haemophilia subjects, although pretransplant mortality is higher. HIV infection, the second leading co‐morbid condition in haemophilia, is managed as a chronic infection with highly active antiretroviral therapy (HAART). HAART also slows hepatitis C virus (HCV) progression in those with HIV/HCV co‐infection. Viral inactivation and recombinant technologies have effectively prevented transfusion‐transmitted viral pathogens in haemophilia. Human parvovirus B19 infection, typically associated with anaemia or, rarely severe aplastic crisis, is a non‐lipid enveloped virus, for which standard inactivation techniques are ineffective. Thus, nucleic acid testing (NAT) to screen the blood supply for B19 DNA is currently under consideration by the Food and Drug Administration. To the extent, viral inactivation, recombinant, and NAT technologies are available worldwide, and the lifespan for those with haemophilia is approaching that of the normal population. The purpose of this chapter is to provide an update on three clinically significant transfusion‐transmitted viral pathogens.
Animal models of inhibitors
Authors: REIPERT B. , ARRUDA V. , LILLICRAP D.
Published: June 2010

Summary.  Antibody responses to clotting factor concentrates remain a major treatment limitation. In conjucation with ongoing clinical studies, the pathogenesis and potential treatment of clotting factor immune responses is being evaluated in a variety of animal models.
Clinical issues in inhibitors
Authors: ASTERMARK J. , SANTAGOSTINO E. , KEITH HOOTS W.
Published: June 2010

Summary.  Anamestic inhibitors represent the major complication of haemophilia therapy now that clotting factor concentrates are virtually free of pathogen‐transmission risk. Conventional clotting factor replacement is usually insufficient to prevent or treat bleeding in a haemophilia patient with a high responding inhibitor so that alternative treatment with bypassing agents is required. Despite their relative efficacy, their use does not achieve the same invariable haemostasis that patients without inhibitors do following treatment with factor concentrate replacement. This has led to the attempt to eradicate such inhibitors with immune tolerance induction. Success is not invariable, however, and many patients with long‐term persistent high‐titre inhibitors continue to experience great morbidity. Recently, this has given rise on a limited basis to attempts to use bypassing agents in prophylaxis regimens in an effort to alleviate this extreme morbidity. Each of these strategies is discussed in the context of their relative benefits and risks.
Bleeding disorders in neonates
Authors: KENET G. , CHAN A. K. C. , SOUCIE J. M. , KULKARNI R.
Published: June 2010

Summary. Bleeding disorders may present during the neonatal period, however, absent patient history along with unique physical signs, physiologically decreased levels of plasma proteins and laboratory variations of platelet function tests may render any diagnosis difficult to establish. Intra cranial haemorrhage (ICH) may be the clinical presenting symptom of a severe coagulation factor deficiency. Haemophilia in the newborn period poses unique challenges in diagnosis and management, Data presented from the UDC and similar surveillance systems world‐wide can be used to further clinical research and improve management strategies.

Development haemostasis should be considered as well as laboratory variations of coagulation tests while evaluating and diagnosis neonates suspected of bleeding disorders. Therapy of bleeding episodes in the neonate relies upon proper replacement and repeated haemostatic evaluation of patients’ status, while dealing with underlying etiological causes. This manuscript discusses the unique aspects of clinical presentation, laboratory assessment, and treatment of various bleeding disorders in neonates.
Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method] demonstrates efficacy, safety and low‐risk for immunogenicity in routine clinical practice
Authors: OLDENBURG J. , GOUDEMAND J. , VALENTINO L. , RICHARDS M. , LUU H. , KRIUKOV A. , GAJEK H. , SPOTTS G. , EWENSTEIN B.
Published: June 2010

Summary.  Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method, (rAHF‐PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on‐demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on‐demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII ≤2%, three (0.75%) developed low‐titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII ≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01–1.59%). A PTP with moderate haemophilia developed a low‐titre inhibitor. High‐titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF‐PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies.
Ultrastructure of culture forms of the eel trypanosome, Trypanosoma granulosum Laveran & Mesnil, 1902, exposed to polyamine biosynthesis inhibitors
Authors: Davies A. J. , Thorborn D. E. , Mastrl C. , Daszak P.
Published: June 2010

Polyamines are important in the growth, division and differentiation of many cell types, including trypanosomes. The ultrastructure of culture forms of Trypanosoma granulosum was examined following growth in a modified semidefined medium (controls) and in the same medium with added polyamine biosynthesis inhibitors (DFMO, MGBG and Berenil). Untreated trypanosomes had ultrastructural features in common with other cultured flagellates. Those treated with DFMO were generally more rounded in contour. Cytoplasmic vacuoles and swollen mitochondrial membranes suggested osmotic imbalance, perhaps resulting from compromised membrane integrity. An anticlockwise arm dividing subtubule B of the peripheral doublets of the flagellum was noted in some trypanosomes treated with 20 mM DFMO. Vacuolation was also induced by MGBG and flagellar division occurred more frequently at 0.2 mM than in controls. With 1 mM MGBG, mitochondria were difficult to discern and kinetoplasts were disrupted. With 0.2 mM Berenil, vacuoles, swollen mitochondria, membranous whorls, additional microtubules underlying subpellicular tubules and disaggregated kinetoplasts were noted. With 1 mM Berenil, much of the cell structure was destroyed, although the pellicle, flagellum and paraxial rod remained intact. The present study illustrates the importance of hnctional polyamine synthetic pathways for the integrity of membranes, mitochondria, kinetoplasts and possibly microtubules in cultured T. granulosum.
Prevalence and clinical significance of GB virus type C/hepatitis G virus coinfection in patients with chronic hepatitis C undergoing antiviral therapy
Authors: Hofer H. , Aydin I. , Neumueller‐Guber S. , Mueller C. , Scherzer T.‐M. , Staufer K. , Steindl‐Munda P. , Wrba F. , Ferenci P.
Published: June 2010

Summary.  Coinfection with GBV‐C/HGV in patients with chronic hepatitis C (CHC) may influence clinical course and response rates of antiviral therapy. Aim of the study was to investigate the prevalence of GBV‐C/HGV/HCV coinfection and its influence on outcome of interferon/ribavirin combination therapy. Three hundred and four patients with CHC [m/f = 211/93, age: 42 (18–65)] were investigated. HGV RNA detection was performed by polymerase chain reaction prior to and 6 months after the end of antiviral therapy. HGV/HCV coinfection could be identified in 37/304 (12.2%) patients with intravenous drug abuse as the most common source of infection (N = 21, (56.8%)). The predominant HCV genotype in coinfected individuals was HCV‐3a (HCV‐3a: 51.4%, HCV‐1: 37.8%, HCV‐4: 10.8%). HGV coinfection was more prevalent in patients infected with HCV‐3 compared to HCV‐1 or HCV‐4 [19/45 (42.2%) vs 14/185 (7.6%) vs 4/52 (7.7%), P < 0.01]. Patients with HGV/HCV coinfection were younger [35 (18–56) vs 43 (19–65), years; P < 0.01], and advanced fibrosis (F3‐F4) was less frequent (22.2%vs 42.9%, P < 0.05). A sustained virological response was achieved more frequently in HGV/HCV coinfected patients [26/37 (70.3%)] than in monoinfected patients [120/267 (44.9%), P < 0.01]. HGV RNA was undetectable in 65.7% of the coinfected patients at the end of follow‐up. Intravenous drug abuse seems to be a major risk factor for HGV coinfection in patients with chronic hepatitis C. Coinfection with HGV does not worsen the clinical course of chronic hepatitis C or diminish response of HCV to antiviral therapy. Interferon/ribavirin combination therapy also clears HGV infection in a high proportion of cases.
Mendelian inheritance of rust resistance to Melampsora larici‐epitea in crosses between Salix sachalinensis and S. viminalis
Authors: Pei M. H. , Ruiz C. , Shield I. , Macalpine W. , Lindegaard K. , Bayon C. , Karp A.
Published: June 2010

Two F1, two F2 and two backcross (BC) full‐sib families of Salix sachalinensis × S. viminalis were tested for resistance to two pathotypes of Melampsora larici‐epitea in leaf‐disc inoculation experiments. Two single‐pustule isolates, VM and ST, belonging to pathotypes LET1 and LET5, respectively, were used in the tests. Disease was scored based on the number of uredinia, uredinial diameter and inoculum densities. Both F1 families were completely resistant to both VM and ST. Resistance to VM segregated at a 9:6:1 ratio in the F2 families and at a 1:2:1 ratio in the BC families, suggesting that two independently segregating genes controlled rust resistance, with resistance dominant over susceptibility. This also indicates incomplete dominance of the resistance alleles over the susceptibility to VM. For ST, the equivalent ratios were 3:1 and 1:1, showing that a single dominant gene was responsible for rust resistance. The broad sense heritabilities were >0·91 for uredinial diameter and 0·1–0·33 for the number of uredinia. There were significant overall correlations between data from inoculations with VM and those from inoculations with ST in the number of uredinia, uredinial diameter and disease scores (Spearman’s rank correlation coefficients = 0·31–0·75).
Infant feeding practices and physician diagnosed atopic dermatitis: a prospective cohort study in Taiwan
Authors: Chuang Chao‐Hua , Hsieh Wu‐Shiun , Chen Yi‐Chun , Chang Pei‐Jen , Hurng Baai‐Shyun , Lin Shio‐Jean , Chen Pau‐Chung
Published: June 2010

To cite this article: Chuang C‐H, Hsieh W‐S, Chen Y‐C, Chang P‐J, Hurng B‐S, Lin S‐J, Chen P‐C. Infant feeding practices and physician diagnosed atopic dermatitis: a prospective cohort study in Taiwan. Pediatric Allergy Immunology 2011: 22: 43–49.

It is common to recommend breastfeeding and a delayed introduction of solids to prevent atopic dermatitis (AD). However, the scientific evidence for this is inconclusive. The aim of this study was to explore the effect of breastfeeding and solids on AD, when taking account of reverse causality. This on‐going birth cohort study was designed to sample 24,200 representative post‐partum women and their babies from the Taiwan National Birth Registration database. Using two home interviews at 6 and 18 months after birth, with structured questionnaires about diet and physician’s diagnosis of AD by parental reports, a total of 20,172 pairs (83.4%) were reviewed completely. Considering reverse causality, we excluded 2399 children with AD in the first 6 months of life and 18,733 were finally recruited. All study participants provided informed consent as approved by the Ethics Review Board of the National Taiwan College of Public Health. After adjustment for potential confounders, the overall results showed that the increased duration of breastfeeding seemed to increase the risk of AD at 18 months in children. However, no significant effect was found for the delayed introduction of solids on the risk of AD. There is no evidence of a protective effect of prolonged breastfeeding and a delayed introduction of solids against AD among children at age 18 months, and may even be a risk factor of AD.
Boron Induced Oxidative Stress, Antioxidant Defence Response and Changes in Artemisinin Content in Artemisia annua L.
Authors: Aftab T. , Khan M. M. A. , Idrees M. , Naeem M. , Ram M.
Published: June 2010

Boron is an essential plant micronutrient and the range between deficient and toxic levels of boron is narrow for most of the plants. Like other elements, boron becomes toxic to growth at high concentrations. High boron concentrations in soil reduce crop productivity in many areas of the world. The effect of increasing levels of boron (0, 0.50, 1.00, 1.50, 2.00 mm) on oxidative stress, antioxidant defence response and changes in artemisinin content in Artemisia annua were investigated in the present study. Boron toxicity reduced the growth parameters viz. stem height, fresh weight and dry weight. Treatments induced oxidative stress resulting in lower net photosynthetic rate, stomatal conductance, internal CO2 and total chlorophyll content. The increased activities of antioxidant enzymes like CAT, POX and SOD were also noted in response to increasing levels of boron stress. However, H2O2 and artemisinin content were found to be high up to 1.00 mm concentration of boron compared to control, and on applying higher doses, further reduced contents were obtained. Thus, the results suggest that a mild stress of boron can be utilized for enhanced artemisinin production.
Anterior perirectal fat tissue thickness is a strong predictor of recurrence after high‐intensity focused ultrasound for prostate cancer
Authors: Sumitomo Makoto , Asakuma Junichi , Yoshii Hidehiko , Sato Akinori , Horiguchi Akio , Ito Keiichi , Nagakura Kazuhiko , Asano Tomohiko
Published: June 2010

Objective:  To evaluate if and why obesity affects the clinical outcome in patients undergoing high‐intensity focused ultrasound (HIFU) treatment for prostate cancer (CaP).

Methods:  115 patients who underwent HIFU treatment for localized CaP were categorized as obese, overweight or normal according to body mass index (BMI). The thickness of the anterior perirectal fat tissue (APFT) was measured by transrectal ultrasonography. Treatment was considered to have failed in the case of biochemical failure according to the Phoenix definition, positive follow‐up biopsy or initiation of salvage therapy. Cox proportional hazards analyses were used to identify possible predictors for disease free survival (DFS), and an experimental fat tissue model was made to evaluate the ablation effect at the target tissue.

Results:  According to the classification by the Western Pacific Regional Office of WHO, 43 patients were of normal weight, 24 were overweight and 48 were obese. The BMI groups did not differ in Gleason score, prostate‐specific antigen level at diagnosis or clinical stage. There were, however, significant correlations between BMI and prostate‐specific antigen nadir (P < 0.001), and BMI and APFT thickness (P < 0.01). Multivariate analyses showed that BMI fails to be an independent predictor of DFS when APFT (P < 0.0001) is included as a variable.

Conclusions:  Our results suggest that APFT thickness, for which obesity could be a useful surrogate, might represent the causative factor for poor clinical outcome after transrectal HIFU treatment for CaP.
Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons
Authors: Kalogiannis M. , Grupke S. L. , Potter P. E. , Edwards J. G. , Chemelli R. M. , Kisanuki Y. Y. , Yanagisawa M. , Leonard C. S.
Published: June 2010

Pharmacological studies of narcoleptic canines indicate that exaggerated pontine cholinergic transmission promotes cataplexy. As disruption of orexin (hypocretin) signaling is a primary defect in narcolepsy with cataplexy, we investigated whether markers of cholinergic synaptic transmission might be altered in mice constitutively lacking orexin receptors (double receptor knockout; DKO). mRNA for Choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT) and the high‐affinity choline transporter (CHT1) but not acetylcholinesterase (AChE) was significantly higher in samples from DKO than wild‐type (WT) mice. This was region‐specific; levels were elevated in samples from the laterodorsal tegmental nucleus (LDT) and the fifth motor nucleus (Mo5) but not in whole brainstem samples. Consistent with region‐specific changes, we were unable to detect significant differences in Western blots for ChAT and CHT1 in isolates from brainstem, thalamus and cortex or in ChAT enzymatic activity in the pons. However, using ChAT immunocytochemistry, we found that while the number of cholinergic neurons in the LDT and Mo5 were not different, the intensity of somatic ChAT immunostaining was significantly greater in the LDT, but not Mo5, from DKO than from WT mice. We also found that ChAT activity was significantly reduced in cortical samples from DKO compared with WT mice. Collectively, these findings suggest that the orexins can regulate neurotransmitter expression and that the constitutive absence of orexin signaling results in an up‐regulation of the machinery necessary for cholinergic neurotransmission in a mesopontine population of neurons that have been associated with both normal rapid eye movement sleep and cataplexy.
HPC‐1/syntaxin 1A gene knockout mice show abnormal behavior possibly related to a disruption in 5‐HTergic systems
Authors: Fujiwara Tomonori , Snada Masumi , Kofuji Takefumi , Yoshikawa Takeo , Akagawa Kimio
Published: June 2010

HPC‐1/syntaxin 1A (STX1A) is thought to regulate the exocytosis of synaptic vesicles in neurons. In recent human genetic studies,STX1Ahas been implicated in neuropsychological disorders. To examine whetherSTX1Agene ablation is responsible for abnormal neuropsychological profiles observed in human psychiatric patients, we analysed the behavioral phenotype ofSTX1Aknockout mice. Abnormal behavior was observed in both homozygotes (STX1A−/−) and heterozygotes (STX1A+/−) in a social interaction test, a novel object exploring test and a latent inhibition (LI) test, but not in a pre‐pulse inhibition test. Interestingly, attenuation of LI, which is closely related to human schizotypic symptoms, was restored by administration of the selective serotonin reuptake inhibitor, fluoxetine, but not by the dopamine reuptake inhibitor, GBR12935, or the noradrenalin reuptake inhibitor, desipramine. We also observed that LI attenuation was restored by DOI (a 5‐HT2Areceptor agonist), but not by 8‐OH‐DPAT (a 5‐HT1Areceptor agonist), mCPP (a 5‐HT2Creceptor agonist), SKF 38393 (a D1receptor agonist), quinpirole (a D2/D3receptor agonist) or haloperidol (a D2/D3receptor antagonist). Thus, attenuation of LI is mainly caused by disruption of 5‐HT‐ergic systems via 5‐HT2Areceptors. In addition, 5‐HT release from hippocampal and hypothalamic slices was significantly reduced. Therefore, ablation ofSTX1Amay cause disruption of 5‐HT‐ergic transmission and induce abnormal behavior.
RapGAPs in brain: multipurpose players in neuronal Rap signalling
Authors: Spilker Christina , Kreutz Michael R.
Published: June 2010

Small Rap guanosine‐tri‐phosphate (GTP)ases are crucially involved in many cellular processes, including cell proliferation, differentiation, survival, adhesion and movement. In line, it has been shown that Rap signalling is involved in various aspects of neuronal differentiation, like the establishment of neuronal polarity or axonal growth cone movement. Rap GTPases can be activated by a wide variety of external stimuli, and this is mediated by specific guanine nucleotide exchange factors (RapGEFs). Inactivation of RapGTP can be achieved with the aid of specific GTPase‐activating proteins (RapGAPs). In the brain, the most prominent RapGAPs are Rap1GAP and those of the spine‐associated RapGAP (SPAR) family. This latter family consists of three members (SPAR1–3), from which two of them, namely SPAR1 and 2, have been investigated in more detail. As such, the localization of RapGAPs is crucially important in regulating Rap signalling at various sites in the cell and, for both SPAR1 and 2, enrichment at synaptic sites has been demonstrated. In recent years particularly the role of SPAR1 in shaping dendritic spine morphology has attracted considerable interest. In this review we will summarize the described actions of different RapGAPs expressed in the brain, and we will focus in particular on the SPAR family members.
INTEGRATING THE HISTORIOGRAPHY OF THE NINETEENTH‐CENTURY GOLD RUSHES
Authors: Reeves Keir , Frost Lionel , Fahey Charles
Published: June 2010

In the century preceding World War I, the world experienced a series of gold rushes. The wealth derived from these was distributed widely because of reduced migration costs and low barriers to entry. While gold mining itself was generally unprofitable for diggers and mine owners, the increase in the world's gold supply stimulated global trade and investment. In this introductory article we integrate the histories of migration, trade, colonisation, and environmental history to identify endogenous factors that increased the world's gold supply and generated sustained economic growth in the regions that were affected by gold rushes.
PEOPLING THE VICTORIAN GOLDFIELDS: FROM BOOM TO BUST, 1851–1901
Authors: Fahey Charles
Published: June 2010

Victoria experienced a surge of migration after the discovery of gold in 1851. I explore the social and geographic background of migrants lured to the colony by opportunities opened up by gold mining. When alluvial gold was exhausted, the skills of migrants enabled them to exploit the more difficult deep lead and quartz reef gold deposits and to establish cities and towns. Urban growth was encouraged by high marriage and birth rates in the 1860s. In the last two decades of the nineteenth century goldfields communities generally suffered economic and demographic declines.
MINERS' COTTAGES
Authors: Dingle Tony
Published: June 2010

The major visual reminder of Victoria's nineteenth‐century gold rushes is the thousands of miners' cottages, which remain a significant part of the housing stock of former mining towns. This article traces the evolution of these modest structures that were adopted to solve the pressing problem of providing affordable and quickly constructed housing for gold miners once the alluvial rushes were over. Simple construction methods combined with cheap land on which to build allowed miners to construct and own their own homes to an extent not achieved elsewhere by manual workers in the developing world in the nineteenth century.