bluuebunny/crossref_metadata_2025 huggingface dataset:
Wave drag due to lift for transonic airplanes
Authors: Cole Julian D. , Malmuth Norman D.
Published: December 2004

Lift–dominated pointed aircraft configurations are considered in the transonic range. To make the approximations more transparent, two–dimensionally cambered untwisted lifting wings of zero thickness with aspect ratio of order one are treated. An inner expansion, which starts as Jones's theory, is matched to a nonlinear outer transonic theory as in Cheng and Barnwell's earlier work. To clarify issues, minimize ad hoc assumptions existing in earlier studies, as well as provide a systematic expansion scheme, a deductive rather than inductive approach is used with the aid of intermediate limits and matching not documented for this problem in previous literature. High–order intermediate–limit overlap–domain representations of inner and outer expansions are derived and used to determine unknown gauge functions, coordinate scaling and other elements of the expansions. The special role of switchback terms is also described. Non–uniformities of the inner approximation associated with leading–edge singularities similar to that in incompressible thin airfoil theory are qualitatively discussed in connection with separation bubbles in a full Navier–Stokes context and interaction of boundary–layer separation and transition. Non–uniformities at the trailing edge are also discussed as well as the important role of the Kutta condition. A new expression for the dominant approximation of the wave drag due to lift is derived. The main result is that although wave drag due to lift integral has the same form as that due to thickness, the source strength of the equivalent body depends on streamwise derivatives of the lift up to a streamwise station rather than the streamwise derivative of cross–sectional area. Some examples of numerical calculations and optimization studies for different configurations are given that provide new insight on how to carry the lift with planform shaping (as one option), so that wave drag can be minimized.
Ser95, Asn97, and Thr78 are important for the catalytic function of porcine NADP‐dependent isocitrate dehydrogenase
Authors: Kim Tae‐Kang , Colman Roberta F.
Published: December 2004

The mammalian mitochondrial NADP‐dependent isocitrate dehydrogenase is a citric acid cycle enzyme and an important contributor to cellular defense against oxidative stress. The Mn2+‐isocitrate complex of the porcine enzyme was recently crystallized; its structure indicates that Ser95, Asn97, and Thr78 are within hydrogen‐bonding distance of the γ‐carboxylate of enzyme‐bound isocitrate. We used site‐directed mutagenesis to replace each of these residues by Ala and Asp. The wild‐type and mutant enzymes were expressed in Escherichia coli and purified to homogeneity. All the enzymes retain their native dimeric structures and secondary structures as monitored by native gel electrophoresis and circular dichroism, respectively. Vmax of the three alanine mutants is decreased to 24%–38% that of wild‐type enzyme, with further decreases in the aspartate mutants. For T78A and S95A mutants, the major changes are the 10‐ to 100‐fold increase in the Km values for isocitrate and Mn2+. The results suggest that Thr78 and Ser95 function to strengthen the enzyme's affinity for Mn2+‐isocitrate by hydrogen bonding to the γ‐carboxylate of isocitrate. For the Asn97 mutants, the Km values are much less affected. The major change in the N97A mutant is the increase in pKa of the ionizable metal‐liganded hydroxyl of enzyme‐bound isocitrate from 5.23 in wild type to 6.23 in the mutant enzyme. The hydrogen bond between Asn97 and the γ‐carboxylate of isocitrate may position the substrate to promote a favorable lowering of the pK of the enzyme–isocitrate complex. Thus, Thr78, Ser95, and Asn97 perform important but distinguishable roles in catalysis by porcine NADP‐specific isocitrate dehydrogenase.
Amyloid accomplices and enforcers
Authors: Alexandrescu Andrei T.
Published: December 2004

Amyloid‐related diseases are often ascribed to protein “misfolding.” Yet in the absence of high‐resolution structures for mature fibrils or intermediates, the connection between the mechanism of amyloid formation and protein folding remains tenuous. The simplistic view of amyloid fibrillogenesis as a homogeneous self‐assembly process is being increasingly challenged by observations that amyloids interact with a variety of cofactors including metals, glycosaminoglycans, glycoproteins such as serum amyloid P and apolipo‐protein E, and constituents of basement membranes such as perlecan, laminin, and agrin. These “pathological chaperones” have effects that range from mediating the rate of amyloid fibril formation to increasing the stability of amyloid deposits, and may contribute to amyloid toxicity. An increasing appreciation of the role of accessory molecules in amyloid etiology has paved the way to novel diagnostics and therapeutic strategies.
A computational method for the analysis and prediction of protein:phosphopeptide‐binding sites
Authors: Joughin Brian A. , Tidor Bruce , Yaffe Michael B.
Published: December 2004

Phosphopeptide‐binding domains, including the FHA, SH2, WW, WD40, MH2, and Polo‐box domains, as well as the 14‐3‐3 proteins, exert control functions in important processes such as cell growth, division, differentiation, and apoptosis. Structures and mechanisms of phosphopeptide binding are generally diverse, revealing few general principles. A computational method for analysis of phosphopeptide‐binding domains was therefore developed to elucidate the physical and chemical nature of phosphopeptide binding, given this lack of structural similarity. The surfaces of nine phosphopeptide‐binding proteins, representing seven distinct classes of phosphopeptide‐binding modules, were discretized, and encoded with information about amino acid identity, surface curvature, and electrostatic potential at every point on the surface in order to identify local surface properties enriched in phosphoresidue contact sites. Cross‐validation indicated that propensities corresponding to this enrichment calculated from a subset of the training data could be used to predict the phosphoresidue contact site on proteins not used in training with no false negative results, and with few unconfirmed positive predictions. The locations of phosphoresidue contact sites were then predicted on the surfaces of the checkpoint kinase Chk1 and the BRCA1 BRCT repeat domain, and these predictions are consistent with recent experimental evidence.
Tocqueville on Mores and the Preservation of Republics
Authors: Maletz Donald J.
Published: December 2004

The chapter Tocqueville originally intended as a conclusion for the Democracy in America of 1835 is devoted to the causes that maintain a democratic republic. His main findings concern the political role of “mores.” Conducting an implicit dialogue with Montesquieu and working from evidence available to no previous student of democracy, Tocqueville finds commercialism less supportive of democracy and mores (especially those connected with religion) more useful to democracy than his great predecessor had believed. Moreover, he draws attention to a “practical” form of “enlightenment” seen in the broad public internalization of democratic practice and norms. These discoveries did not lead to confident predictions about the republic's future, largely because much of what is useful in mores seems beyond direct political control. They did inspire his argument that modern democrats are best advised to make use of, rather than repudiate, the inherited mores. These mores, if adapted to new conditions, may help to support effective democratic practice.
Local Context and Democratization in Mexico
Authors: Hiskey Jonathan T. , Bowler Shaun
Published: December 2004

While democratization is often seen as a national‐level process, we argue that there is important scope for local effects. Through analysis of Mexican public opinion data collected on the eve of that country's historic 2000 elections, we demonstrate that local context greatly affects evaluations of the legitimacy of the system, and these evaluations, in turn, help to shape the willingness of citizens to engage with the system. Citizens are more willing to participate in politics if they think the process is fair, and direct evidence of the fairness of the system is provided by the local political context. This local connection, then, becomes critical in the process of individuals becoming, in Almond and Verba's classic term, “participatory” citizens (1963).
Signals from the Tenth Justice: The Political Role of the Solicitor General in Supreme Court Decision Making
Authors: Bailey Michael A. , Kamoie Brian , Maltzman Forrest
Published: December 2004

Conventional explanations of the solicitor general's influence on the Supreme Court emphasize his expertise or experience. We articulate and test a more political account based on insights from signaling theory. We argue justices will be more receptive to signals from the solicitor general (S.G.) when either the justice and S.G. are ideologically proximate or the S.G.'s signal is contrary to his ideological predisposition. We test our account over the period from 1953 to 2002 using a newly developed interinstitutional measure of ideology that places executive and judicial actors on the same spatial scale. Our results highlight the political nature of the S.G.'s influence, challenging the received wisdom about the S.G.'s impact on the Supreme Court.
Assessing the Effectiveness of International Environmental Agreements: The Case of the 1985 Helsinki Protocol
Authors: Ringquist Evan J. , Kostadinova Tatiana
Published: December 2004

The last few decades have been marked by the emergence of a number of environmental protection regimes in the international arena. We know little about the effectiveness of these regimes, however, largely because such evaluations face the formidable obstacles of a scarcity of time series data on environmental quality, a complex mix of nonpolicy factors that affect environmental quality, and the fact that participation in nearly all international environmental agreements is voluntary, which means that policy effectiveness must be estimated from self‐selected samples. In this article we assess the effects of the 1985 Helsinki Protocol for reducing sulfur dioxide emissions in Europe, paying particularly close attention to the obstacles noted above. We find that while nations ratifying the Helsinki Protocol have experienced significant emission reductions, the protocol itself has had no discernible effect on emissions. We end the article by discussing the implication of these results for the effectiveness of international environmental regimes in general.
The Effect of Information on Voter Turnout: Evidence from a Natural Experiment
Authors: Lassen David Dreyer
Published: December 2004

Do better‐informed people vote more? Recent formal theories of voter turnout emphasize a positive effect of being informed on the propensity to vote, but the possibility of endogenous information acquisition makes estimation of causal effects difficult. I estimate the causal effects of being informed on voter turnout using unique data from a natural experiment Copenhagen referendum on decentralization. Four of fifteen districts carried out a pilot project, exogenously making pilot city district voters more informed about the effects of decentralization. Empirical estimates based on survey data confirm a sizeable and statistically significant causal effect of being informed on the propensity to vote.
Labor, Democracy, Utility, and Mill's Critique of Private Property
Authors: Medearis John
Published: December 2004

Scholars have long debated whether John Stuart Mill became a socialist, as he claimed in his
Autobiography
. This article strengthens the case that he did, ironically, by examining Mill's longstanding adherence to a labor‐based justification for private property in means of production. Even while he developed sharp criticisms of capitalist property relations based on democratic principles of individuality and freedom, Mill held on to this labor justification, which partly offset his growing socialist sympathies. But relatively late in life, Mill reconsidered and discarded the labor justification and began to argue for a more explicit utilitarian analysis of the relevant questions, thus bolstering the importance of his democratic critiques of the system of private property. A recognition of the slow gestation of Mill's views on the labor justification enriches our understanding of his thought on socialism versus capitalism and provides an insight into how he applied utilitarianism in a practical context.
The Logic of Private and Collective Action
Authors: Hansen Wendy L. , Mitchell Neil J. , Drope Jeffrey M.
Published: December 2004

Since Mancur Olson's Logic of Collective Action (1965), it is impossible for political scientists to conceive of political participation without reference to his powerful argument linking numbers of participants, public goods, and participatory outcomes. What is puzzling is the poor empirical support for this argument in the domain where it should work best, namely explaining business political activity. Olson thought his arguments principally applicable to economic groups, and for the empirical development of his arguments Olson drew heavily on business interests, the most active segment of the interest group community. We explore these arguments with business political activities data by examining the statistical performance of various measures of market structure in determining business political activity, and find little empirical support. We do offer an alternative basis for business behavior lodged in both private and collective goods that preserves business rationality and also helps explain not only the amount of business political participation but the modes of business participation.
Thinking for Thousands: Emerson's Theory of Political Representation in the Public Sphere
Authors: Von Rautenfeld Hans
Published: December 2004

This article develops Emerson's theory of representative democracy as it applies to a deliberative public sphere. By highlighting the democratic content of Emerson's thought, this article challenges tradition readings of Emerson that claim his thought to be elitist or antipolitical. According to Emerson, the public sphere is structured by representative individuals who are analogous to those representatives found in electoral institutions. These representatives make public the beliefs and values present in their “constituencies.” They deliberate in the name of their constituencies, saying what their constituencies could and would say, were they to also directly engage in such deliberations. Representative individuals are tied to their constituencies through bonds of “sympathy and likeness.” The moral consequences of a representative public sphere include the development of a sense of deliberative justice on the part of the citizenry and the reduction of the possibility of domination and oppression by ideologically oriented elites.
Characterization of Splenic Glycosaminoglycans Accumulated In Vivo in Experimentally Induced Amyloid‐Susceptible and Amyloid‐Resistant Mice
Authors: Sugumaran G. , Elliott‐Bryant R. , Phung N. , Vitseva O. , Kuberan B. , Lech M.
Published: December 2004

The pathogenesis of the amyloid deposition diseases is poorly understood. The CE/J mouse, which is naturally protected from amyloid A (AA) protein amyloidosis, has provided a tool to study mechanisms that may be implicated in amyloid deposition diseases by means of comparison of findings with those in an AA‐susceptible mouse strain. We have compared proteoglycan/glycosaminoglycan accumulation in vivo in amyloid‐protected CE/J mouse strain and in AA‐susceptible CBA/J mouse strain in homeostasis and when injected with amyloid‐inducing agents. Results indicate that there is an overall increase in [35S]proteoglycan/glycosaminoglycan accumulation in the spleens of both strains of mice, but with a specific increase in heparan sulfate in only CBA/J mouse spleens that are rich in amyloid. Further, we report the absence of heparan sulfate in the splenic perifollicular areas of amyloid‐free CE/J mouse, whereas in the amyloid‐laden CBA/J mouse there is co‐localization of heparan sulfate with the AA deposits. We have also examined the glycosaminoglycan disaccharide products in both these strains of mice for their sulfation positions and found no differences in the disaccharide composition of chondroitin/dermatan sulfate and heparan sulfate isolated from the control CBA/J and control CE/J mice. There were no differences in chondroitin/dermatan sulfate in both strains after experimental induction. However, analysis of the heparan sulfate disaccharides by means of capillary high‐performance liquid chromatography linked to microelectrospray ionization time‐of‐flight mass spectrometry indicated that the disaccharide composition of the splenic heparan sulfate obtained from the treated CBA/J mice that had developed amyloid was markedly different from that obtained from the control CBA/J mice and the treated amyloid‐resistant CE/J mice. These findings suggest that unique heparan sulfates play a fundamental role in the pathogenesis of amyloid.
B‐Lymphocytes Activated by CD40 Ligand Induce an Antigen‐Specific Anti‐Tumour Immune Response by Direct and Indirect Activation of CD8+ T‐cells
Authors: Ritchie D. S. , Yang J. , Hermans I. F. , Ronchese F.
Published: December 2004

In this report, we describe the ability of CD40‐ligand (CD40L)‐activated, antigen‐loaded B‐cells to initiate antigen‐specific anti‐tumour immune responses in vivo. Mice immunized by means of intravenous administration of CD40L‐activated B‐cells loaded with an MHC class‐I‐binding peptide, and challenged with a tumour cell line expressing the same class‐I epitope, showed a marked delay in tumour growth, compared to non‐immunized controls or to mice receiving either freshly isolated B‐cells or B‐cells activated with lipopolysaccharide or interleukin‐4.

The ability of CD40L‐activated B‐cells to induce antigen‐specific T‐cell activation appeared to be through a combination of cross‐presentation of antigen from activated B‐cells to resident antigen‐presenting cells and direct T‐cell activation by the administered B‐cells themselves. Immunization with CD40L‐activated B‐cells may, therefore, represent a means by which to stimulate anti‐tumour CD8+ T‐cell responses in vivo.
Activation of Human Umbilical Vein Endothelial Cells Leads to Relocation and Release of High‐Mobility Group Box Chromosomal Protein 1
Authors: Mullins G. E. , Sunden‐Cullberg J. , Johansson A.‐S. , Rouhiainen A. , Erlandsson‐Harris H. , Yang H. , Tracey K. J. , Rauvala H. , Palmblad J. , Andersson J. , Treutiger C. J.
Published: December 2004

The nuclear protein high‐mobility group box chromosomal protein 1 (HMGB1) was recently described to act as a pro‐inflammatory cytokine and as a late mediator of severe sepsis and septic shock. The protein is released from monocytes in response to endotoxin and activates monocytes and endothelial cells through nuclear factor kappa B. We have previously demonstrated that the B‐box of HMGB1 mediates a pro‐inflammatory effect on endothelial cells including the upregulation of cell‐adhesion molecules and release of interleukin (IL)‐8 and granulocyte colony‐stimulating factor. Here, we report that HMGB1 is released from human umbilical vein endothelial cells (HUVEC) in response to lipopolysaccharide (LPS) and tumour necrosis factor (TNF)‐α. A nuclear relocation of HMGB1 to the cytoplasm was seen at 4 h. Subsequently, high amounts of HMGB1 could be seen in the supernatants from stimulated cells after 16 h. It was also observed that the pro‐inflammatory activity of HMGB1 is sensitive to dexamethasone. Interestingly, the HMGB1‐induced TNF‐α release from monocytes could be inhibited by either the A‐box of the protein or the p38 inhibitor CNI‐1493, but neither had any inhibitory effects on the HMGB1‐dependent upregulation of cell‐adhesion molecules on HUVEC. Altogether, these results suggest that HUVEC may be an important source of HMGB1 secretion in response to systemic infection and that endothelial cells and monocytes may use different signalling pathways.
Gene Expression in Human Macrophages Infected with Dengue Virus Serotype‐2
Authors: Moreno‐Altamirano M. M. B. , Romano M. , Legorreta‐Herrera M. , Sánchez‐García F. J. , Colston M. J.
Published: December 2004

Infection by any of the four serotypes of dengue viruses (DEN‐1, ‐2, ‐3 and ‐4) may result in either a relatively benign fever, called dengue fever (DF), a fatal disease, such as dengue haemorrhagic fever (DHF) or dengue shock syndrome (DSS). Several lines of evidence suggest that soluble immune response mediators may be involved in the severity of dengue infections. For instance, elevated seric levels of IL‐8 are a common feature in DHF patients. Because other chemokines, cytokines, adhesion molecules, chemokine and cytokine receptors, as well as cytokine‐related molecules may also be involved in dengue virus pathogenesis, we aimed at analysing the gene expression of such molecules in the course of an in vitro DEN‐2 infection of human peripheral blood monocyte‐derived macrophages, a cell type regarded as a primary target for DEN. Nylon membrane gene arrays containing 375 different human cytokine‐related genes were used as a first step to search for differentially expressed genes upon infection. Transcripts for IL‐8, IL‐1β, osteopontin, GRO‐α, ‐β and ‐γ, I‐309, and some other molecules showed to be upregulated upon infection, whereas others such as MIC‐1, CD27L and CD30L, were downregulated. Four genes were selected for reverse transcriptase‐polymerase chain reaction based gene‐expression analysis as a way to partially confirm microarray results. This approach pointed out 25 macrophage‐expressed cytokine‐related genes that could be relevant in DEN‐2 pathogenesis.
Differential Regulation of MHC Class‐I‐Restricted and Unrestricted Cytotoxicity by the Us3 Protein Kinase of Herpes Simplex Virus‐1
Authors: Cartier A. , Masucci M. G.
Published: December 2004

Modulation of cytotoxic responses by viral immunoevasins plays an important role in the establishment of latent and persistent viral infections. Together with MHC class‐I‐restricted CD8T‐lymphocytes, non‐MHC‐restricted natural killer (NK) and lymphokine‐activated killer (LAK) cells participate in this anti‐viral control. The Us3 protein kinase of herpes simplex virus‐1 (HSV‐1) inhibits CD8T‐cell cytotoxicity, which correlates with the inhibition of granzyme‐B (GrB)‐induced activation of pro‐apoptotic Bid. We have investigated the effect of Us3 on NK and LAK cytotoxicity, because these effectors are believed to share common mechanisms for inducing cell death. We show that, in contrast to their lower sensitivity to CD8T‐cell lysis, HSV‐1‐infected cells are lysed by NK cells or LAK cells as efficiently as the uninfected controls. Both CD8T and NK/LAK effectors were dependent on the activity of GrB and were efficiently blocked by means of treatment with a GrB inhibitor. However, unlike CD8T cells, LAK cells and NK cells failed to induce Bid cleavage, suggesting that various GrB downstream targets be involved in the induction of cell lysis. This finding explains their various sensitivities to viral modulation, which is likely to be important for the respective role of MHC‐restricted and non‐restricted effectors in the control of HSV‐1 infection.
Cyclorraphan yolk proteins and lepidopteran minor yolk proteins originate from two unrelated lipase families
Authors: Hens K. , Lemey P. , Macours N. , Francis C. , Huybrechts R.
Published: December 2004

Vitellogenins, cyclorraphan yolk proteins and lepidopteran minor yolk proteins are three classes of female‐specific proteins that serve as an embryonic nutritional store. Similarity to vertebrate lipid‐binding proteins was established for vitellogenins and yolk proteins, vitellogenins being related to apolipoprotein B and yolk proteins to lipases. Recently, similarity between yolk proteins and minor yolk proteins was reported and it was suggested that yolk proteins are more related to minor yolk proteins than to vertebrate lipases. In this study, we cloned five additional yolk proteins from the grey fleshfly Neobellieria bullata, formerly known as Sarcophaga bullata. We used this sequence data, combined with sequence data retrieved from the NCBI protein database to evaluate the yolk protein–lipase and the yolk protein–minor yolk protein relationship. We found no similarity between yolk proteins and minor yolk proteins, but we showed that yolk proteins are related to a family of lipases containing vertebrate hepatic and pancreatic lipases while minor yolk proteins are related to a family of lipases containing vertebrate gastric and lingual lipases. The fact that three different classes of yolk storage proteins show similarity to three different classes of vertebrate lipid‐binding proteins strongly suggests that this lipid‐binding feature is important for insect yolk storage proteins.
Infection patterns of o’nyong nyong virus in the malaria‐transmitting mosquito, Anopheles gambiae
Authors: Brault A. C. , Foy B. D. , Myles K. M. , Kelly C. L. H. , Higgs S. , Weaver S. C. , Olson K. E. , Miller B. R. , Powers A. M.
Published: December 2004

Arthropod‐borne alphaviruses transmitted by mosquitoes almost exclusively use culicines; however, the alphavirus o’nyong‐nyong (ONNV) has the unusual characteristic of being transmitted primarily by anopheline mosquitoes. This unusual attribute makes ONNV a valuable tool in the characterization of mosquito determinants of infection as well as a useful expression system in Anopheles species. We developed a series of recombinant alphaviruses, based upon the genome of ONNV, designed for the expression of heterologous genes. The backbone genome is a full‐length infectious cDNA clone of ONNV from which wild‐type virus can be rescued. Additional constructs are variants of the primary clone and contain the complete genome plus a duplicated subgenomic promoter element with a multiple cloning site for insertion of heterologous genes. We inserted a green fluorescent protein (GFP) gene downstream of this promoter and used it to characterize infection and dissemination patterns of ONNV within An. gambiae mosquitoes. These experiments allowed us to identify atypical sites of initial infection and dissemination patterns in this mosquito species not frequently observed in comparable culicine infections. The utility of these ONNVs for studies in anopheline mosquitoes includes the potential for identification of vector infection determinants and to serve as tools for antimalaria studies. Viruses that can express a heterologous gene in a vector and rapidly and efficiently infect numerous tissues in An. gambiae mosquitoes will be a valuable asset in parasite–mosquito interaction and interference research.
Survivors of childhood acute lymphoblastic leukaemia, with radiation‐induced GH deficiency, exhibit hyperleptinaemia and impaired insulin sensitivity, unaffected by 12 months of GH treatment
Authors: Bülow Birgitta , Link Katarina , Ahrén Bo , Nilsson Ann‐Sofie , Erfurth Eva Marie
Published: December 2004

OBJECTIVE  Adult survivors of childhood acute lymphoblastic leukaemia (ALL) often exhibit GH deficiency (GHD), due to prophylactic cranial radiotherapy (CRT). It is not known whether the observed risk for adiposity in these patients is associated with impaired insulin sensitivity and whether the insulin sensitivity is affected by GH replacement therapy.

SUBJECTS AND DESIGN  Eleven patients with GHD (median age 29 years), previously given prophylactic CRT for ALL, and 11 sex‐, age‐ and body mass index (BMI)‐matched controls were investigated with bioimpedance analysis (BIA) and analysis of serum leptin, serum free fatty acids (FFA) and serum insulin. Insulin sensitivity was measured by a euglycaemic–hyperinsulinaemic clamp technique (IS‐clamp). Moreover, the effects of 12 months of individually titrated GH treatment (median dose 0·5 mg/day) on these parameters were investigated.

RESULTS  At baseline, the patients had lower fat free mass (FFM) (P = 0·003), higher percentage fat mass (FM) (P = 0·05), serum insulin (P = 0·02) and serum leptin/kg FM (P = 0·01) than controls. The patients had a tendency towards impaired IS‐clamp (P = 0·06), which disappeared after correction for body composition (IS‐clamp/kg FFM; P > 0·5). In the patients, time since CRT was positively correlated with percentage FM (r = 0·70, P = 0·02), and there was an independent negative association between serum FFA and IS‐clamp (P = 0·05). Twelve months of GH treatment increased serum IGF‐I (P = 0·003) and FFM (P = 0·02) and decreased percentage FM (P = 0·03), but no significant changes were seen in serum leptin/kg FM, serum FFA, FFA‐clamp, serum insulin or IS‐clamp (all, P ≥ 0·2).

CONCLUSIONS  Young adult survivors of childhood ALL with GHD had increased fat mass, hyperleptinaemia and impaired insulin sensitivity, which could be a consequence of radiation‐induced impairment of GH secretion or mediated by other hypothalamic dysfunctions, such as leptin resistance or other unknown factors, affected by CRT. Twelve months of individualized GH replacement therapy led to positive effects on body composition, but the hyperleptinaemia, hyperinsulinaemia and the impaired insulin sensitivity remained unchanged.
Seminal elastase‐inhibitor complex, a marker of genital tract inflammation, and negative IVF outcome measures: role for a silent inflammation?
Authors: Zorn Branko , Virant‐klun Irma , Vidmar Gaj , Sešek‐Briški Alenka , Kolbezen Mojca , Meden‐vrtovec Helena
Published: December 2004

There is no consensus on whether and how male genital tract inflammation affects sperm fertilizing potential. The aims of this prospective study were to evaluate the elastase‐inhibitor complex in seminal plasma (s‐EI) level, a marker of male genital tract inflammation, in men undergoing in vitro fertilization (IVF) having no clinical signs of inflammation, and its association with semen characteristics, and the predictive role of s‐EI for the outcome of IVF in terms of fertilization, embryo development to the blastocyst stage and pregnancy. The study involved 104 male partners of infertile couples with normal spermiogram undergoing IVF. On the day of oocyte retrieval, spermiogram and s‐EI assessment using homogeneous immunoassay were performed. The outcome of IVF according to the s‐EI level was assessed in 85 cycles with two or more oocytes. In 67 cycles embryos were cultured to the blastocyst stage. Spearman's and Pearson's correlation tests, chi‐square test, and multiple linear and logistic regression analyses were used for statistical evaluation. Increased s‐EI level (≥250 μg/L) was detected in semen of 32% of men, and in 24% of men without leucocytospermia. We found an association between the s‐EI level and semen leucocytes (r = 0.49, p = 0.004) but not with classical sperm characteristics. No correlation between the s‐EI level and fertilization was observed. Increased s‐EI levels were associated with a poorer blastocyst development rate (p = 0.03) and a higher number of arrested embryos (p = 0.04). Extended embryo culture to the blastocyst stage shows a negative effect of clinically silent male genital tract inflammation on embryo developmental potential.
Hormonal regulation of spermatogenesis
Authors: Holdcraft Robert W. , Braun Robert E.
Published: December 2004

Proper functioning of the mammalian testis is dependent upon an array of hormonal messengers acting through endocrine, paracrine, and autocrine pathways. Within the testis, the primary messengers are the gonadotrophins, follicle stimulating hormone and luteinizing hormone, and the androgens. Abundant evidence indicates that the role of the gonadotrophins is to maintain proper functioning of testicular somatic cells. It is the androgens, primarily testosterone, which act through the somatic cells to regulate germ cell differentiation. Despite extensive research in this area, little is known about the cell‐specific requirements for androgens and even less is understood about the downstream effectors of androgen signalling. However, recent work using cell‐specific ablation of androgen receptor function has demonstrated a clear requirement for androgen signalling at multiple, discrete time points during spermatogenesis. These models also provide useful tools for identifying the targets of androgen receptor activity. The purpose of this review is to provide a brief overview of recent advances in our understanding of hormonal regulation of spermatogenesis, with an emphasis on the role of testosterone within the testis, and to pose important questions for future research in this field.
Effect of cyclooxygenase‐2 inhibitors on gastric emptying and small intestinal transit in humans
Authors: Bouras E. P. , Burton D. D. , Camilleri M. , Stephens D. A. , Thomforde G. M.
Published: December 2004

Abstract  Endogenous prostaglandins regulate smooth muscle activity; prostaglandins and cyclooxygenase (COX) inhibitors influence gastrointestinal motility in inflammatory states such as postoperative ileus in animal models. The objective of this study was to evaluate the effects of two COX‐2 inhibitors on gastric emptying and intestinal transit in healthy humans. In a double‐blind, placebo‐controlled, parallel‐group study, 66 healthy volunteers were randomized to one of two commercially available oral COX‐2 inhibitors (celecoxib and rofecoxib), cisapride (positive control), or placebo. Following 7 days on therapy, study participants underwent a test of gastric emptying and small bowel transit of liquids and solids using scintigraphy. Data were analysed using Kruskal–Wallis (anova on ranks)and Mann–Whitney rank sum tests. There were significant group effects on transit of solids: gastric emptying (anova, P = 0.005) and small bowel transit (anova, P = 0.056). However, neither COX‐2 inhibitor significantly accelerated the liquid or solid gastric emptying or small bowel transit compared with placebo. The positive control, cisapride, accelerated gastric emptying of solids (post‐lag slope of gastric emptying, P < 0.05), and small bowel transit of solids (t10%, P = 0.016). At maximum clinically approved dosages, celecoxib and rofecoxib have no significant effects on gastric emptying or small intestinal transit in healthy humans. Cisapride accelerates gastric emptying and small bowel transit in healthy humans.
Minimum sample frequency for multichannel intraluminal impedance measurement of the oesophagus
Authors: Bredenoord A. J. , Weusten B. L. A. M. , Timmer R. , Smout A. J. P. M.
Published: December 2004

Abstract  In all systems for impedance monitoring signals are stored in digital format after analog‐to‐digital conversion at a predefined rate, the sample frequency. We aimed to find the minimum sample frequency required to evaluate oesophageal transit and gastro‐oesophageal reflux studies using impedance monitoring. In 10 healthy subjects and five patients with gastro‐oesophageal reflux disease impedance signals were acquired during a 90‐min postprandial period, using a sample frequency of 1000 Hz. Additionally, 10 liquid swallows were recorded in the healthy subjects. A dedicated computer program was used to derive, from the original 1000‐Hz files, series of new data files with sample frequencies of 500, 200, 100, 50, 20, 10, 8, 5 and 4 Hz. In all of these files, liquid and gas reflux events were identified. In the analysis of the swallows, bolus head advance time (BHAT) and total bolus transit time were measured. Reflux events were detectable down to a sample frequency of 50 Hz. In transit analysis errors for BHAT at frequencies below 8 Hz errors exceeded 2.5%. Therefore, in impedance monitoring the minimum sample frequency is 50 Hz for the detection of reflux and 8 Hz for the evaluation of oesophageal transit.
Spatial determination of successive spikes in the isolated cat duodenum
Authors: Lammers W. J. E. P. , Faes C. , Stephen B. , Bijnens L. , Ver Donck L. , Schuurkes J. A. J.
Published: December 2004

Abstract  In seven isolated segments of the feline duodenum, the timings of all spikes and the locations of all spike patches that occurred after 12–16 successive slow waves were analysed. Simultaneous recordings were performed during 1‐min periods using 240 extracellular electrodes (24 × 10 array; interelectrode distance 2 mm) positioned onto the serosal surface. In all seven preparations, spikes always occurred during the first half of the slow wave cycle. From preparation to preparation, and within 1‐min periods in each preparation, there was limited variation in the spike–spike intervals, in the times between the spikes and the preceding slow wave and in the number of spikes at each electrode site. In contrast, the number of electrode sites that recorded spikes and the number of spike patches both showed great variability between preparations and sometimes within a single preparation. In addition, the location of spikes and spike patches was not random but was significantly concentrated in certain areas, often located along the anti‐mesenteric border, while other sites showed little or no spike activity. In conclusion, spikes and spike patches tend to occur significantly in some areas and not in others. This spatial heterogeneity will play a role in intestinal motility.
The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen
Authors: Cockcroft D. W. , Davis B. E. , Boulet L.‐P. , Deschesnes F. , Gauvreau G. M. , O'Byrne P. M. , Watson R. M.
Published: December 2004

Background:  The allergen‐induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint.

Objectives:  We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20‐based prediction of allergen PC20 (using methacholine) and a new methacholine PC20‐based prediction equation.

Methods:  From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20‐based and the new methacholine‐based formulae.

Results:  In single regressions, allergen PC20 correlated with both methacholine PC20 (r = 0.25, P = 0.0015) and skin test endpoint (r = 0.52, P < 0.00005). The relationship was improved by multiple regression of log‐allergen PC20vs. log‐methacholine PC20 and log‐endpoint (r = 0.61, P < 0.00005). The histamine‐based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine‐based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations.

Conclusions:  We have confirmed the dependence of the allergen‐induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.
Inflammatory events in severe acute asthma
Authors: Tillie‐Leblond I. , Gosset P. , Tonnel A.‐B.
Published: December 2004

Severe acute asthma can be induced by different triggers, allergens, irritants, viruses, etc., which induce inflammation and provoke acute bronchoconstriction. Inflammatory cells, such as activated eosinophils and neutrophils identified in sputum and bronchial lavages (BL) in severe acute asthma from children and adults are associated with increased levels of IL‐5, IL‐8, and of proinflammatory mediators. Viruses, but also endotoxin or allergen exposure, are able to recruit neutrophils, via an IL‐8 production by activated macrophages or epithelial cells. Together, these inflammatory mediators are responsible for the diffuse bronchial inflammation, which involve large and small airways. Activated T cells may also be related to the pathogenesis of severe asthma. An aberrant CD8+ T lymphocyte response in bronchi, with a cytotoxic activity has been associated with fatal asthma. Moreover, the persistence of inflammatory cells in bronchi, particularly neutrophils, which respond poorly to corticosteroids, could be in part responsible for the epithelial damage, the extensive mucus plugging, and the abnormalities of epithelial and endothelial permeability which are associated with severe acute asthma. Further studies are necessary to better identify the implication of this increased bronchial permeability in the persistence of high levels of airway resistance, particularly in patients with status asthmaticus.
Differential effects of fluticasone and montelukast on allergen‐induced asthma
Authors: Palmqvist M. , Bruce C. , Sjöstrand M. , Arvidsson P. , Lötvall J.
Published: December 2004

Early asthmatic responses (EAR) and late asthmatic responses (LAR) to allergen are induced by the local release of a series of bronchoconstrictor mediators, including leukotrienes and histamine. Both anti‐leukotrienes and other anti‐asthma drugs, such as inhaled glucocorticoids, have been shown to reduce both EAR and LAR. The aim of the present study was to directly compare the effects of regular treatment with an oral anti‐leukotriene, montelukast (Mont; 10 mg once daily, for 8 days), and an inhaled glucocorticoid [fluticasone propionate (FP) 250 μg twice daily for 8 days] on the EAR and LAR to an inhaled allergen challenge. Patients with a documented EAR and LAR at a screening visit were randomized to these treatments, or placebo, in a double‐blind, double‐dummy, crossover fashion. Allergen challenge at a dose causing both an EAR and LAR was given on the eighth day of treatment. The maximum fall in FEV1 during the EAR was 17.8% during placebo treatment, 8.3% during Mont and 16.3% during FP (P < 0.05 for Mont vs placebo). The maximum fall during the EAR was 13.8% during placebo treatment, 11.8% during Mont and 2% during FP treatment (P < 0.05 for FP vs placebo and FP vs Mont). PC20 methacholine was significantly higher 24 h after allergen challenge during FP‐treatment compared with Mont (P < 0.05). Both montelukast and fluticasone reduced the relative amount of sputum eosinophils after allergen compared with placebo treatment. This study shows that anti‐leukotrienes are effective to attenuate the EAR, whereas inhaled glucocorticoids are more effective than anti‐leukotrienes in attenuating the EARs and improves bronchial hyperresponsiveness to a greater extent. In conclusion, inhaled glucocorticoids have overall greater efficacy than oral anti‐leukotrienes to attenuate allergen‐induced airway responses in mild asthmatic patients.
Association of hepatitis A virus infection with allergic sensitization in a population with high prevalence of hepatitis A virus exposure
Authors: Gonzalez‐Quintela A. , Gude F. , Boquete O. , Aguilera A. , Rey J. , Meijide L. M. , Fernandez‐Merino M. C. , Vidal C.
Published: December 2004

Background:  An inverse association between allergic sensitization and markers of exposure to food‐borne and orofecal infections (particularly hepatitis A virus, HAV) has been reported. The prevalence of HAV exposure and allergic sensitization vary widely in different areas, and vary along with age within a given area.

Aim:  To investigate the association between HAV exposure and allergic sensitization in adults from a mostly rural area of Spain.

Methods:  An age‐stratified random sample of 720 subjects was drawn from the population older than 18 years of A‐Estrada, Spain. From 697 eligible subjects, 469 (67.2%, median age 54 years, range: 18–92) participated in the study. Positive skin prick tests to a panel of aeroallergens defined allergic sensitization. Positive serum HAV antibodies (assayed in 465 subjects) defined HAV exposure.

Results:  The prevalence of HAV exposure was 83.6% (95% CI: 80.7–86.5). The prevalence of allergic sensitization was lower in subjects with HAV exposure than in patients without it (25.0%vs 40.0%, OR 0.44, 95% CI: 0.25–0.77, P = 0.004), but this association became substantially altered after adjusting for age, which was closely linked to both allergic sensitization and HAV exposure (adjusted OR 1.15, 95% CI: 0.60–2.19, P = 0.66).

Conclusions:  In a population with high prevalence of HAV exposure, no significant association between HAV exposure and allergic sensitization is observed after controlling for the confounding effect of age.
Biscogniauxia nummularia: pathogenic agent of a beech decline
Authors: Granata G. , Sidoti A.
Published: December 2004

Decline of European beech (Fagus sylvatica) in Sicily and Calabria (Italy) was observed to be associated with the ascomycete Biscogniauxia nummularia. This fungus is naturally present in beech stands and to date has not been considered a primary pathogenic agent. Artificial inoculations were performed to assess its pathogenicity on beech and to determine if Sicilian and Calabrian isolates differ in virulence. Biscogniauxia nummularia played an evident primary pathogenic role under the environmental conditions studied. Virulence of the isolates was variable and did not depend neither on the geographic origin nor the environmental conditions at the sites where pathogenicity testing was performed.
The relationship between Swiss needle cast symptom severity and level of Phaeocryptopus gaeumannii colonization in coastal Douglas‐fir (Pseudotsuga menziesii var. menziesii)*
Authors: Temel F. , Johnson G. R. , Stone J. K.
Published: December 2004

This study examined 108 15‐year‐old Douglas‐fir (Pseudotsuga menziesii var. menziesii) trees to investigate whether trees exhibiting less severe Swiss needle cast (SNC) symptoms were more resistant (had less fungal colonization) or more tolerant (maintained healthy foliage under similar infection levels). Trees were sampled from six open pollinated families that were categorized into three disease severity groups (two families for each group; mild, moderate and severe disease symptoms). The amount of retained foliage and level of discoloration were visually assessed on trees in the field. Fungal colonization (as determined by proportion of stomata occluded with pseudothecia and by amount of Phaeocryptopus gaeumannii DNA in sampled needles) was measured on 1‐ and 2‐year‐old needles in the laboratory. Trees in the different disease severity groups were similar with respect to amount of fungus in their needles, yet the trees in the mild symptom group retained higher proportions of needles and maintained greener foliage. The relationship between amount of P. gaeumannii in needles and SNC symptom severity was statistically significant (p < 0.05) for amount of fungal DNA in 1‐year‐old needles and average needle retention (NR) over the last four growing seasons. Average NR decreased with increased amount of pathogen DNA in the mild disease symptom families. This relationship was reversed in the severe disease symptom group and there was no relationship in the moderate disease symptom group. Because the amount of P. gaeumannii DNA in foliage did not differ significantly among the groups, differences in symptom severity were attributed to tolerance, not resistance. Visual scoring of individual trees for average NR over the past four growing seasons could be used to effectively assess for SNC tolerance in Douglas‐fir.