bluuebunny/crossref_metadata_2025 huggingface dataset:
Random sampling of stony and non-stony soils for testing a national soil carbon monitoring system
Authors: Hedley C. B. , Payton I. J. , Lynn I. H. , Carrick S. T. , Webb T. H. , McNeill S.
Published: February 2012

The New Zealand Soil Carbon Monitoring System (Soil CMS) was designed, and has been used, to account for soil organic carbon change under land-use change, during New Zealand’s first Commitment Period (2008–2012) to the Kyoto Protocol. The efficacy of the Soil CMS model has been tested for assessing soil organic carbon stocks in a selected climate–land-use–soil grouping (cell). The cell selected for this test represents an area of 709 683 ha and contains soils with a high-activity clay mineralogy promoting long-term stabilisation of organic matter, and is under low-producing grassland in a dry temperate New Zealand climate. These soils have been sampled at randomly selected positions to assess total soil organic carbon stocks to 0.3 m, and to compare with the modelled value. Results show no significant difference between the field estimation (67 ± 30 Mg C/ha), the mean value of the model calibration dataset (79 ± 28 Mg C/ha), and the value predicted by the model (101 ± 41 Mg C/ha), although all estimates have large uncertainties associated with them. The model predicts national soil organic carbon stocks as a function of soil texture, clay mineralogy, land use, climate class, and a slope–rainfall erosivity product. Components of uncertainty within the model include the size and distribution of the calibration dataset, and lack of representativeness of the calibration soil samples, which were sampled for other reasons, e.g. soil survey and forest mensuration.
Our study has shown that major components of uncertainty in our field estimation of soil organic carbon stocks (investigated using the indices reproducibility, RP; and coefficient of variation, CV) are short-range (within-plot) and regional (between-sites) spatial variability. Soil organic carbon stocks vary within our selected climate–land-use–soil cell due to varying stoniness (stony soils RP 44%, CV 21%; non-stony soils RP 27%, CV 13%), soil depth, slope position, and climatic effects. When one outlier soil was removed from the model calibration dataset, and the three very stony sites were removed from the randomly selected field validation set, the model calibration dataset and the field dataset means agreed well (78 ± 26 and 78 ± 21 Mg C/ha, respectively). The higher modelled value, before removal of the outlier, is likely to reflect a bias in the model dataset towards conventionally selected modal profiles containing less stony soils than those encountered by the random sampling strategy of our field campaign. Therefore, our results indicate (1) that the Soil CMS provides an adequate estimation of soil organic carbon for the selected cell, and (2) ongoing refinements are required to reduce the uncertainty of prediction.
Effect of soil type and rainfall on dicyandiamide concentrations in drainage from lysimeters
Authors: Shepherd Mark , Wyatt Justin , Welten Brendon
Published: February 2012

The nitrification inhibitor dicyandiamide (DCD) is mobile in drainage water, which has implications for its effectiveness in reducing nitrate leaching from urine patches. Lysimeters had been used to investigate the effect of soil type (clay, silt loam, or sandy loam) and precipitation (target ~1140 or 2280 mm/year) on the effectiveness of DCD to decrease nitrate leaching. This paper reports the associated effects on DCD in drainage water. DCD was applied in May and July at a rate of 10 kg/ha, and natural rainfall was supplemented with irrigation to ensure that the target precipitation was achieved for each treatment. The experiment was undertaken twice. The pattern of DCD concentrations in drainage water suggested that movement of DCD in the silt loam and sandy loam soils was typical of convective–dispersive flow. Although there was some preferential flow of DCD from the soil surface to depth in the clay soil, DCD concentration profiles suggested that the main transport mechanism was also by convective–dispersive flow. There were significant soil-type and precipitation effects on DCD leaching (P < 0.05). The soil-type effect could be attributed to differences in drainage volume between soils. Combining data from the two experimental years, DCD leaching losses ranged from 12 to 46% of applied, with annual drainage in the range 422–1292 mm. DCD was detected in drainage up to 15 months after application, demonstrating the longevity of the compound. The experiment demonstrates that leaching of DCD on all of the soil types tested can be substantial under high rainfall. This is likely to have implications for the effectiveness of DCD to decrease nitrogen losses from urine patches under such rainfall conditions, as well as being a source of nitrogen itself.
A review of operations research methods applicable to wildfire management
Authors: Minas James P. , Hearne John W. , Handmer John W.
Published: February 2012

Across the globe, wildfire-related destruction appears to be worsening despite increased fire suppression expenditure. At the same time, wildfire management is becoming increasingly complicated owing to factors such as an expanding wildland–urban interface, interagency resource sharing and the recognition of the beneficial effects of fire on ecosystems. Operations research is the use of analytical techniques such as mathematical modelling to analyse interactions between people, resources and the environment to aid decision-making in complex systems. Fire managers operate in a highly challenging decision environment characterised by complexity, multiple conflicting objectives and uncertainty. We assert that some of these difficulties can be resolved with the use of operations research methods. We present a range of operations research methods and discuss their applicability to wildfire management with illustrative examples drawn from the wildfire and disaster operations research literature.
The extracellular matrix: A dynamic niche in cancer progression
Authors: Lu Pengfei , Weaver Valerie M. , Werb Zena
Published: February 2012

The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.
Numerical computation of a certain Dirichlet series attached to Siegel modular forms of degree two
Authors: Ryan Nathan , Skoruppa Nils-Peter , Strömberg Fredrik
Published: February 2012

The Rankin convolution type Dirichlet series

D

F
,
G

(
s
)

D_{F,G}(s)

of Siegel modular forms

F
F

and

G
G

of degree two, which was introduced by Kohnen and the second author, is computed numerically for various

F
F

and

G
G

. In particular, we prove that the series

D

F
,
G

(
s
)

D_{F,G}(s)

, which shares the same functional equation and analytic behavior with the spinor

L
L

-functions of eigenforms of the same weight are not linear combinations of those. In order to conduct these experiments a numerical method to compute the Petersson scalar products of Jacobi Forms is developed and discussed in detail.
Structure and functionalization of mesoporous bioceramics for bone tissue regeneration and local drug delivery
Authors: Vallet-Regí María , Izquierdo-Barba Isabel , Colilla Montserrat
Published: February 2012

This review article describes the importance of structure and functionalization in the performance of mesoporous silica bioceramics for bone tissue regeneration and local drug delivery purposes. Herein, we summarize the pivotal features of mesoporous bioactive glasses, also known as ‘templated glasses’ (TGs), which present chemical compositions similar to those of conventional bioactive sol–gel glasses and the added value of an ordered mesopore arrangement. An in-depth study concerning the possibility of tailoring the structural and textural characteristics of TGs at the nanometric scale and their influence on bioactive behaviour is discussed. The highly ordered mesoporous arrangement of cavities allows these materials to confine drugs to be subsequently released, acting as drug delivery devices. The functionalization of mesoporous silica walls has been revealed as the cornerstone in the performance of these materials as controlled release systems. The synergy between the improved bioactive behaviour and local sustained drug release capability of mesostructured materials makes them suitable to manufacture three-dimensional macroporous scaffolds for bone tissue engineering. Finally, this review tackles the possibility of covalently grafting different osteoinductive agents to the scaffold surface that act as attracting signals for bone cells to promote the bone regeneration process.
Disentangling protein–silica interactions
Authors: Giussani Lara , Tabacchi Gloria , Gianotti Enrica , Coluccia Salvatore , Fois Ettore
Published: February 2012

We present the results of modelling studies aimed at the understanding of the interaction of a 7 nm sized water droplet containing a negatively charged globular protein with flat silica surfaces. We show how the droplet interaction with the surface depends on the electrostatic surface charge, and that adhesion of the droplet occurs when the surface is negatively charged as well. The key role of water and of the charge-balancing counter ions in mediating the surface-protein adhesion is highlighted. The relevance of the present results with respect to the production of bioinorganic hybrids via encapsulation of proteins inside mesoporous silica materials is discussed.
Coordination chemistry of Ca sites at the surface of nanosized hydroxyapatite: interaction with H2O and CO
Authors: Bolis Vera , Busco Claudia , Martra Gianmario , Bertinetti Luca , Sakhno Yuriy , Ugliengo Piero , Chiatti Fabio , Corno  Marta , Roveri Norberto
Published: February 2012

The affinity towards water of a selection of well-defined, nanostructured hydroxyapatite (HA) samples was investigated by H2O vapour adsorption microcalorimetry and infrared (IR) spectroscopy. A large hydrophilicity of all investigated materials was confirmed. The surface features of hydrated HA were investigated on the as-synthesized samples pre-treated in mild conditions atT=303 K, whereas dehydrated HA features were characterized on samples activated atT=573 K. The relatively large hydrophilicity of the hydrated surface (−ΔadsH∼100–50 kJ mol−1) was due to the interaction of water with the highly polarized H2O molecules strongly coordinated to the surface Ca2+cations. At the dehydrated surface, exposing coordinatively unsaturated (cus) Ca2+cations, H2O was still molecularly adsorbed but more strongly (−ΔadsH∼120–90 kJ mol−1). The use of CO adsorption to quantify the Lewis acidic strength of HA surface sites revealed only a moderate strength ofcusCa2+cations, as confirmed by both microcalorimetric and IR spectroscopic measurements andab initiocalculations. This result implies that the large HA/H2O interaction energy is due to the interplay betweencusCa2+sites and nearby hydrophilic PO4groups, not revealed by the CO probe. The lower density ofcusCa2+cations at the 573 K activated HA surface with respect to the pristine one did not affect the whole hydrophilicity of the surface, as the polarizing effect of Ca sites is so strong to extend up to the fourth hydrated layer, as confirmed by both high-coverage microcalorimetric and IR spectroscopic data. No specific effects due to the investigated specimen preparation method and/or different morphology were observed.
Bach1‐mediated suppression of p53 is inhibited by p19ARF independently of MDM2
Authors: Nishizawa Hironari , Ota Kazushige , Dohi Yoshihiro , Ikura Tsuyoshi , Igarashi Kazuhiko
Published: February 2012

Cellular senescence prevents the aberrant proliferation of damaged cells. The transcription factor Bach1 binds to p53 to repress cellular senescence, but it is still unclear how the Bach1–p53 interaction is regulated. We found that the Bach1–p53 interaction was inhibited by oncogenic Ras, bleomycin, and hydrogen peroxide. Proteomics analysis of Bach1 complex revealed its interaction with p19ARF, a tumor suppressor that competitively inhibited the Bach1–p53 interaction when overexpressed within cells. Reduction of MDM2 expression in wild‐type murine embryonic fibroblasts (MEFs) did not result in slower proliferation, showing that Bach1 plays a role in keeping the proliferation of MEFs independent of MDM2. Consistent with this interpretation, expression of p21 was highly induced in MEFs when both Bach1 and MDM2 were abrogated. The level of Bach1 protein was reduced on knockdown of p53. These results suggest that p53 activation involves its dissociation from Bach1, achieved in part by the competitive binding of p19ARF to Bach1. The p19ARF–Bach1 interaction constitutes a regulatory pathway of p53 in parallel with the p19ARF–MDM2 pathway. (Cancer Sci 2012; 103: 897–903)
The record of Himalayan erosion preserved in the sedimentary rocks of the Hatia Trough of the Bengal Basin and the Chittagong Hill Tracts, Bangladesh
Authors: Najman Y. , Allen R. , Willett E. A. F. , Carter A. , Barfod D. , Garzanti E. , Wijbrans J. , Bickle M. J. , Vezzoli G. , Ando S. , Oliver G. , Uddin M. J.
Published: February 2012

The Cenozoic sedimentary succession of Bangladesh provides an archive of Himalayan erosion. However, its potential as an archive is currently hampered by a poor lithostratigaphic framework with limited age control. We focus on the Hatia Trough of the Bengal Basin and the adjacent fold belt of the Chittagong Hill Tracts which forms the outermost part of the west‐propagating Indo‐Burmese wedge. We present a basin‐wide seismic stratigraphic framework for the Neogene rocks, calibrated by biostratigraphy, which divides the succession into three seismically distinct and regionally correlatable Megasequences (MS). MS1 extends to NN15‐NN16 (ca. 2.5–3.9 Ma), MS2 to NN19‐NN20 (ca. 0.4–1.9 Ma) and MS3 to present day. Our seismic mapping, thermochronological analyses of detrital mineral grains, isotopic analyses of bulk rock, heavy mineral and petrographic data, show that the Neogene rocks of the Hatia Trough and Chittagong Hill Tracts are predominantly Himalayan‐derived, with a subordinate arc‐derived input possibly from the Paleogene IndoBurman Ranges as well as the Trans‐Himalaya. Our seismic data allow us to concur with previous work that suggests folding of the outer part of the west‐propagating wedge only commenced recently, within the last few million years. We suggest that it could have been the westward encroachment and final abutment of the Chittagong Hill Tracts fold belt onto the already‐uplifted Shillong Plateau that caused diversion of the palaeo‐Brahmaputra to the west of the plateau as the north‐east drainage route closed.
Late Cretaceous‐Palaeogene stratigraphic and basin evolution in the Zhepure Mountain of southern Tibet: implications for the timing of India‐Asia initial collision
Authors: Hu Xiumian , Sinclair Hugh D. , Wang Jiangang , Jiang Hehe , Wu Fuyuan
Published: February 2012

This article presents combined stratigraphic, sedimentological, subsidence and provenance data for the Cretaceous–Palaeogene succession from the Zhepure Mountain of southern Tibet. This region records the northernmost sedimentation of the Tethyan passive margin of India, and this time interval represents the transition into continental collision with Asia. The uppermost Cretaceous Zhepure Shanpo and Jidula formations record the transition from pelagic into upper slope to delta‐plain environments. The Palaeocene–lower Eocene Zongpu Formation records a carbonate ramp that is overlain by the deep‐water Enba Formation (lower Eocene). The upper part of the Enba Formation records shallowing into a storm‐influenced, outer shelf environment. Detrital zircon U–Pb and Hf isotopic data indicate that the terrigenous strata of the Enba Formation were sourced from the Lhasa terrane. Unconformably overlying the Enba Formation is the Zhaguo Formation comprising fluvial deposits with evidence of recycling from the underlying successions. Backstripped subsidence analysis indicates shallowing during latest Cretaceous‐earliest Palaeocene time (Zhepure Shanpo and Jidula formations) driven by basement uplift, followed by stability (Zongpu Formation) until early Eocene time (Enba Formation) when accelerated subsidence occurred. The provenance, subsidence and stratigraphy suggest that the Enba and Zhaguo formations record foredeep and wedge‐top sedimentation respectively within the early Himalayan foreland basin. The underlying Zongpu Formation is interpreted to record the accumulation of a carbonate ramp at the margin of a submarine forebulge. The precursor tectonic uplift during latest Cretaceous time could either record surface uplift over a mantle plume related to the Réunion hotspot, or an early signal of lithospheric flexure related to oceanic subduction, continental collision or ophiolite obduction. The results indicate that the collision of India with Asia occurred before late Danian (ca. 62 Ma) time.
Cardiovascular risk
Authors: Payne Rupert A.
Published: February 2012

Cardiovascular disease is a major, growing, worldwide problem. It is important that individuals at risk of developing cardiovascular disease can be effectively identified and appropriately stratified according to risk. This review examines what we understand by the term risk, traditional and novel risk factors, clinical scoring systems, and the use of risk for informing prescribing decisions. Many different cardiovascular risk factors have been identified. Established, traditional factors such as ageing are powerful predictors of adverse outcome, and in the case of hypertension and dyslipidaemia are the major targets for therapeutic intervention. Numerous novel biomarkers have also been described, such as inflammatory and genetic markers. These have yet to be shown to be of value in improving risk prediction, but may represent potential therapeutic targets and facilitate more targeted use of existing therapies. Risk factors have been incorporated into several cardiovascular disease prediction algorithms, such as the Framingham equation, SCORE and QRISK. These have relatively poor predictive power, and uncertainties remain with regards to aspects such as choice of equation, different risk thresholds and the roles of relative risk, lifetime risk and reversible factors in identifying and treating at‐risk individuals. Nonetheless, such scores provide objective and transparent means of quantifying risk and their integration into therapeutic guidelines enables equitable and cost‐effective distribution of health service resources and improves the consistency and quality of clinical decision making.
Incidence, risk factors and outcome of histological transformation in follicular lymphoma
Authors: Conconi Annarita , Ponzio Carlotta , Lobetti‐Bodoni Chiara , Motta Maddalena , Rancoita Paola M.V. , Stathis Anastasios , Moccia Alden A. , Mazzucchelli Luca , Bertoni Francesco , Ghielmini Michele , Cavalli Franco , Zucca Emanuele
Published: February 2012

Histological transformation (HT) into diffuse large B‐cell lymphoma (DLBCL) was documented in 37 of the 281 (13%; 95% CI, 9–18) follicular lymphoma (FL) patients treated at our institute from 1979 to 2007. HT occurred at a median of 2·75 years from initial FL diagnosis and HT rate was 15% at 10 years and 26% at 14 years, with a plateau from that point onward. Patients with bulky or extranodal disease, or those diagnosed before 1990 had a significantly higher risk of HT. When initial treatment strategies were taken into account, a reduced HT risk was seen in the patients initially managed with a ‘watch and wait’ policy, while the risk appeared significantly increased in the small subset of 18 patients initially managed with rituximab plus chemotherapy (P = 0·0005). HT was associated with a significantly shorter cause‐specific survival (P = 0·0002). Predictors of survival after HT were the Follicular Lymphoma International Prognostic Index at diagnosis, as well as age and performance status at the time of HT. Our data confirm the adverse clinical outcome of FL after HT. In keeping with previous isolated reports, our findings suggest that there is a subgroup of patients in whom HT may not occur.
Critical Thermal Minima of age‐0 Australian bass, Macquaria novemaculeata, fingerlings: implications for stocking programmes
Authors: CAMERON L. M. , BAUMGARTNER L. J. , BUCHER D. J. , ROBINSON W.
Published: February 2012

Abstract  Fishes are often stocked outside natural distribution ranges with inadequate information on target streams, particularly thermal regimes. Australian bass, Macquaria novemaculeata (Steindachner), is a catadromous species that is regularly stocked into upland reaches of rivers and impoundments in south‐eastern Australia. Critical Thermal Minima (CTMin) were determined for age‐0 Australian bass fingerlings with a mean fork length of 64.4 ± 0.4 mm and weighing 3.8 ± 0.8 g. Four treatments were used, including three replicate aquaria for each treatment. Fingerlings were acclimated at either 8 or 15 °C at densities of 15 fish in 56‐L glass aquaria. Water temperatures were then decreased at either 1 °C day−1 or 1 °C h−1 until loss of equilibrium (LOE), which occurred between 3 and 7 °C. Mean CTMin among treatments was 3.22–4.64 °C and was influenced by acclimation temperature and rate of temperature decline. Fingerlings acclimated at 8 °C subjected to a temperature decline of 1 °C h−1 experienced highest LOE temperature. Post‐LOE mortality among treatments was highest at 100% in the 8 °C acclimation with a 1 °C day−1 temperature decline. Mortalities following LOE occurred within 5 days. The results suggest that stocking age‐0 Australian bass is unlikely to be successful in areas where winter temperatures fall below 6 °C.
ACTN4 gene amplification and actinin‐4 protein overexpression drive tumour development and histological progression in a high‐grade subset of ovarian clear‐cell adenocarcinomas
Authors: Yamamoto Sohei , Tsuda Hitoshi , Honda Kazufumi , Takano Masashi , Tamai Seiichi , Imoto Issei , Inazawa Johji , Yamada Tesshi , Matsubara Osamu
Published: February 2012

Yamamoto S, Tsuda H, Honda K, Takano M, Tamai S, Imoto I, Inazawa J, Yamada T & Matsubara O  (2012) Histopathology 60,1073–1083

ACTN4 gene amplification and actinin‐4 protein overexpression drive tumour development and histological progression in a high‐grade subset of ovarian clear‐cell adenocarcinomas

Aims:  Actinin‐4, encoded by the ACTN4 gene located on chromosome 19q13.2, enhances cell motility by bundling the actin cytoskeleton. We assessed how ACTN4/actinin‐4 alterations contribute to the tumorigenesis of ovarian clear‐cell adenocarcinomas (CCAs).

Methods and results:  Fluorescence in‐situ hybridization analysis demonstrated that ACTN4 amplification (≥4 ACTN4 copies in ≥40% of cells) occurred in 27 (33%) of 81 CCAs and genomic gains of ACTN4 were associated strongly with immunohistochemical actinin‐4 overexpression, poorly differentiated tumour histology and shorter patient survival (all P < 0.05). From the 27 ACTN4‐amplified CCAs, 23 tumours with adjacent putative precursor lesions were selected and examined for ACTN4/actinin‐4 alterations with respect to their intratumoral heterogeneity. In this selected cohort, none of the precursors lacking cytological atypia exhibited gains of ACTN4 or actinin‐4 overexpression; 50% of the atypical endometrioses and 75% of the borderline CCAFs showed low‐level gains of ACTN4 and actinin‐4 overexpression, respectively. In 12 of 23 ACTN4‐amplified CCAs, intratumoral heterogeneity for ACTN4 alterations was documented in carcinomatous components; the better differentiated carcinoma components exhibited fewer alterations than those with poorly differentiated histology.

Conclusion:  Accumulative genomic gains of ACTN4, causing actinin‐4 protein overexpression, drive the development and progression of ovarian CCAs with high‐grade histology.
MUC5AC, cytokeratin 20 and HER2 expression and K‐RAS mutations within mucinogenic growth in congenital pulmonary airway malformations
Authors: Rossi Giulio , Gasser Bernard , Sartori Giuliana , Migaldi Mario , Costantini Matteo , Mengoli Maria Cecilia , Piccioli Silvia , Cavazza Alberto , Rivasi Francesco
Published: February 2012

Rossi G, Gasser B, Sartori G, Migaldi M, Costantini M, Mengoli M C, Piccioli S, Cavazza A & Rivasi F  (2012) Histopathology 60, 1133–1143

MUC5AC, cytokeratin 20 and HER2 expression and K‐RAS mutations within mucinogenic growth in congenital pulmonary airway malformations

Aims:  To analyse the expression of several mucins (MUC1, MUC2, MUC3, MUC5AC and MUC6), epidermal growth factor receptor (EGFR), v‐erb‐b2 erythroblastic leukaemia viral oncogene homologue 2 (HER2), thyroid transcription factor‐1 (TTF‐1), caudal type homeobox 2 (CDX2) and cytokeratin 20 (CK20), and the presence of mutations of EGFR, KRAS and HER2 in congenital pulmonary airway malformations (CPAM).

Methods and results:  Forty‐one cases of CPAM and six pulmonary sequestrations were included. TTF‐1 expression was observed in all cases but was not seen in mucinogenic growths in CPAM. CDX2 expression was completely negative. MUC1 expression was noted in 12 (29%) CPAM and in 33% sequestrations. MUC5AC was noted in only five cases (26%) by immunohistochemistry and was found in the mucinogenic proliferations of type 1 CPAM. No immunolabelling was noted for the other mucins. EGFR was expressed variably in almost all cases, while HER2 and CK20 was seen exclusively in the mucinogenic proliferations. All mucinous growths were characterized by KRAS mutations. No EGFR and HER2 gene alterations were identified.

Conclusions:  KRAS mutations and MUC5AC, CK20 and HER2 expression was seen in all mucinogenic proliferations, supporting the neoplastic nature of these cytologically bland growths. These findings emphasize the importance of complete surgical resection of such lesions.
Somatic mutations of the KEAP1 gene in common solid cancers
Authors: Yoo Nam Jin , Kim Hyung Ran , Kim Yoo Ri , An Chang Hyeok , Lee Sug Hyung
Published: February 2012

Yoo N J, Kim H R, Kim Y R, An C H & Lee S H  (2012) Histopathology 60, 943–952

Somatic mutations of the KEAP1 gene in common solid cancers

Aims:  KEAP1 inhibits nuclear factor erythroid 2‐related factor 2 (NRF2)‐induced cytoprotection, and is considered to be a candidate tumour suppressor. Somatic mutation of NRF2 has been analysed in a wide variety of human cancers, whereas somatic mutation of KEAP1 has been reported only in lung and gall bladder cancers. The aim of our study was to investigate whether KEAP1 mutations are widespread in human cancers.

Methods and results:  We analysed 499 cancer tissues from lung, breast, colon, stomach, liver, larynx and prostate, and leukaemias, by single‐strand conformation polymorphism analysis. We detected somatic mutations of KEAP1 in gastric (11.1%), hepatocellular (8.9%), colorectal (7.8%), lung (4.6%), breast (2.0%) and prostate (1.3%) carcinomas. Allelic losses of the KEAP1 locus were identified in 42.9% of cancers with KEAP1 mutations, but no NRF2 mutations were detected in these cancers. The NRF2‐activated cytoprotective proteins (NAD(P)H dehydrogenase quinone 1 and glutamine‐cysteine ligase catalytic subunit) were expressed in all of the cancers with KEAP1 mutations.

Conclusions:  Our data show that KEAP1 mutations occur widely in solid cancers, irrespective of histological type. Biallelic inactivation of KEAP1 and increased levels of cytoprotective proteins in the cancers suggest that KEAP1 mutations might protect cancer cells from oxidative insults and play a role in the development of solid cancers.
Immune cell activation by trophoblast‐derived microvesicles is mediated by syncytin 1
Authors: Holder Beth S. , Tower Clare L. , Forbes Karen , Mulla Melissa J. , Aplin John D. , Abrahams Vikki M.
Published: February 2012

Envelope glycoproteins of human endogenous retrovirus (HERV), such as syncytin 1 (HERV‐W), are highly expressed in the placenta and some family members have immunomodulatory properties. Placental microvesicles (MV), which are shed into the maternal circulation during pregnancy, have been demonstrated to induce immune cell activation. Therefore, the aim of this study was to investigate the immunological properties of the highly expressed placental HERV‐W protein, syncytin 1, and its potential involvement in placental MV modulation of immune cell activity. The MV shed from first trimester, normal term and pre‐eclamptic term placentas, and from the BeWo trophoblast cell line, all contain syncytin 1. Recombinant syncytin 1 and syncytin 1‐positive BeWo trophoblast MV both induced peripheral blood mononuclear cell (PBMC) activation, indicated through production of cytokines and chemokines. Reducing syncytin 1 content in BeWo MV inhibited PBMC activation. Recombinant syncytin 1 and syncytin‐1‐positive BeWo MV dampened PBMC responses to lipopolysaccharide challenge. Our findings suggest that syncytin 1 is shed from the placenta into the maternal circulation in association with MV, and modulates immune cell activation and the responses of immune cells to subsequent lipopolysaccharide stimulation. These studies implicate placental MV‐associated HERV in fetal regulation of the maternal immune system.
Regulatory T‐cell therapy for inflammatory bowel disease: more questions than answers
Authors: Himmel Megan E. , Yao Yu , Orban Paul C. , Steiner Theodore S. , Levings Megan K.
Published: February 2012

T regulatory (Treg) cells are critical for maintaining immune homeostasis and establishing tolerance to foreign, non‐pathogenic antigens including those found in commensal bacteria and food. Because of their multiple suppressive mechanisms, Tregs represent a promising strategy for engineering tolerance to self and non‐self antigens in chronic inflammatory diseases. Already in clinical trials in the transplantation setting, the question remains whether this therapy would be effective for the treatment of mucosal inflammatory diseases that do not pose an immediate threat to life. In this review we will discuss evidence from both animal models and patients suggesting that Treg therapy would be beneficial in the context of inflammatory bowel disease (IBD). We will examine the role of T‐cell versus Treg dysfunction in IBD and discuss the putative antigens that could be potential targets of antigen‐directed Treg therapy. Finally, the challenges of using Treg therapy in IBD will be discussed, with a specific emphasis on the role that the microbiota may play in the outcome of this treatment. As Treg therapy becomes a bedside reality in the field of transplantation, there is great hope that it will soon also be deployed in the setting of IBD and ultimately prove more effective than the current non‐specific immunosuppressive therapies.
Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood
Authors: Fan Huahua , Yang Jie , Hao Jun , Ren Yana , Chen Liang , Li Guiping , Xie Rufeng , Yang Yiming , Gao Feng , Liu Mingyao
Published: February 2012

In this study, we expanded regulatory T cells (Tregs) ex vivo from CD4+ CD25+ T cells from cord blood (CB) and CD4+ CD25+ CD127− T cells from adult peripheral blood (APB) and compared the suppressive functions of the newly generated Tregs. The Tregs from CB and APB were expanded either in two cycles with a polyclonal stimulus or in two cycles with an alloantigen stimulus in the first cycle and a polyclonal stimulus in the second cycle. Cell yield after Treg expansion with polyclonal stimulation was greater than that of Tregs expanded with combined alloantigen and polyclonal stimulation. The expanded Tregs expressed high levels of Foxp3, CD39 and cytotoxic T‐lymphocyte antigen‐4 and low levels of CD127, interleukin‐2 and interferon‐γ. After two cycles of expansion, the CB Tregs maintained expression of the GARP gene and showed greater suppressive function than APB Tregs. The CB Tregs that were expanded with two cycles of polyclonal stimulation suppressed not only the polyclonal antigen‐driven responder T (Tresp) cell proliferation but also the HLA mismatched dendritic cell‐driven Tresp cell proliferation. When CB and APB Tregs were expanded with a primary alloantigen stimulus followed by a secondary polyclonal stimulus, the Tregs showed a potent, antigen‐specific suppressive capacity. The Tregs expanded with two cycles of polyclonal stimulation from both CB and APB alleviated acute graft‐versus‐host disease symptoms and prolonged survival in a murine model of graft‐versus‐host disease. In conclusion, CB Tregs expanded with two cycles of polyclonal stimulation had a stronger immunosuppressive function than APB Tregs. It is feasible to obtain human functional alloantigen‐specific Tregs expanded ex vivo from CB and APB in large numbers.
Disruption of the ESX‐5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation
Authors: Bottai Daria , Di Luca Mariagrazia , Majlessi Laleh , Frigui Wafa , Simeone Roxane , Sayes Fadel , Bitter Wilbert , Brennan Michael J. , Leclerc Claude , Batoni Giovanna , Campa Mario , Brosch Roland , Esin Semih
Published: February 2012

The chromosome of Mycobacterium tuberculosis encodes five type VII secretion systems (ESX‐1–ESX‐5). While the role of the ESX‐1 and ESX‐3 systems in M. tuberculosis has been elucidated, predictions for the function of the ESX‐5 system came from data obtained in Mycobacterium marinum, where it transports PPE and PE_PGRS proteins and modulates innate immune responses. To define the role of the ESX‐5 system in M. tuberculosis, in this study, we have constructed five M. tuberculosis H37Rv ESX‐5 knockout/deletion mutants, inactivating eccA5, eccD5, rv1794 and esxM genes or the ppe25‐pe19 region. Whereas the Mtbrv1794ko displayed no obvious phenotype, the other four mutants showed defects in secretion of the ESX‐5‐encoded EsxN and PPE41, a representative member of the large PPE protein family. Strikingly, the MtbeccD5ko mutant also showed enhanced sensitivity to detergents and hydrophilic antibiotics. When the virulence of the five mutants was evaluated, the MtbeccD5ko and MtbΔppe25‐pe19 mutants were found attenuated both in macrophages and in the severe combined immune‐deficient mouse infection model. Altogether these findings indicate an essential role of ESX‐5 for transport of PPE proteins, cell wall integrity and full virulence of M. tuberculosis, thereby opening interesting new perspectives for the study of this human pathogen.
Formation mechanism of the internal structure of type I protein bodies in rice endosperm: relationship between the localization of prolamin species and the expression of individual genes
Authors: Saito Yuhi , Shigemitsu Takanari , Yamasaki Ryuichi , Sasou Ai , Goto Futami , Kishida Koichi , Kuroda Masaharu , Tanaka Kunisuke , Morita Shigeto , Satoh Shigeru , Masumura Takehiro
Published: February 2012

Rice prolamins, a group of seed storage proteins, are synthesized on the rough endoplasmic reticulum (ER) and form type I protein bodies (PB‐Is) in endosperm cells. Rice prolamins are encoded by a multigene family. In this study, the spatial accumulation patterns of various prolamin species in rice endosperm cells were investigated to determine the mechanism of formation of the internal structure of PB‐Is. Immunofluorescence microscopic analysis of mature endosperm cells showed that the 10 kDa prolamin is mainly localized in the core of the PB‐Is, the 13b prolamin is localized in the inner layer surrounding the core and the outermost layer, and the 13a and 16 kDa prolamins are localized in the middle layer. Real‐time RT‐PCR analysis showed that expression of the mRNA for 10 kDa prolamin precedes expression of 13a, 13b‐1 and 16 kDa prolamin in the developing stages. mRNA expression for 13b‐2 prolamin occurred after that of the other prolamin species. Immunoelectron microscopy of developing seeds showed that the 10 kDa prolamin polypeptide initially accumulates in the ER, and then 13b, 13a, 16 kDa and 13b prolamins are stacked in layers within the ER. Studies with transgenic rice seeds expressing prolamin–GFP fusion proteins under the control of native and constitutive promoters indicated that the temporal expression pattern of prolamin genes influenced the localization of prolamin proteins within the PB‐Is. These findings indicate that the control of gene expression of prolamin species contributes to the internal structure of PB‐Is.
Impaired quality of life in adults and children with scabies from an impoverished community in Brazil
Authors: Worth Christine , Heukelbach Jorg , Fengler Gernot , Walter Birke , Liesenfeld Oliver , Feldmeier Hermann
Published: February 2012

Background  Scabies is highly prevalent in resource‐poor communities in developing countries and is associated with considerable morbidity in this setting. How the parasitic skin disease impairs the quality of life of patients has rarely been investigated.

Methodology  A modified Dermatology Life Quality Index (mDLQI) was developed to assess the quality of life in adults and children with scabies living in an urban slum in Fortaleza, capital of Ceará State, Brazil. A total of 105 patients with scabies (58 children and 57 adults) were included in the study. The diagnosis was made by dermatoscopy, skin scraping, and adhesive film test.

Results  Feelings of shame was the restriction most frequently noted (adults 77.2% and children 46.6%). Other types of quality of life impairment were the need to dress differently (35.1 vs. 29.3%), restriction on leisure activities (24.6 vs. 36.8%), social exclusion (24.6 vs. 17.9%), stigmatization (21.1 vs. 25.0%), teasing (only children: 26.3%), and problems with sexual partners (only adults: 10.9%). Women and girls perceived more restrictions than men and boys. mDLQI scores indicated that 13.9% of the patients noticed a large or very large effect on their life, 65.2% considered their quality of life lightly or moderately reduced by scabies, and 20.9% did not feel any restrictions. The degree of impairment increased parallel to the degree of itching and severity of scabies (P = 0.003).

Limitations  Owing to active case finding, most of the patients were in an early phase of scabies, and clinical pathology was not very pronounced.

Conclusion  Scabies considerably impaired the quality of life in adults and children living in poverty in an urban slum. Females particularly suffered from restrictions.
The cutaneous manifestations of metastatic malignant melanoma
Authors: Reed Kurtis B. , Cook‐Norris Robert H. , Brewer Jerry D.
Published: February 2012

Cutaneous metastases are common sequelae of primary malignant melanoma. Because patients with melanoma are examined frequently after diagnosis, it is important that dermatologists are aware of the range of findings that may represent metastatic disease. Many case reports and a few retrospective series have been published detailing the wide variety of clinical presentations of cutaneous metastatic melanoma. This article reviews the various manifestations of metastatic melanoma of the skin and oral mucous membranes and summarizes treatment options for metastatic disease.
Cryptosporidium enteritis in solid organ transplant recipients: multicenter retrospective evaluation of 10 cases reveals an association with elevated tacrolimus concentrations
Authors: Bonatti H. , Barroso II L.F. , Sawyer R.G. , Kotton C.N. , Sifri C.D.
Published: February 2012

Background

Cryptosporidial enteritis, a diarrheal infection of the small intestine caused by the apicomplexan protozoa Cryptosporidium, is infrequently recognized in transplant recipients from developed countries.

Methods

A retrospective review of all cases of cryptosporidiosis in solid organ transplant (SOT) recipients at 2 centers from January 2001 to October 2010 was performed and compared with transplant recipients with community‐onset Clostridium difficile infection (CDI). A literature search was performed with regard to reported cases of cryptosporidiosis in SOT recipients.

Results

Eight renal, 1 liver, and 1 lung transplant recipient were diagnosed with cryptosporidiosis at median 46.0 months (interquartile range [IQR] 25.2–62.8) following SOT. Symptoms existed for a median 14 days (IQR 10.5–14.8) before diagnosis. For the 9 patients receiving tacrolimus (TAC), mean TAC levels increased from 6.3 ± 1.1 to 21.3 ± 9.2 ng/mL (P = 0.0007) and median serum creatinine increased temporarily from 1.3 (IQR 1.1–1.7) to 2.4 (IQR 2.0–4.6) mg/dL (P = 0.008). By comparison, 8 SOT recipients (6 kidney, 2 liver) hospitalized with community‐onset CDI had a mean TAC level of 10.8 ± 2.8 ng/dL during disease compared with 9.2 ± 2.3 ng/mL at baseline (P = 0.07) and had no change in median creatinine. All patients recovered from Cryptosporidium enteritis after receiving various chemotherapeutic regimens.

Conclusions

Cryptosporidiosis should be recognized as an important cause of diarrhea after SOT and is associated with elevated TAC levels and acute kidney injury. Increased TAC levels may reflect altered drug metabolism in the small intestine.
A new AQP1 null allele identified in a Gypsy woman who developed an anti‐CO3 during her first pregnancy
Authors: Saison C. , Peyrard T. , Landre C. , Ballif B. A. , Schlosser K. A. , Dettori I. , Chicheportiche C. , Nemeth P. , Cartron J.‐P. , Arnaud L.
Published: February 2012

Background and objectives  The Colton blood group antigens are carried by the AQP1 water channel. AQP1‐/‐ individuals, also known as Colton‐null since they express no Colton antigens, do not suffer any apparent clinical consequence but may develop a clinically significant alloantibody (anti‐CO3) induced by transfusion or pregnancy. Identification and transfusion support of Colton‐null patients are highly challenging, not only due to the extreme rarity of this phenotype, the lack of appropriate reagents in most laboratories, as well as the possibility of confusing it with the recently described CO:‐1,‐2,3,‐4 phenotype where AQP1 is present. This study investigated a new Colton‐null case and evaluated three commercially available anti‐AQP1s to identify Colton‐null red blood cell samples.

Methods  The Colton‐null phenotype was investigated by standard serological techniques, AQP1 sequencing, immunoblot and flow cytometry analyses.

Results  We identified and characterized the Colton‐null phenotype in a Gypsy woman who developed an anti‐CO3 during her first pregnancy. After developing a simple and robust method to sequence AQP1, we showed that she was apparently homozygous for a new AQP1 null allele, AQP1 601delG, whose product is not expressed in her red blood cells. We also established the Colton specificity of three commercially available anti‐AQP1s in immunoblot and/or flow cytometry analyses.

Conclusion  This Gypsy woman represents the sixth Colton‐null case characterized at the serological, genetic and biochemical levels. The validation here of new reagents and methods should facilitate the identification of Colton‐null individuals.
Regrowth of black hair in two red‐haired alopecia areata patients
Authors: Ramot Yuval , Sinclair Rodney D , Zlotogorski Abraham
Published: February 2012

The occurrence of alopecia areata (AA) in a red‐haired individual is considered to be rare. We report two cases of red‐haired men who were afflicted with patch‐type AA. Astonishingly, the hair regrowth was coloured black, in contrast to the surrounding red hair, an event which has been reported only once in the past after cyclophosphamide administration. This phenomenon raises some interesting questions regarding the significance of pigmentation and the melanocortin‐1 receptor in AA pathogenesis.
Improving partnerships with families and carers in in‐patient mental health services for older people: a staff training programme and family liaison service
Authors: Stanbridge Roger I. , Burbach Frank R. , Rapsey Estelle H.S. , Leftwich Simon H. , McIver Catherine C.
Published: February 2012

In spite of policies advocating the involvement of families in the care of mental health service users in the UK, there are few examples of initiatives to develop staff confidence and skills in partnership working. This article describes a whole team training initiative and family liaison service to promote family inclusive working on in‐patient wards for older people in Somerset, UK. A three‐day staff‐training programme is described and training outcomes are reported. Staff report a substantial increase in confidence and family meetings held. A pre‐and post‐ training case note audit shows increased consideration of the needs of families. To further increase face to face meetings with families a family liaison service has been established, whereby a staff member with systemic family therapy training joins ward staff to hold family meetings as part of the assessment/admission process. Evaluation of this service has shown it to be effective with positive feedback from families and staff.
Earnings Distribution and Labour Supply after a Retirement Earnings Test Reform*
Authors: HernæS Erik , Jia Zhiyang
Published: February 2012

Norwegian administrative data are used to evaluate the impact of a doubling of the threshold in the retirement earnings test. We find almost no impact on the extensive margin, but a positive effect on the intensive margin. This positive effect is uneven over the earnings distribution, and concentrated on workers around the threshold, increasing with exposure to the reform and leading to a decrease in earnings inequality. Individuals who remain active until retirement age respond more to the reform. Conditional on prereform earnings, we find little evidence that individual characteristics such as working histories influence the responsiveness to the reform.
Late‐onset alopecia areata: A retrospective study of 73 patients from Taiwan
Authors: Wu M.C. , Yang C.‐C. , Tsai R.Y. , Chen W.C.
Published: February 2012

Background  Alopecia areata (AA) is regarded to be mediated by autoimmune process, and manifests as patchy non‐scarring hair loss with occult onset. Little is known about AA occurring later in life.

Objective  To define the characteristics of late‐onset AA.

Methods  Patients with first onset of AA at age 50 years and above were retrospectively recruited from two separate institutes in southern and northern Taiwan. The onset age, patterns, severity, past history, serological findings and therapeutic responses were reviewed.

Results  Seventy‐three AA patients were enrolled, including 49 females (67%) and 24 males (33%). The onset age ranged from 50–78 years with the median age of 57 years. Multifocal lesions (41%) constituted the most common pattern and 55% of the recruited patients had a hair loss of less than 10%. Seventeen patients (23%) had co‐existent dermatological or systemic diseases while six patients (8%) had a history of malignancy. Among 27 patients (37%) with available laboratory data, positive anti‐nuclear antibody, anti‐microsomal antibody and anti‐thyroglobulin antibody was demonstrated in 26%, 40% and 30% of them, respectively. Association with personal or family history of atopy was absent. In 15 patients of follow‐up longer than 6 months, a complete hair regrowth was found in three patients with mild disease severity.

Conclusion  Late‐onset AA is characterized by marked female predominance and milder disease activity with increasing age. The link to cancer in the old age remains to be determined. The influence of aging on the pathogenesis and prognosis of AA deserves further studies.