bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of simultaneous Na lidar and mesospheric nightglow temperature measurements and the effects of tides on the emission layer heights
Authors: Zhao Y. , Taylor M. J. , Chu X.
Published: February 2005

A detailed comparative study of two new mesospheric temperature data sets, measured by different remote‐sensing techniques, has been performed as part of a long‐term investigation of low‐latitude mesospheric dynamics. Coincident observations using the University of Illinois Na wind/temperature lidar and the Utah State University CEDAR Mesospheric Temperature Mapper (MTM) were conducted from the summit of Haleakala Crater, Maui, Hawaii (20.8°N, 156.2°W, ∼3000 m) as part of the Maui‐MALT program. High‐quality joint measurements were obtained during four lidar campaign periods, and 16 nights of data, spanning the interval January 2002 to October 2003, are presented here as example observations during each season. The Na lidar was coupled to the Air Force 3.7 m diameter steerable telescope providing exceptional quality temperature (and wind) data spanning the altitude range ∼80–105 km. At the same time the MTM sequentially sampled the NIR OH (6,2) Meinel band and the O2 (0,1) Atmospheric band nightglow emissions to determine the height‐weighted mesospheric temperature at two nominal altitudes within this region. Comparison of these two nocturnal data sets shows exceptionally good agreement on a point‐to‐point, as well as a nightly mean basis, especially when allowances were made for physically reasonable changes in height during the course of the night for each of the nightglow layers. This analysis yields mean nocturnal altitudes of 88.6 km with a nocturnal variability of ±3.0 km for the OH M (6,2) band emission layer and 94.4 km for the O2 (0,1) Atmospheric band mean altitude with a nocturnal variability of ±4.2 km. These results are in excellent accord with previous rocket, satellite and ground‐based observations and further establish the validity of these two complementary measurement techniques. Furthermore, analysis of the computed height changes inferred from this study indicates a systematic decrease in altitude of both emission layers by up to several kilometers, whenever the lidar data showed evidence of strong diurnal or semidiurnal tidal forcing. The apparent downward trend in altitude was found to track the phase of the prevailing tidal motion providing new evidence for the effects of tides (or long‐period gravity waves) on the height variability of the nightglow layers.
Analysis of seasonal and interannual variability in transpacific transport
Authors: Liu Junfeng , Mauzerall Denise L. , Horowitz Larry W.
Published: February 2005

The purpose of our analysis is both to evaluate the meteorological component of the seasonal and interannual variability of transpacific transport and to identify meteorological features that can be used to estimate transpacific transport. To accomplish this goal, we simulate the transport of nine continental tracers with uniform emissions and two‐week lifetimes using the global Model of Ozone and Related Tracers Version 2 (MOZART‐2) driven with NCEP reanalysis meteorology from 1991–2001. In addition, we define a transpacific “transport potential,” a measure of the quantity of a tracer transported from a particular region normalized by its total emissions from that region, across a meridional plane in the eastern Pacific at 130°W. We find that at midlatitudes, the east Asian and Indian tracers have the largest transport potentials, particularly in spring. The interannual variability of the transpacific transport potentials of most tracers is relatively high in winter and fall (particularly in February and September) but is low from April to August. At high latitudes the former Soviet Union, east Asian, and European tracers have the largest transpacific transport potentials, especially in late summer and fall, when the lowest interannual variability is observed. We find that El Niño winters are associated with stronger eastward transport of east Asian emissions in the subtropical eastern Pacific. Transport of the east Asian tracer in the central North Pacific is well correlated with the North Pacific Index. However, we find that the interannual variability of transport across the west coast of North America is mostly driven by local meteorology. We therefore created a new index based on meteorology over the eastern Pacific, which we call the Eastern Pacific Index (EPI). The EPI captures most of the interannual variability of transpacific transport at both middle‐ and high‐latitude regions across the west coast of North America.
Statistical downscaling using K‐nearest neighbors
Authors: Gangopadhyay Subhrendu , Clark Martyn , Rajagopalan Balaji
Published: February 2005

Statistical downscaling provides a technique for deriving local‐scale information of precipitation and temperature from numerical weather prediction model output. The K‐nearest neighbor (K‐nn) is a new analog‐type approach that is used in this paper to downscale the National Centers for Environmental Prediction 1998 medium‐range forecast model output. The K‐nn algorithm queries days similar to a given feature vector in this archive and using empirical orthogonal function analysis identifies a subset of days (K) similar to the feature day. These K days are then weighted using a bisquare weight function and randomly sampled to generate ensembles. A set of 15 medium‐range forecast runs was used, and seven ensemble members were generated from each run. The ensemble of 105 members was then used to select the local‐scale precipitation and temperature values in four diverse basins across the contiguous United States. These downscaled precipitation and temperature estimates were subsequently analyzed to test the performance of this downscaling approach. The downscaled ensembles were evaluated in terms of bias, the ranked probability skill score as a measure of forecast skill, spatial covariability between stations, temporal persistence, consistency between variables, and conditional bias and to develop spread‐skill relationships. Though this approach does not explicitly model the space‐time variability of the weather fields at each individual station, the above statistics were extremely well captured. The K‐nn method was also compared with a multiple‐linear‐regression‐based downscaling model.
Transport of bromide in the Bainsvlei soil: Field experiment and deterministic/stochastic model simulation. II. Intermittent water application
Authors: Tilahun Ketema , Botha J. F. , Bennie A. T. P.
Published: February 2005

Despite the fact that non-uniform soil water content and variable input water fluxes are usually encountered in the field, tracer experiments have usually been carried out under steady-state conditions. The objective of this study was to analyse solute transport in a Bainsvlei soil under intermittent water application using Br– as a tracer. Sprinkler was used to apply water on a plot 200 by 200 cm. Soil core samples were taken every 20 cm to a depth of 160 cm several times during the experiment. The soil Br– concentration data were fitted to the steady-state convection–dispersion analytical model in the CXTFIT package. The average coefficients of determination yielded by this fit (r2 = 0.810) clearly support that the data could be analysed successfully with CXTFIT. The average pore-water velocity of 1.72 cm/day and average dispersion coefficient of 26.19 cm2/day determined from this fit are lower than the fitted values of the steady-state experiments. The Br– moved slower under the intermittent application of water than in the steady case, a conclusion supported by the deeper location of Br– peaks under continuous application than intermittent application after the same amount of water is applied.
Restricting the grazing time of cattle to decrease phosphorus, sediment and E. coli losses in overland flow from cropland
Authors: McDowell R. W. , Drewry J. J. , Muirhead R. W. , Paton R. J.
Published: February 2005

This study investigated the effects of grazing management of brassica crops during winter on soil physical properties and sediment, phosphorus (P), and E. coli loss via overland flow. Dairy cows were allowed either unrestricted grazing, grazing restricted to 3 h, or no grazing. Treading in the unrestricted treatment decreased soil bulk density and saturated hydraulic conductivity (Ksat), and increased surface roughness, loads and concentrations of suspended sediment, and E. coli and P loss in overland flow relative to the ungrazed treatment. Only bulk density was different in the restricted compared with the ungrazed treatment. For total P, the mean load in overland flow from the unrestricted grazing treatment after grazing was 3.31 mg/plot compared with restricted grazing (0.74 mg/plot) and ungrazed (0.76 mg/plot) treatments, with most of the increase in particulate form. E. coli concentrations only exceeded water quality guidelines in the first event after grazing, and only in the unrestricted grazing treatment. We found that restricting grazing on forage crops during winter was beneficial for minimising contaminant loss.
Some possible interconnections between shrinkage cracking and gilgai
Authors: Chertkov V. Y.
Published: February 2005

There is the specific form of a microrelief of swelling clay soils, called gilgai. The relief consists of mounds, depressions, and even sections of the surface. Existing models of the phenomenon do not account for the role of horizontal shrinkage cracks and are qualitative. The objective of this work is to propose a quantitative model of possible interconnections between the formation of shrinkage cracks, vertical and horizontal, and the gilgai microrelief. First, a summary is given of available models of the vertical and horizontal shrinkage cracks in soils. A proposed mechanism of the gilgai formation is based on a width increase of the air-filled horizontal cracks during a wetting season. Some simple relations are considered between the gilgai microrelief and vertical and horizontal shrinkage cracking. The analysis results of available data on geometrical gilgai characteristics favour the feasibility of the model.
Stability of aggression during early adolescence as moderated by reciprocated friendship status and friend’s aggression
Authors: Adams Ryan E. , Bukowski William M. , Bagwell Catherine
Published: February 2005

The effect of friendship reciprocation and friend aggression on the stability of aggression across a 6-month period following the transition to secondary school was studied in a sample of 298 Grade 6 children from a predominately white, middle-class, Midwestern American community. The stability of aggression was generally high but it varied as a function of (1) the level of aggression of both individuals in the friendship and (2) whether the friendship was reciprocated. For children with high initial levels of aggression, those with unreciprocated aggressive friends were the most stable in their aggression. For children with low initial levels of aggression, most children remained stably low in aggression, with type of friendship and friend aggression having little effect on stability. Adolescents who were high in aggression at time 1 (T1) and had an aggressive friend (reciprocated or not) remained aggressive at time 2 (T2), but those who were aggressive at T1 and had nonaggressive friends actually displayed much lower levels of aggression at T2. The opposite did not occur for those adolescents low in aggression at T1. Those low in aggression with aggressive friends at T1 did not increase in aggression. These findings were discussed in light of current thinking about the effect of friendship on development.
Dyadic and group perspectives on close relationships
Authors: Laursen Brett
Published: February 2005

Recent advances in the study of close relationships hold the potential for new insignts into the significance of interdependence and the mechanism of relationship influence. The papers in this special issue apply two new data analytic techniques to the study of family and friend relationships. The Actor–Partner Interdependence Model incorporates the perspectives of both participants in a dyad into analyses that describe shared and unique views of the relationship. The Social Relations Model incorporates the perspectives of all members of a group into analyses that ascribe views unique to individuals and relationships, and views shared by the entire group. Developmental applications of techniques originally designed for concurrent interdependent data are described with the aim of advancing these analytic procedures to the study of lifespan human development.
The Type Iα Inositol Polyphosphate 4-Phosphatase Generates and Terminates Phosphoinositide 3-Kinase Signals on Endosomes and the Plasma Membrane
Authors: Ivetac Ivan , Munday Adam D. , Kisseleva Marina V. , Zhang Xiang-Ming , Luff Susan , Tiganis Tony , Whisstock James C. , Rowe Tony , Majerus Phillip W. , Mitchell Christina A.
Published: February 2005

Endosomal trafficking is regulated by the recruitment of effector proteins to phosphatidylinositol 3-phosphate [PtdIns(3)P] on early endosomes. At the plasma membrane, phosphatidylinositol-(3,4)-bisphosphate [PtdIns(3,4)P2] binds the pleckstrin homology (PH) domain-containing proteins Akt and TAPP1. Type Iα inositol polyphosphate 4-phosphatase (4-phosphatase) dephosphorylates PtdIns(3,4)P2, forming PtdIns(3)P, but its subcellular localization is unknown. We report here in quiescent cells, the 4-phosphatase colocalized with early and recycling endosomes. On growth factor stimulation, 4-phosphatase endosomal localization persisted, but in addition the 4-phosphatase localized at the plasma membrane. Overexpression of the 4-phosphatase in serum-stimulated cells increased cellular PtdIns(3)P levels and prevented wortmannin-induced endosomal dilatation. Furthermore, mouse embryonic fibroblasts from homozygous Weeble mice, which have a mutation in the type I 4-phosphatase, exhibited dilated early endosomes. 4-Phosphatase translocation to the plasma membrane upon growth factor stimulation inhibited the recruitment of the TAPP1 PH domain. The 4-phosphatase contains C2 domains, which bound PtdIns(3,4)P2, and C2-domain-deletion mutants lost PtdIns(3,4)P24-phosphatase activity, did not localize to endosomes or inhibit TAPP1 PH domain membrane recruitment. The 4-phosphatase therefore both generates and terminates phosphoinositide 3-kinase signals at distinct subcellular locations.
Menstrual cycle, pregnancy and oral contraceptive use alter attraction to apparent health in faces
Authors: Jones B. C. , Perrett D. I. , Little A. C. , Boothroyd L. , Cornwell R. E. , Feinberg D. R. , Tiddeman B. P. , Whiten S. , Pitman R. M. , Hillier S. G. , Burt D. M. , Stirrat M. R. , Law Smith M. J. , Moore F. R.
Published: February 2005

Previous studies demonstrating changes in women's face preferences have emphasized increased attraction to cues to possible indirect benefits (e.g. heritable immunity to infection) that coincides with periods of high fertility (e.g. the late follicular phase of the menstrual cycle). By contrast, here we show that when choosing between composite faces with raised or lowered apparent health, women's preferences for faces that are perceived as healthy are (i) stronger during the luteal phase of the menstrual cycle than during the late follicular, fertile phase, (ii) stronger in pregnant women than in non–pregnant women and (iii) stronger in women using oral contraceptives than in women with natural menstrual cycles. Change in preference for male faces was greater for short– than long–term relationships. These findings indicate raised progesterone level is associated with increased attraction to facial cues associated with possible direct benefits (e.g. low risk of infection) and suggest that women's face preferences are influenced by adaptations that compensate for weakened immune system responses during pregnancy and reduce the risk of infection disrupting foetal development.
Discrete hierarchical organization of social group sizes
Authors: Zhou W.-X. , Sornette D. , Hill R. A. , Dunbar R. I. M.
Published: February 2005

The ‘social brain hypothesis’ for the evolution of large brains in primates has led to evidence for the coevolution of neocortical size and social group sizes, suggesting that there is a cognitive constraint on group size that depends, in some way, on the volume of neural material available for processing and synthesizing information on social relationships. More recently, work on both human and non–human primates has suggested that social groups are often hierarchically structured. We combine data on human grouping patterns in a comprehensive and systematic study. Using fractal analysis, we identify, with high statistical confidence, a discrete hierarchy of group sizes with a preferred scaling ratio close to three: rather than a single or a continuous spectrum of group sizes, humans spontaneously form groups of preferred sizes organized in a geometrical series approximating 3–5, 9–15, 30–45, etc. Such discrete scale invariance could be related to that identified in signatures of herding behaviour in financial markets and might reflect a hierarchical processing of social nearness by human brains.
Cardiovascular reactivity and family history of hypertension: A meta‐analysis
Authors: Pierce Thomas W. , Grim Rodney D. , King Joseph S.
Published: February 2005

A regression‐based meta‐analysis examined the degree to which the effects of a family history of hypertension on cardiovascular reactivity are moderated by the magnitude of cardiovascular responses elicited in challenge/task conditions. Mean change scores for negative family history groups were regressed on mean change scores for positive family history groups. The slopes of separate regression lines obtained for systolic and diastolic blood pressure and heart rate were significantly less than 1.0 and the y‐intercepts for these regression lines were significantly greater than zero. This pattern indicates that family history differences in cardiovascular reactivity to stress are greatest in situations that elicit the smallest baseline‐stressor change scores in non‐family‐history groups.
Diversity of leukaemic cell morphology in ATL correlates with prognostic factors, aberrant immunophenotype and defective HTLV‐1 genotype
Authors: Tsukasaki Kunihiro , Imaizumi Yoshitaka , Tawara Masayuki , Fujimoto Takeshi , Fukushima Takuya , Hata Tomoko , Maeda Takahiro , Yamada Yasuaki , Kamihira Shimeru , Tomonaga Masao
Published: February 2005

To investigate the diversity of morphology in adult T‐cell leukaemia/lymphoma (ATL) and its possible association with the pathophysiology of ATL, we selected 36 acute cases and 14 chronic cases phenotypically confirmed to have >90% ATL cells in peripheral blood mononuclear cells. Prototype ATL cells were observed in all cases, although the percentage of all lymphoid cells varied considerably (48.9 ± 23.8 in acute type, 29.6 ± 18.9 in chronic type; P = 0.015). Chronic lymphocytic leukaemia (CLL)‐like morphology with round nuclei was more frequent in chronic type than in acute type (52.0 ± 24.9% v 16.6 ± 13.1%; P < 0.0001). Unusual morphology (UM; lymphoblastic, vacuolated, granular pleomorphic or large cells) was more frequent in acute type than in chronic type (20.1 ± 18.7% v 2.7 ± 3.2%; P < 0.0001). Furthermore, there were significant negative and positive correlations of % CLL‐like cells and % UM cells respectively, with serum LDH level, hypercalcaemia, performance status, and total number of involved lesions. Cases with aberrant immunophenotype (n = 6) or defective HTLV‐1 integration (n = 22) showed lower % CLL‐like cells and higher % UM cells than other cases, respectively. Cases with >50% CLL‐like cells (n = 7; all chronic type) were younger (53.1 ± 12.2 v 66.9 ± 10.6 years; P = 0.038) and showed longer acute‐crisis free survival (mean: 16.7 v 3.0 years; P = 0.012) than chronic cases with <50% CLL‐like cells. These results suggest that diversity in genotype, phenotype, morphology and behaviour of ATL are closely associated, and that CLL‐like morphology is a good prognostic factor for chronic type.
Gene expression profile identifies a rare epithelioid variant case of pleomorphic liposarcoma carrying FUS‐CHOP transcript
Authors: De Cecco L , Gariboldi M , Reid J F , Lagonigro M S , Tamborini E , Albertini V , Staurengo S , Pilotti S , Pierotti M A
Published: February 2005

Aims : To describe a tumour with morphological and immunophenotypic characteristics of epithelioid variant of pleomorphic liposarcoma. Pleomorphic liposarcoma is a very rare variant of liposarcoma defined morphologically by the presence of pleomorphic lipoblasts showing peculiar epithelial‐like features that can be confused with primary or metastatic carcinoma.

Methods and results : Molecular analysis demonstrated for the first time the presence of FUS‐CHOP transcript in this liposarcoma variant. Microarray analysis revealed a gene expression profile related to a more aggressive tumour type when compared with other myxoid/round cell liposarcomas.

Conclusions : The present data show that the epithelioid variant of pleomorphic liposarcoma represents a further variant of myxoid liposarcoma sharing the FUS‐CHOP fusion transcript but carrying a distinct expression profile, in keeping with its aggressive clinical course.
Aggressive B‐cell lymphomas: a review based on the workshop of the XI Meeting of the European Association for Haematopathology
Authors: Leoncini L , Delsol G , Gascoyne R D , Harris N L , Pileri S A , Piris M A , Stein H
Published: February 2005

The generic term aggressive B‐cell lymphoma includes a variety of entities, each with particular diagnostic and therapeutic issues. To define these entities better and to help confront such issues, a workshop was organized by the European Association of Haematopathology (EAHP) and the Society of Haematology during the XI Meeting of the EAHP, held in Italy in May 2002. Participants were asked to submit cases under various categories and all cases submitted were examined and reviewed by the panel members. The panel's diagnoses formed the basis for discussion at the workshop and a limited number of cases were selected to be presented in more detail and discussed during the workshop. After the workshop the panel met again to discuss the outcome, summarized in this report, which describes the panel's proposals regarding diagnostic criteria, terminology, the definition of new entities and evaluation of biological differential and new prognostic parameters.
Needle core biopsy can reliably distinguish between benign and malignant papillary lesions of the breast
Authors: Carder P J , Garvican J , Haigh I , Liston J C
Published: February 2005

Aims : To review 21 screen‐detected papillary lesions in which the core biopsy findings suggested a papillary lesion and to correlate pathological and radiological findings in order to assess the risks of associated malignancy and the need for surgical intervention. The appropriate management of non‐malignant papillary breast lesions detected on needle core biopsy (NCB) is currently uncertain.

Methods and results : Forty‐seven papillary breast lesions with a histological diagnosis of papilloma, papilloma with atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS), multiple papillomas, ‘papillomatosis’ or papillary carcinoma (invasive or in situ) were identified from records at the Leeds Breast Screening and Assessment Unit. The cases were diagnosed between between May 1995 and May 2002. In 21 cases the previous NCB contained a papillary proliferation which had been categorized as either ‘B2’, benign, ‘B3’, of uncertain malignant potential, or ‘B4’, suspicious of malignancy. All of the 19 ‘B3’ or ‘B4’ cases and one of the two ‘B2’ lesions had undergone open surgical biopsy. All cases with a previous ‘B4’ were malignant on subsequent excision. All excised cases with a previous ‘B3’ or ‘B2’ were found benign, although four of the ‘B3's derived from papillomata associated with an atypical proliferation amounting to ADH. In three of these four (75%) the papillary proliferation had been associated with epithelial hyperplasia of usual type (HUT) on the core and the radiological features were of a mass lesion detected on incident round screen which had increased in size.

Conclusion : Our results confirm the accuracy of NCB in the diagnosis of screen‐detected papillary lesions of the breast. Surgical excision may not always be necessary following a ‘B3’ core biopsy.
Association between cyclooxygenase‐2‐expressing macrophages, ulceration and microvessel density in colorectal cancer
Authors: Sheehan K M , Steele C , Sheahan K , O'Grady A , Leader M B , Murray F E , Kay E W
Published: February 2005

Aim : In colorectal carcinomas, cyclooxygenase‐2 (COX‐2) is expressed predominantly by epithelial cells and is implicated in tumour progression. Tumour‐associated macrophages may influence tumour growth, proliferative rate and angiogenesis and also express COX‐2 when activated. Thus they may play an important stromal‐epithelial role in carcinogenesis. Τhe aim of this study was to define the relationship between microvessel density (MVD), tumour COX‐2 and macrophage COX‐2 expression.

Methods and results : Sixty‐five cases of formalin‐fixed paraffin‐embedded colorectal cancer were included in the study. Tissues were immunostained for COX‐2, CD68 (macrophage marker) and CD34 (endothelial marker to assess MVD). Thirty‐six cases were grossly ulcerated cancers and 29 cases showed focal/microscopic ulceration. Macrophages were in high concentration at the base of ulcerated areas, and were also diffusely dispersed within tumoral stroma. However, the pattern of macrophage COX‐2 expression revealed two populations of macrophages—those deep within the tumour (negative for COX‐2) and those at the base of ulcers (positive for COX‐2). In all cases, the tumour epithelial cells expressed COX‐2. MVD was higher at the base of ulcers, adjacent to COX‐2+ macrophages, and was lower deep within the tumour.

Conclusions : In colorectal cancers, macrophages may have a dual role. Those concentrated at the base of the ulcers, where there is an associated high MVD, may induce angiogenesis, but their function may be in a healing/repair process. The lack of COX‐2+ macrophages and lower MVD deep within the tumour suggests that it may be the epithelial COX‐2 component that is important in tumour progression.
CD10 and Bcl‐2 expression combined with the International Prognostic Index can identify subgroups of patients with diffuse large‐cell lymphoma with very good or very poor prognoses
Authors: Biasoli I , Morais J C , Scheliga A , Milito C B , Romano S , Land M , Pulcheri W , Spector N
Published: February 2005

Aims : Diffuse large B‐cell lymphoma (DLBCL) is characterized by marked biological heterogeneity. The identification of reproducible parameters that can be combined with the International Prognostic Index (IPI) to better predict outcome could lead to the development of effective risk‐adaptive strategies.

Methods and results : Bcl‐2 and CD10 expression was determined by immunohistochemistry. The impact of the positivity on survival was evaluated in combination with the IPI in 86 patients with a confirmed diagnosis of DLBCL. Patients were divided according to the IPI into low‐risk (no to two factors) or high‐risk (three to five factors) groups. Positivity rates were 25% for CD10 and 42% for Bcl‐2. In a Cox analysis, the high‐risk IPI group [hazard ratio (HR) 5.98, P < 0.0001) and Bcl‐2 expression (HR 2.43, P = 0.02) were independent poor prognostic factors, and expression of CD10 (HR 0.41, P = 0.052) predicted a favourable outcome. Among patients in the low‐risk IPI group, CD10 positivity was associated with an excellent 8‐year overall survival (92% versus 45%, P = 0.06). In the high‐risk IPI group, Bcl‐2 positivity identified a subgroup with invariably fatal disease.

Conclusions : The expression of CD10 in the low‐risk IPI group, and the expression of Bcl‐2 in the high‐risk IPI group can identify two subgroups of patients who might benefit from new risk‐adaptive treatment approaches.
Natural killer T‐cell populations in C57BL/6 and NK1.1 congenic BALB.NK mice—a novel thymic subset defined in BALB.NK mice
Authors: Stenström Martin , Sköld Markus , Andersson Åsa , Cardell Susanna L.
Published: February 2005

Natural killer (NK) T lymphocytes are a subpopulation of T lymphocytes regarded as early regulators of immune responses. The majority of NKT cells are restricted by the CD1d molecule. NKT cells have mostly been studied in one single mouse strain, C57BL/6 (B6), because of the absence of NK1.1 in other common mouse strains, and the lack of other reliable surface markers for CD1d‐restricted cells. To investigate NKT cell subsets in a mouse strain of a genetic background different from B6, we have back‐crossed the NKT cell marker NK1.1 from the B6 mouse to the BALB/c mouse strain. We show that NKT cells in the congenic BALB.B6‐NK1.1b mouse share many characteristics with their B6 counterparts, but seem to be deficient in the functional NKT cell subtype characterized by low interleukin‐4 and high interferon‐γ production, and surface expression of CD49b but not CD69. Moreover, in the thymus but not the spleen of BALB.B6‐NK1.1b mice we find a novel Vα14‐Jα18 invariant NKT cell subset which is devoid of a set of NK markers, suggesting that these cells represent a less differentiated NKT cell stage, and carries high levels of the T‐cell receptor and uses a skewed T‐cell receptor Vβ‐repertoire.
Lupus autoantibodies to native DNA preferentially bind DNA presented on PolIV
Authors: Kumar Sanjeev , Bunting Karen A. , Kalsi Jatinderpal , Hinks John A. , Latchman David S. , Pearl Laurence H. , Isenberg David A.
Published: February 2005

While immunoglobulin G (IgG) antibodies to double‐stranded (ds)DNA are serological markers of systemic lupus erythematosus (SLE), not all antibodies to DNA (anti‐DNA) are able to cause tissue damage to a similar extent. It has been proposed that anti‐DNA‐induced renal damage could be linked to differences in the fine specificity of the antibodies. In an attempt to gain insight into their fine binding properties, we investigated the cross‐reactivity of two human lupus monoclonal IgG anti‐dsDNA (B3 and RH14) to a recently described Escherichia coli PolIV (a DNA polymerase). These autoantibodies possess distinct pathogenic properties in severe combined immunodeficient (SCID) mice. Although both antibodies cause proteinuria, only RH14 induces early histological features of lupus nephritis. Both RH14 and B3 bound PolIV; however, they exhibited a marked difference in their reactivity to the PolIV–dsDNA complex. Alhough RH14 exhibited significant activity to the complex, the binding of B3 to PolIV complexed with dsDNA was almost abolished. Furthermore, there was a significant difference in the way the lupus sera recognized naked dsDNA and that presented on PolIV. Although 67% of lupus sera bound naked dsDNA, ≈ 90% of these sera (93% calf thymus DNA; 90% synthetic oligonucleotide) reacted to the complex when dsDNA was presented on PolIV. Thus, the IgG anti‐dsDNA likely to exist in lupus patients may be distinguished into those that recognize dsDNA in the context of PolIV and those which do not. This difference in binding ability may help to distinguish those dsDNA antibodies that are more pathogenic.
Haemopoietic mechanisms in murine allergic upper and lower airway inflammation
Authors: Li Jing , Saito Hiroko , Crawford Lynn , Inman Mark D. , Cyr Michael M. , Denburg Judah A.
Published: February 2005

Eosinophil recruitment to the airways, including involvement of haemopoietic eosinophil–basophil progenitors (Eo/B‐CFU), is primarily regulated by interleukin‐5 (IL‐5) and eotaxin. In this study, we investigated the haemopoietic mechanisms in upper and lower airway eosinophilic inflammation. Ovalbumin (OVA) sensitized and challenged BALB/c mice were used to establish isolated upper (UAC), isolated lower (LAC), or combined upper and lower airway (ULAC) inflammation. Airway, blood and bone marrow responses were evaluated in each model. Numbers of airway eosinophils and CD4+ cells were increased significantly in the nasal mucosa in UAC and ULAC mice, and in the lung tissue in LAC and ULAC groups. Levels of IL‐5 and eotaxin were increased significantly in the nasal lavage fluid (NL) in UAC and ULAC mice, and in the bronchoalveolar lavage fluid (BAL) in LAC and ULAC groups. The proportion of IL‐5‐responsive bone marrow Eo/B‐CFU was significantly higher than the control in all treatment groups, but peaked much earlier in the ULAC group. Kinetic studies revealed that IL‐5 and eotaxin in NL, BAL and serum peaked between 2 and 12 hr after OVA challenge in ULAC mice, and at 24 hr in UAC mice, related to the timing of maximal progenitor responses. These data support the concept that the systemic mechanisms linking rhinitis to asthma depend on the location and extent of airway allergen exposure.
Long‐term follow‐up of chronic hepatitis B after the emergence of mutations in the hepatitis B virus polymerase region
Authors: Natsuizaka M. , Hige S. , Ono Y. , Ogawa K. , Nakanishi M. , Chuma M. , Yoshida S. , Asaka M.
Published: February 2005

Summary.  Treatment of chronic hepatitis B has been greatly improved by the use of lamivudine, but mutations occur in the polymerase region of hepatitis B virus (HBV) and lamivudine‐resistant mutants frequently develop. The emergence of lamivudine‐resistant strains of HBV is a problem for treating chronic hepatitis B using lamivudine. We observed biochemical and virological changes in 15 patients with chronic hepatitis B for a median period of 29 months (range: 4–42 months) after the emergence of lamivudine‐resistant mutants of HBV. Patterns of mutation of the polymerase gene were examined by sequencing the LLAQ motif in domain B and the YMDD motif in domain C. Exacerbation of liver dysfunction occurred in 14 (93.3%) of the 15 patients at a median of 4 months after the emergence of mutations. However, exacerbation of liver dysfunction was observed only in four patients (26.7%) at the time of appearance of the first mutations and in 80.0% of the patients at the time of appearance of the second mutations. Increase in serum alanine aminotransferase (ALT) levels was significantly greater at the time of appearance of second mutations (P = 0.0096). In most cases, wild‐type HBV was mutated with the substitution of only rtM204I at first, and rtL180M/M204I mutations and then rtL180M/M204V mutations subsequently appeared. Further mutations of the polymerase region caused clinical deterioration. Thus as mutations emerge in the polymerase region, the clinical outcome deteriorates. Thus, monitoring the patterns of mutation of the polymerase gene is useful when using lamivudine for treating HBV.
Low frequency of mutations in the X gene, core promoter and precore region of hepatitis B virus infected Vietnamese
Authors: Song L. H. , Duy D. N. , Binh V. Q. , Luty A. J. F. , Kremsner P. G. , Bock C. T.
Published: February 2005

Summary.  Numerous mutations in the hepatitis B virus (HBV) genome have been described, but in most cases their role in the pathogenesis of HBV infection is still unclear. Therefore, we analysed specific mutations in HBV‐infected Vietnamese patients and assessed their potential relationship with their clinical outcome. A total of 153 HBV‐infected Vietnamese patients with well‐characterised clinical profiles were enrolled. None of the study participants had a history of alcohol or drug use and none received any antiviral or immunosuppressive therapy before or during the course of this study. The HBx‐ and core promoter regions were analysed by sequencing. The majority of isolates corresponded to genotype A. The presence of hepatitis B e antigen (HBeAg) was associated with significantly higher viral loads in the chronic HBV‐infection group (P = 0.026). Double mutations in the core promoter (1762/1764) were more frequent in those with cancer than in noncancer patients (P < 0.01). Mutations at nucleotide (nt) 1766/1773 were found at low prevalence but with no obvious association to clinical presentation. Cytosine at nt 1858 was predominant but the stop codon mutation in the precore region was not detected. In the study, 4/48 hepatocellular carcinoma (HCC) patients revealed truncated HBx, whilst the serine to alanine mutation (codon 31) of HBx was more prevalent in cancer patients than in asymptomatic HBV carriers (P < 0.01). Thus, the low frequency of mutations indicates the relation of the absence of antiviral pressure in this population. The exclusively found prevalence of certain mutations detected in those with HBV‐related carcinoma nevertheless indicates a degree of association with disease progression.
Intrahepatic and peripheral blood virus‐specific cytotoxic T lymphocyte activity is associated with a response to combination IFN‐α and ribavirin treatment among patients with chronic hepatitis C virus infection*
Authors: Freeman A. J. , Marinos G. , Ffrench R. A. , Lloyd A. R.
Published: February 2005

Summary.  This report describes an association between intrahepatic and peripheral blood cytotoxic T lymphocytes (CTL) activity present prior to receiving treatment, and a response to combination interferon‐α (IFN‐α) and ribavirin therapy for chronic hepatitis C virus (HCV) infection. Recombinant vaccinia virus constructs were used to expand and detect cytotoxic effectors against the entire genotype 1a HCV polyprotein. Six patients with a sustained response to therapy were significantly more likely to display intrahepatic and peripheral blood HCV‐specific CTL activity than patients who relapsed or had no treatment response. Limited longitudinal data suggested that rather than combination therapy acting to enhance the CTL response to achieve viral clearance, detectable CTL prior to treatment increases the likehood of the host responding to the direct antiviral activity of IFN‐α and ribavirin.
Enhanced expression of suppressor of cytokine signalling‐1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy
Authors: Imanaka K. , Tamura S. , Fukui K. , Ito N. , Kiso S. , Imai Y. , Naka T. , Kishimoto T. , Kawata S. , Shinomura Y. ,   The Kansai Viral Hepatitis Research Group
Published: February 2005

Summary.  Interferon‐α (IFN‐α) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK–STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN‐α is demonstrated here. The transcriptional levels of SOCS‐1 and ‐3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription‐polymerase chain reaction. We established stable transfectants of SOCS‐1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS‐1 on the phosphorylation of IFN‐α‐induced STAT‐1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS‐1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS‐1, but not SOCS‐3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN‐α‐induced STAT‐1 phosphorylation and the expression of antiviral genes were inhibited in SOCS‐1‐transfected cells. Patients showing high SOCS‐1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS‐1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS‐1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS‐1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy.
Clinical outcome and virological characteristics of hepatitis B‐related acute liver failure in the United States
Authors: Wai C.‐T. , Fontana R. J. , Polson J. , Hussain M. , Shakil A. O. , Han S.‐H. , Davern T. J. , Lee W. M. , Lok A. S.‐F ,   The US Acute Liver Failure Study Group
Published: February 2005

Summary.  The role of hepatitis B virus (HBV) genotypes in the outcome of acute HBV infection is unclear. In this study, we aimed to evaluate the clinical and virological features of patients with hepatitis B‐related acute liver failure (HBV‐ALF) in the US. Clinical and laboratory features of consecutive patients with HBV‐ALF from the US ALF Study Group were analysed. Prevalence of HBV genotypes, precore stop (G1896A) and core promoter dual (T1762A, A1764T) variants among patients with HBV‐ALF were compared with a cohort of 530 patients with chronic HBV infection. Thirty‐four HBV‐ALF patients were studied: mean age 41 years, 56% men, 25 had detectable HBV‐DNA. HBV genotypes A, B, C and D were found in 36, 24, 8 and 32% patients, respectively. Precore stop and core promoter dual variants were detected in 32 and 44% of patients, respectively. Twenty‐three (68%) patients survived: 14 after liver transplant, nine without transplant. Older age was the only independent factor associated with poor outcome. Compared with patients with chronic HBV infection, patients with ALF were more likely to be non‐Asians (88%vs 44%, P = 0.005) and to have genotype D (32%vs 10%, P < 0.01). A higher prevalence of HBV genotype D persisted even after matching for race and HBeAg status (32%vs 16%, P = 0.007). We concluded that HBV genotype D was more frequently found in patients with HBV‐ALF than those with chronic HBV infection in the US. Further studies are needed to determine if HBV genotypes play a role in the outcome of acute HBV infection.
HBV vaccination in liver transplant recipients: not an effective strategy in the prophylaxis of HBV recurrence
Authors: Karasu Z. , Ozacar T. , Akarca U. , Ersoz G. , Erensoy S. , Gunsar F. , Kobat A. , Tokat Y. , Batur Y.
Published: February 2005

Summary. Anti‐HBs immunoglobulins (HBIG) and lamivudine are main options to prevent hepatitis B virus (HBV) reinfection after liver transplantation. Although they are very effective, development of mutant viruses and high cost of treatment are main limitations for their application. Additionally there is an uncertainity for the duration of that prophylaxis regimen and its mostly applied indefinitely. Recently, post‐transplant HBV vaccination is reported to be a cheaper alternative prophylaksis strategy, that enables discontinuation of HBIG. To investigate the efficacy of HBV vaccination in patients transplanted for HBV cirrhosis, we administered double course of double dose recombinant HBV vaccine (Genhavac B; containing HBV pre‐S1, pre‐S2, and S gene products). Vaccination has been started 1 month after HBIg discontinuation, and lamivudine (100 mg/day) was given throughout the study. The first cycle consisted of 0, 1‐ and 6‐month schedule, and, in nonresponders, second cycle 0, 1‐, 2‐month schedule. Fourteen patients included into the study. Only one patient seroconverted (an anti‐HBs titre of 37 IU/L) after the first cycle. No other patient responded to second cycle. HBV vaccination in the post‐transplantation setting does not seems like an effective strategy in the prophylaxis of HBV recurrence.
Three‐phase sequential combined treatment with lamivudine and interferon in young patients with chronic hepatitis B
Authors: Marrone A. , Zampino R. , Portella G. , Grimaldi M. , Mangoni E. D. , Santarpia L. , Ruggiero G. , Utili R.
Published: February 2005

Summary.  Alpha‐interferon (IFN) or lamivudine monotherapy are ineffective in treating chronic HBeAg positive patients with high viral load and low alanine aminotransferase (ALT) levels. We investigated whether priming lamivudine treatment might enhance the antiviral and immunostimulant action of lamivudine/IFN combination in young tolerant patients. Eleven chronic HBeAg positive patients received: 100 mg/day lamivudine for 3 months followed by IFN 5 MU/m2/tiw with lamivudine 100 mg/day for 6 months and then lamivudine alone 100 mg/day for 9 months. Quantitative hepatitis B virus (HBV)‐DNA was evaluated during treatment and core‐promoter, precore and polymerase HBV mutants were detected by direct sequencing at the end of therapy. Serum HBV‐DNA levels dropped during lamivudine monotherapy and in combination with IFN. After IFN withdrawal, viraemia transiently increased to high levels in five of 11 (45%) patients who showed rt M204V/I lamivudine mutant resistant. Two patients cleared HBeAg without anti‐HBe seroconversion. One patient presented core‐promoter (A1762T/G1764A) and precore stop codon mutations. Hence, three‐phase sequential combined lamivudine/IFN treatment reduced HBV‐DNA serum level, but did not lead to HBeAg and HBV‐DNA clearance in these highly viraemic, normal ALT patients. Lamivudine/IFN combination did not prevent the emergence of YMDD lamivudine resistance. New schedules of antiviral treatments must be evaluated in this population at risk of disease progression.
Sulphated tyrosines mediate association of chemokines and Plasmodium vivax Duffy binding protein with the Duffy antigen/receptor for chemokines (DARC)
Authors: Choe Hyeryun , Moore Michael J. , Owens Christopher M. , Wright Paulette L. , Vasilieva Natalya , Li Wenhui , Singh Agam P. , Shakri Rushdi , Chitnis Chetan E. , Farzan Michael
Published: February 2005

Plasmodium vivax is one of four Plasmodium species that cause human malaria. P. vivax and a related simian malaria parasite, Plasmodium knowlesi, invade erythrocytes by binding the Duffy antigen/receptor for chemokines (DARC) through their respective Duffy binding proteins. Here we show that tyrosines 30 and 41 of DARC are modified by addition of sulphate groups, and that the sulphated tyrosine 41 is essential for association of the Duffy binding proteins of P. vivax (PvDBP) and P. knowlesi (PkDaBP) with DARC‐expressing cells. These sulphated tyrosines also participate in the association of DARC with each of its four known chemokine ligands. Alteration of tyrosine 41 to phenylalanine interferes with MCP‐1, RANTES and MGSA association with DARC, but not with that of IL8. In contrast, alteration of tyrosine 30 to phenylalanine interferes with the association of IL8 with DARC. A soluble sulphated amino‐terminal domain of DARC, but not one modified to phenylalanine at residue 41, can be used to block the association of PvDBP and PkDaBP with red blood cells, with an IC50 of approximately 5 nM. These data are consistent with a role for tyrosine sulphation in the association of many or most chemokines with their receptors, and identify a key molecular determinant of erythrocyte invasion by P. vivax.
Two substrate‐targeting sites in the Yersinia protein tyrosine phosphatase co‐operate to promote bacterial virulence
Authors: Ivanov Maya I. , Stuckey Jeanne A. , Schubert Heidi L. , Saper Mark A. , Bliska James B.
Published: February 2005

YopH is a protein tyrosine phosphatase and an essential virulence determinant of the pathogenic bacterium Yersinia. Yersinia delivers YopH into infected host cells using a type III secretion mechanism. YopH dephosphorylates several focal adhesion proteins including p130Cas in human epithelial cells, resulting in disruption of focal adhesions and cell detachment from the extracellular matrix. How the C‐terminal protein tyrosine phosphatase domain of YopH targets specific substrates such as p130Cas in the complex milieu of the host cell has not been fully elucidated. An N‐terminal non‐catalytic domain of YopH binds p130Cas in a phosphotyrosine‐dependent manner and functions as a novel substrate‐targeting site. The structure of the YopH protein tyrosine phosphatase domain bound to a model phosphopeptide substrate was solved and the resulting structure revealed a second substrate‐targeting site (‘site 2’) within the catalytic domain. Site 2 binds to p130Cas in a phosphotyrosine‐dependent manner, and co‐operates with the N‐terminal domain (‘site 1’) to promote efficient recognition of p130Cas by YopH in epithelial cells. The identification of two substrate‐targeting sites in YopH that co‐operate to promote epithelial cell detachment and bacterial virulence reinforces the importance of protein–protein interactions for determining protein tyrosine phosphatase specificity in vivo, and highlights the sophisticated nature of microbial pathogenicity factors.