bluuebunny/crossref_metadata_2025 huggingface dataset:
HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment
Authors: Corzo Cesar A. , Condamine Thomas , Lu Lily , Cotter Matthew J. , Youn Je-In , Cheng Pingyan , Cho Hyun-Il , Celis Esteban , Quiceno David G. , Padhya Tapan , McCaffrey Thomas V. , McCaffrey Judith C. , Gabrilovich Dmitry I.
Published: September 2010

Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8+ T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate–oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment.
Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway
Authors: Grainger John R. , Smith Katie A. , Hewitson James P. , McSorley Henry J. , Harcus Yvonne , Filbey Kara J. , Finney Constance A.M. , Greenwood Edward J.D. , Knox David P. , Wilson Mark S. , Belkaid Yasmine , Rudensky Alexander Y. , Maizels Rick M.
Published: September 2010

Foxp3-expressing regulatory T (T reg) cells have been implicated in parasite-driven inhibition of host immunity during chronic infection. We addressed whether parasites can directly induce T reg cells. Foxp3 expression was stimulated in naive Foxp3− T cells in mice infected with the intestinal helminth Heligmosomoides polygyrus. In vitro, parasite-secreted proteins (termed H. polygyrus excretory-secretory antigen [HES]) induced de novo Foxp3 expression in fluorescence-sorted Foxp3− splenocytes from Foxp3–green fluorescent protein reporter mice. HES-induced T reg cells suppressed both in vitro effector cell proliferation and in vivo allergic airway inflammation. HES ligated the transforming growth factor (TGF) β receptor and promoted Smad2/3 phosphorylation. Foxp3 induction by HES was lost in dominant-negative TGF-βRII cells and was abolished by the TGF-β signaling inhibitor SB431542. This inhibitor also reduced worm burdens in H. polygyrus–infected mice. HES induced IL-17 in the presence of IL-6 but did not promote Th1 or Th2 development under any conditions. Importantly, antibody to mammalian TGF-β did not recognize HES, whereas antisera that inhibited HES did not affect TGF-β. Foxp3 was also induced by secreted products of Teladorsagia circumcincta, a related nematode which is widespread in ruminant animals. We have therefore identified a novel pathway through which helminth parasites may stimulate T reg cells, which is likely to be a key part of the parasite’s immunological relationship with the host.
Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma
Authors: Byun Minji , Abhyankar Avinash , Lelarge Virginie , Plancoulaine Sabine , Palanduz Ayse , Telhan Leyla , Boisson Bertrand , Picard Capucine , Dewell Scott , Zhao Connie , Jouanguy Emmanuelle , Feske Stefan , Abel Laurent , Casanova Jean-Laurent
Published: September 2010

Classic Kaposi sarcoma (KS) is exceedingly rare in children from the Mediterranean Basin, despite the high prevalence of human herpesvirus-8 (HHV-8) infection in this region. We hypothesized that rare single-gene inborn errors of immunity to HHV-8 may underlie classic KS in childhood. We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age. Whole-exome sequencing in the patient revealed a homozygous splice-site mutation in STIM1, the gene encoding stromal interaction molecule 1, which regulates store-operated Ca2+ entry. STIM1 mRNA splicing, protein production, and Ca2+ influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1. Based on the previous discovery of STIM1 deficiency in a single family with a severe T cell immunodeficiency and the much higher risk of KS in individuals with acquired T cell deficiencies, we conclude that STIM1 T cell deficiency precipitated the development of lethal KS in this child upon infection with HHV-8. Our report provides the first evidence that isolated classic KS in childhood may result from single-gene defects and provides proof-of-principle that whole-exome sequencing in single patients can decipher the genetic basis of rare inborn errors.
Deficiency in Silicon Uptake Affects Cytological, Physiological, and Biochemical Events in the Rice–Bipolaris oryzae Interaction
Authors: Dallagnol Leandro J. , Rodrigues Fabrício A. , DaMatta Fábio M. , Mielli Mateus V. B. , Pereira Sandra C.
Published: September 2010

This study investigated how a defect in the active uptake of silicon (Si) affects rice resistance to brown spot. Plants from a rice mutant (low silicon 1 [lsi1]) and its wild-type counterpart (cv. Oochikara), growing in hydroponic culture with (+Si; 2 mM) or without (–Si) Si, were inoculated with Bipolaris oryzae. Si concentration in leaf tissue of cv. Oochikara and the lsi1 mutant increased by 381 and 263%, respectively, for the +Si treatment compared with the –Si treatment. The incubation period was 6 h longer in the presence of Si. The area under brown spot progress curve for plants from cv. Oochikara and the lsi1 mutant was reduced 81 and 50%, respectively, in the presence of Si. The reduced number of brown epidermal cells on leaves from cv. Oochikara and the lsi1 mutant supplied with Si contributed to the lower lipid peroxidation and electrolyte leakage. The concentration of total soluble phenolics in cv. Oochikara supplied with Si (values of 4.2 to 15.4 μg g–1 fresh weight) was greater compared with plants not supplied with Si (values of 1.9 to 11.5 μg g–1 fresh weight). The concentration of lignin was also important to the resistance of cv. Oochikara and the lsi1 mutant. Polyphenoloxidase activity did not contribute to the resistance of cv. Oochikara and the lsi1 mutant to brown spot, regardless of Si supply. Peroxidase and chitinase activities were higher in cv. Oochikara and the lsi1 mutant supplied with Si. These results bring novel evidence of the involvement of Si in a more complex defense mechanism than simply the formation of a physical barrier to avoid or delay fungal penetration.
Cellulase Activity as a Mechanism for Suppression of Phytophthora Root Rot in Mulches
Authors: Richter Brantlee Spakes , Ivors Kelly , Shi Wei , Benson D. M.
Published: September 2010

Wood-based mulches are used in avocado production and are being tested on Fraser fir for reduction of Phytophthora root rot, caused by Phytophthora cinnamomi. Research with avocado has suggested a role of microbial cellulase enzymes in pathogen suppression through effects on the cellulosic cell walls of Phytophthora. This work was conducted to determine whether cellulase activity could account for disease suppression in mulch systems. A standard curve was developed to correlate cellulase activity in mulches with concentrations of a cellulase product. Based on this curve, cellulase activity in mulch samples was equivalent to a cellulase enzyme concentration of 25 U ml–1 or greater of product. Sustained exposure of P. cinnamomi to cellulase at 10 to 50 U ml–1 significantly reduced sporangia production, but biomass was only reduced with concentrations over 100 U ml–1. In a lupine bioassay, cellulase was applied to infested soil at 100 or 1,000 U ml–1 with three timings. Cellulase activity diminished by 47% between 1 and 15 days after application. Cellulase applied at 100 U ml–1 2 weeks before planting yielded activity of 20.08 μmol glucose equivalents per gram of soil water (GE g–1 aq) at planting, a level equivalent to mulch samples. Cellulase activity at planting ranged from 3.35 to 48.67 μmol GE g–1 aq, but no treatment significantly affected disease progress. Based on in vitro assays, cellulase activity in mulch was sufficient to impair sporangia production of P. cinnamomi, but not always sufficient to impact vegetative biomass.
Mapping Quantitative Trait Loci for Resistance to Rice Blast
Authors: Jia Y. , Liu G.
Published: September 2010

Quantitative trait loci (QTLs) conferring resistance to rice blast, caused by Magnaporthe oryzae, have been under-explored. In the present study, composite interval mapping was used to identify the QTLs that condition resistance to the 6 out of the 12 common races (IB1, IB45, IB49, IB54, IC17, and ID1) of M. oryzae using a recombinant inbred line (RIL) population derived from a cross of the moderately susceptible japonica cultivar Lemont with the moderately resistant indica cultivar Jasmine 85. Disease reactions of 227 F7 RILs were determined using a category scale of ratings from 0, representing the most resistant, to 5, representing the most susceptible. A total of nine QTLs responsive to different degrees of phenotypic variation ranging from 5.17 to 26.53% were mapped on chromosomes 3, 8, 9, 11, and 12: qBLAST3 at 1.9 centimorgans (cM) to simple sequence repeat (SSR) marker RM282 on chromosome 3 to IB45 accounting for 5.17%; qBLAST8.1 co-segregated with SSR marker RM1148 to IB49 accounting for 6.69%, qBLAST8.2 at 0.1 cM to SSR marker RM72 to IC17 on chromosome 8 accounting for 7.22%; qBLAST9.1 at 0.1 cM to SSR marker RM257 to IB54, qBLAST9.2 at 2.1 cM to SSR marker RM108, and qBLAST9.3 at 0.1 cM to SSR marker RM215 to IC17 on chromosome 9 accounting for 4.64, 7.62, and 4.49%; qBLAST11 at 2.2 cM to SSR marker RM244 to IB45 and IB54 on chromosome 11 accounting for 26.53 and 19.60%; qBLAST12.1 at 0.3 cM to SSR marker OSM89 to IB1 on chromosome 12 accounting for 5.44%; and qBLAST12.2 at 0.3 and 0.1 cM to SSR marker OSM89 to IB49 and ID1 on chromosome 12 accounting for 9.7 and 10.18% of phenotypic variation, respectively. This study demonstrates the usefulness of tagging blast QTLs using physiological races by composite interval mapping.
Neurofibromatosis-1 regulates neuroglial progenitor proliferation and glial differentiation in a brain region-specific manner
Authors: Lee Da Yong , Yeh Tu-Hsueh , Emnett Ryan J. , White Crystal R. , Gutmann David H.
Published: September 2010

Recent studies have shown that neuroglial progenitor/stem cells (NSCs) from different brain regions exhibit varying capacities for self-renewal and differentiation. In this study, we used neurofibromatosis-1 (NF1) as a model system to elucidate a novel molecular mechanism underlying brain region-specific NSC functional heterogeneity. We demonstrate thatNf1loss leads to increased NSC proliferation and gliogenesis in the brainstem, but not in the cortex. UsingNf1genetically engineered mice and derivative NSC neurosphere cultures, we show that this brain region-specific increase in NSC proliferation and gliogenesis results from selective Akt hyperactivation. The molecular basis for the increased brainstem-specific Akt activation in brainstem NSCs is the consequence of differential rictor expression, leading to region-specific mammalian target of rapamycin (mTOR)/rictor-mediated Akt phosphorylation and Akt-regulated p27 phosphorylation. Collectively, these findings establish mTOR/rictor-mediated Akt activation as a key driver of NSC proliferation and gliogenesis, and identify a unique mechanism for conferring brain region-specific responses to cancer-causing genetic changes.
Impact of predatory threat on fear extinction in Lewis rats
Authors: Goswami Sonal , Cascardi Michele , Rodríguez-Sierra Olga E. , Duvarci Sevil , Paré Denis
Published: September 2010

Humans with post-traumatic stress disorder (PTSD) are deficient at extinguishing conditioned fear responses. A study of identical twins concluded that this extinction deficit does not predate trauma but develops as a result of trauma. The present study tested whether the Lewis rat model of PTSD reproduces these features of the human syndrome. Lewis rats were subjected to classical auditory fear conditioning before or after exposure to a predatory threat that mimics a type of traumatic stress that leads to PTSD in humans. Exploratory behavior on the elevated plus maze 1 wk after predatory threat exposure was used to distinguish resilient vs. PTSD-like rats. Properties of extinction varied depending on whether fear conditioning and extinction occurred before or after predatory threat. When fear conditioning was carried out after predatory threat, PTSD-like rats showed a marked extinction deficit compared with resilient rats. In contrast, no differences were seen between resilient and PTSD-like rats when fear conditioning and extinction occurred prior to predatory threat. These findings in Lewis rats closely match the results seen in humans with PTSD, thereby suggesting that studies comparing neuronal interactions in resilient vs. at-risk Lewis rats might shed light on the causes and pathophysiology of human PTSD.
Ethylene Suppression of Sugar-Induced Anthocyanin Pigmentation in Arabidopsis
Authors: Jeong Seok-Won , Das Prasanta Kumar , Jeoung Sae Chae , Song Ji-Young , Lee Hyun Kyoung , Kim Yeon-Ki , Kim Woo Jung , Park Yong Il , Yoo Sang-Dong , Choi Sang-Bong , Choi Giltsu , Park Youn-Il
Published: September 2010

Anthocyanin accumulation is regulated negatively by ethylene signaling and positively by sugar and light signaling. However, the antagonistic interactions underlying these signalings remain to be elucidated fully. We show that ethylene inhibits anthocyanin accumulation induced by sucrose (Suc) and light by suppressing the expression of transcription factors that positively regulate anthocyanin biosynthesis, including GLABRA3, TRANSPARENT TESTA8, and PRODUCTION OF ANTHOCYANIN PIGMENT1, while stimulating the concomitant expression of the negative R3-MYB regulator MYBL2. Genetic analyses show that the ethylene-mediated suppression of anthocyanin accumulation is dependent upon ethylene signaling components responsible for the triple response. Furthermore, these positive and negative signaling pathways appear to be under photosynthetic control. Suc and light induction of anthocyanin accumulation was almost fully inhibited in wild-type Arabidopsis (Arabidopsis thaliana) ecotype Columbia and ethylene (ethylene response1 [etr1-1]) and light (long hypocotyl1 [hy1], cryptochrome1/2, and hy5) signaling mutants treated with the photosynthetic electron transport inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea. The transcript level of the sugar transporter gene SUC1 was enhanced in ecotype Columbia treated with the ethylene-binding inhibitor silver and in etr1-1, ethylene insensitive2 (ein2-1), and ein3 ein3-like1 mutants. In contrast, 3-(3,4-dichlorophenyl)-1,1-dimethylurea treatment reduced SUC1 expression, which indicates strongly that SUC1 represents an integrator for signals provided by sugar, light, and ethylene. SUC1 mutations lowered accumulations of anthocyanin pigment, soluble sugar content, and ethylene production in response to Suc and light signals. These data demonstrate that the suppression of SUC1 expression by ethylene inhibits Suc-induced anthocyanin accumulation in the presence of light and, hence, fine-tunes anthocyanin homeostasis.
Identification of Tyrosyl-DNA Phosphodiesterase as a Novel DNA Damage Repair Enzyme in Arabidopsis
Authors: Lee So-Young , Kim Hoyeun , Hwang Hyun-Ju , Jeong Young-Min , Na Sang Hyeon , Woo Je-Chang , Kim Sang-Gu
Published: September 2010

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a key enzyme that hydrolyzes the phosphodiester bond between tyrosine of topoisomerase and 3′-phosphate of DNA and repairs topoisomerase-mediated DNA damage during chromosome metabolism. However, functional Tdp1 has only been described in yeast and human to date. In human, mutations of the Tdp1 gene are involved in the disease spinocerebellar ataxia with axonal neuropathy. In plants, we have identified the functional nuclear protein AtTDP, homolog to human Tdp1 from Arabidopsis (Arabidopsis thaliana). The recombinant AtTDP protein certainly hydrolyzes the 3′-phosphotyrosyl DNA substrates related to repairing in vivo topoisomerase I-DNA-induced damage. The loss-of-function AtTDP mutation displays developmental defects and dwarf phenotype in Arabidopsis. This phenotype is substantially caused by decreased cell numbers without any change of individual cell sizes. The tdp plants exhibit hypersensitivities to camptothecin, a potent topoisomerase I inhibitor, and show rigorous cell death in cotyledons and rosette leaves, suggesting the failure of DNA damage repair in tdp mutants. These results indicate that AtTDP plays a clear role in the repair of topoisomerase I-DNA complexes in Arabidopsis.
Cytotoxic immunological synapses
Authors: Dustin Michael L. , Long Eric O.
Published: September 2010

Summary:  One of the most fundamental activities of the adaptive immune system is to kill infected cells and tumor cells. Two distinct pathways mediate this process, both of which are facilitated by a cytotoxic immunological synapse. While traditionally thought of as innate immune cells, natural killer (NK) cells are now appreciated to have the capacity for long‐term adaptation to chemical and viral insults. These cells integrate multiple positive and negative signals through NK cell cytotoxic or inhibitory synapses. The traditional CD8+αβ T‐cell receptor‐positive cells are among the best models for the concept of an immunological synapse, in which vectoral signaling is linked to directed secretion in a stable interface to induce apoptotic cell death in an infected cell. Large‐scale molecular organization in synapses generated a number of hypotheses. Studies in the past 5 years have started to provide clear answers regarding the validity of these models. In vivo imaging approaches have provided some hints as to the physiologic relevance of these processes with great promise for the future. This review provides an overview of work on cytotoxic immunological synapses and suggests pathways forward in applying this information to the development of therapeutic agents.
Two cases of mycosis fungoides treated by reduced‐intensity cord blood transplantation
Authors: TSUJI Hitomi , WADA Takashi , MURAKAMI Masamoto , KASHIWAGI Takayuki , ITO Yasuhiro , ISHIDA‐YAMAMOTO Akemi , JIMBO Junko , SHINDO Motohiro , SATO Kazuya , KOHGO Yutaka , IIZUKA Hajime
Published: September 2010

Mycosis fungoides is a cutaneous T‐cell lymphoma, which is clinically divided into three stages: patch, plaque and tumor. Despite a variety of treatments the prognosis is poor in advanced mycosis fungoides. Recently, allogeneic hematopoietic stem cell transplantation has been successfully applied for such cases. We performed reduced‐intensity umbilical cord blood transplantation for two advanced mycosis fungoides patients. Case 1 was a 56‐year‐old man and case 2 was a 30‐year‐old woman. Tumors of each case were refractory to conventional chemotherapy. Although radiation therapy was considerably effective, tumors relapsed after several months. Reduced‐intensity umbilical cord blood transplantation was performed because case 1 had no human leukocyte antigen‐identical siblings and the sibling of case 2 did not agree to be the donor. The male patient died of pulmonary failure 23 days after reduced‐intensity umbilical cord blood transplantation. The case 2 patient succeeded in reduced‐intensity umbilical cord blood transplantation and remained in complete/partial remission for 13 months. However, chemotherapy‐resistant tumors relapsed, and allogeneic hematopoietic stem cell transplantation was performed at 17 months. She died of cerebral hemorrhage 23 days after the procedure. Reduced‐intensity umbilical cord blood transplantation may be included in the treatments for advanced mycosis fungoides, where graft‐versus‐lymphoma effect seems to be a significant factor for the success of the treatment.
Primary cutaneous γδ‐T‐cell lymphoma treated with low‐dose methotrexate and narrowband ultraviolet B irradiation: Report of a case with testicular involvement
Authors: FUJII Mizue , UEHARA Jiro , HONMA Masaru , ITO Yasuhiro , TAKAHASHI Hidetoshi , ISHIDA‐YAMAMOTO Akemi , IIZUKA Hajime
Published: September 2010

Primary cutaneous γδ‐T‐cell lymphoma (CGD‐TCL) is a rare entity of cutaneous T‐cell lymphomas (CTCL) and is characterized by tumoral growth of mature γδ‐T‐cell expressing cytotoxic molecules. The prognosis of CGD‐TCL is generally worse than other CTCL. However, relatively indolent patch/plaque lesions have been described suggesting the heterogeneous nature of this entity. Here, we present a case of CGD‐TCL with various skin manifestations, such as erythematous plaques/tumors and subcutaneous panniculitis‐like lesions. During the follow up, testicular involvement was detected, which was surgically removed. Histopathology showed mixed features from epidermotropism, dermal infiltration and subcutaneous panniculitis‐like lesions depending on the clinical manifestations. The tumor cells were positive for CD3 and revealed cytotoxic markers, TIA‐1 and perforin, but not for CD4, CD8, CD20, CD56, TCRβF1 or EBER. Topical glucocorticoid ointment, narrowband ultraviolet B (NB‐UVB) irradiation and low‐dose methotrexate (MTX) were effective to control these skin lesions. No visceral involvement was detected thereafter. While CGD‐TCL is usually associated with poor prognosis, it seems to be composed of various clinical manifestations, and NB‐UVB and low‐dose MTX could be a choice for indolent patch/plaque and possibly nodular lesions, especially for the aged.
Immunogenetics features and genomic lesions in splenic marginal zone lymphoma
Authors: Rinaldi Andrea , Forconi Francesco , Arcaini Luca , Mian Michael , Sozzi Elena , Zibellini Silvia , Baldini Luca , Franceschetti Silvia , Gaidano Gianluca , Marasca Roberto , Mollejo Manuela , Piris Miguel A. , Tucci Alessandra , Facchetti Fabio , Bhagat Govind , Favera Riccardo D. , Rancoita Paola M. V. , Zucca Emanuele , Kwee Ivo , Bertoni Francesco
Published: September 2010

Splenic marginal zone lymphomas (MZL) express mutated (M−) or unmutated (U−) immunoglobulin heavy chain (IGHV) genes. To investigate the IGHV mutational status impact on genetic lesions, this study combined single nucleotide polymorphism‐arrays and IGHV sequencing in 83 cases. Clinical features and outcome were similar between U‐ and M‐IGHV cases. Recurrent lesions frequency was higher in U‐IGHV cases, including poor prognosticators. Frequencies differed among cases bearing individual IGHV genes or lambda light chains. In conclusion, SMZL comprises subgroups based on genetic abnormalities and immunogenetic status. Genomic lesion frequency differed and was higher in U‐IGHV cases, possibly affecting the outcome.
Lidocaine‐derivative JMF2‐1 prevents ovalbumin‐induced airway inflammation by regulating the function and survival of T cells
Authors: Olsen P. C. , Ferreira T. P. T. , Serra M. F. , Farias‐Filho F. A. , Fonseca B. P. , Viola J. P. B. , Cordeiro R. S. B. , Silva P. M. R. , Costa J. C. S. , Martins M. A.
Published: September 2010

Cite this as: P. C. Olsen, T. P. T. Ferreira, M. F. Serra, F. A. Farias‐Filho, B. P. Fonseca, J. P. B. Viola, R. S. B. Cordeiro, P. M. R. Silva, J. C. S. Costa and M. A. Martins, Clinical & Experimental Allergy, 2011 (41) 250–259.

Background
Inhalation of the local anaesthetic lidocaine has been suggested to be beneficial for asthmatics, but airway anaesthesia is unpleasant and may exacerbate bronchoconstriction. Our previous study showed that inhalation of the lidocaine analogue JMF2‐1 can elicit the anti‐inflammatory properties of lidocaine without anaesthesia. This prompted further research on the mechanism of action and putative therapeutic application of JMF2‐1.

Objective
We tested the hypothesis that JMF2‐1 would prevent allergen‐induced lung inflammation and airway hyperresponsiveness (AHR) by modulating T cell function in vivo and in vitro.

Methods
Local and systemic changes in leucocyte levels, cytokine production and lung mechanics were examined in a murine model of lung inflammation. JMF2‐1 (0.05–2%) or saline was aerosolized twice a day during the ovalbumin (OVA)‐provocation period (19–21 days post‐sensitization). Analyses were performed 24 h after the final challenge. Primary cultured lymph node cells were used to assess the effects of JMF2‐1 (100–600 μm) at the cellular level.

Results
OVA challenge resulted in lung recruitment of CD4+ T cells and eosinophils, increased generation of inflammatory cytokines and AHR to inhaled methacholine within 24 h. These changes were prevented by JMF2‐1 nebulization, and occurred in parallel with an increase in the number of apoptotic cells in the lung. JMF2‐1 treatment did not alter levels of CD4+ or CD8+ T cells in the thymus or lymph nodes of naïve mice, although it inhibited OVA‐induced IL‐13 production and the lymphocyte proliferative response in vitro. It also induced apoptosis of OVA‐activated lymphocytes in a mechanism sensitive to z‐VAD, indicating that JMF2‐1 mediates caspase‐dependent apoptosis.

Conclusion
Inhalation of JMF2‐1 prevents the cardinal features of asthma by reducing TH2 cytokine generation and lung eosinophilic inflammatory infiltrates via local inhibition of T cell function and survival. JMF2‐1 may represent a novel therapeutic alternative for asthma control with distinct advantages over local anaesthetics.
Plasma brain‐derived neurotrophic factor levels are associated with clinical severity in school age children with asthma
Authors: Müller G. C. , Pitrez P. M. , Teixeira A. L. , Pires P. S. , Jones M. H. , Stein R. T. , Bauer M. E.
Published: September 2010

Background
Asthma is characterized by chronic inflammation of the airways with significant changes in leucocyte trafficking, cellular activation and tissue remodelling. Brain‐derived neurotrophic factor (BDNF) has been involved with asthma and allergic diseases but its role as a severity marker in paediatric asthma has not been clinically assessed.

Objectives
To evaluate plasma BDNF and inflammatory markers in order to address their relationships with disease severity in children (6–15 years) with controlled persistent asthma.

Methods
Children with persistent asthma were selected and lung function and skin prick tests were performed in all patients. Plasma BDNF levels and various inflammatory markers (CCL3, CCL11, CCL22, CCL24, CXCL8, CXCL9, CXCL10, soluble TNF receptors) were assessed by ELISAs.

Results
Subjects with moderate and severe asthma had higher BDNF levels than mild asthma and controls (P<0.001). The chemokines studied and soluble TNF receptors did not differ between the studied groups.

Conclusion and Clinical Relevance
Our results indicate BDNF as a potential biomarker for clinical severity in children with asthma.

Cite this as: G. C. Müller, P. M. Pitrez, A. L. Teixeira, P. S. Pires, M. H. Jones, R. T. Stein and M. E. Bauer, Clinical & Experimental Allergy, 2010 (40) 1755–1759.
Evaluation of serum parathyroid hormone‐related peptide in hyperthyroid patients
Authors: Giovanella Luca , Suriano Sergio , Keller Franco , Borretta Giorgio , Ceriani Luca
Published: September 2010

Eur J Clin Invest 2010; 41 (1): 93–97

Background  Hypercalcemia occurs in 10–20% of patients with hyperthyroidism, but its pathogenesis is still unclear.

Aim  To evaluate changes in parathyroid hormone‐related peptide (PTH‐rP) concentration in hyperthyroid patients compared with healthy controls.

Methods  We studied PTH‐rP, parathormone (PTH) and ionized calcium levels in 153 hyperthyroid patients, and 89 control subjects. These variables were revaluated after attainment of euthyroidism with the antithyroid drug carbimazole for 6 months in a subgroup of 47 patients.

Results  Pretreatment PTH‐rP and ionized calcium level were significantly higher in hyperthyroid patients than in controls, whereas an opposite trend occurred for PTH. All parameters normalized after carbimazole therapy.

Conclusion  Untreated hyperthyroid patients exhibited a significant elevation in serum ionized calcium and PTH‐rP and a significant reduction in serum PTH levels when compared with healthy controls. Our data favoured the hypothesis of a direct involvement of PTH‐rP in the pathogenesis of hypercalcemia in hyperthyroid patients.
Are temporal variations of leaf traits responsible for seasonal and inter‐annual variability in ecosystem CO2 exchange?
Authors: Ma Siyan , Baldocchi Dennis D. , Mambelli Stefania , Dawson Todd E.
Published: September 2010

1. Seasonal and inter‐annual variability in ecosystem carbon dioxide (CO2) exchange is attributed to numerous climate drivers. However, climate effects on metabolism often override ecological functions. This study seeks insight into which biological and ecological processes influence temporal patterns of ecosystem productivity in natural ecosystems.

2. The specific objectives of this study are to (i) identify seasonal and inter‐annual patterns of ecosystem‐level photosynthesis in relation to climatic conditions, (ii) examine and compare seasonal and inter‐annual variations in leaf traits for annual grasses and oak trees across multiple years, and (iii) explore interactions among leaf traits and ecosystem‐level photosynthesis across multiple seasons and years.

3. We conducted this study in a woody savanna and open grassland in California, USA. Ecosystem‐level photosynthetic rates of annual grasses (Agrass) and oak tree canopy (Acanopy) were deduced from eddy covariance measurements over a 7‐year period (2001 and 2007). In conjunction, we sampled grass and oak leaves at weekly to monthly intervals and constructed a multi‐year time series of leaf nitrogen concentration (N), leaf mass per unit area (LMA), leaf carbon concentration (C), and leaf carbon stable isotope discrimination (Δ).

4. Given the same grass community age or tree canopy age, inter‐annual variations of the photosynthetic rates were up to 1–2 gC m−2 day−1 for annual grasses and oak trees while the two types of vegetation were exposed to different, wide ranges of inter‐annual climate fluctuations: up to 5 °C in daily mean soil temperature, 15% in soil moisture, and 10 mol m−2 day−1 in photosynthetically active radiation.

5. While both grass and oak leaf traits varied seasonally and inter‐annually, they experienced temporal patterns and seasonal peaks that were distinct from one another. Multi‐year means of grass leaf N, C, Δ, and LMA were 2·3%, 40·8%, 22·6‰ and 71·3 g m−2, respectively; multi‐year means of oak leaf N, C, Δ, and LMA were 1·9%, 45·1%, 20·5‰ and 132 g m−2, respectively.

6. Based on the analysis of variance, seasonal and inter‐annual terms were associated with Agrass or Acanopy up to 90% or 81%. On the other hand, variations in leaf N, LMA, C, Δ, and their interactions could statistically explain about 53% and 26% of variations in Agrass and Acanopy, respectively.

7. We discussed possible biological and ecological processes involved in regulating seasonal and inter‐annual variability in ecosystem‐level photosynthesis. Clearly, seasonal and inter‐annual variation in ecosystem photosynthesis was strongly associated with the dynamics of leaf traits.
Pancreatic intraepithelial neoplasia – can we detect early pancreatic cancer?
Authors: Haugk Beate
Published: September 2010

Haugk B (2010) Histopathology 57, 503–514 Pancreatic intraepithelial neoplasia – can we detect early pancreatic cancer?

Pancreatic cancer is one of the most lethal cancers, with an incidence equalling mortality. Pancreatic cancer is a heterogeneous group in which pancreatic ductal adenocarcinoma (PDAC) is the most common. It is now established that PDAC develops through stepwise progression from precursor lesions. Detection and treatment of these precursor lesions would allow curative treatment. Three precursor lesions for PDAC have been identified. Two of these – mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) – are rare, radiologically detectable, cystic precursor lesions which can be cured if treated at the preinvasive stage. The third and most common precursor lesion has recently been defined as pancreatic intraepithelial neoplasia (PanIN). PanINs are microscopic lesions with no clinical correlate. They display a spectrum of cyto‐architectural changes (PanIN‐1, PanIN‐2 and PanIN‐3) mirrored in an increasing accumulation of molecular genetic changes, with PanIN‐3 sharing many of the alterations with PDAC. Great advances in the understanding of pancreatic carcinogenesis have opened avenues for diagnosis and chemoprevention. However, access to the pancreas is limited, molecular tests are at the early stages and too little is known about the natural history of early PanINs to justify resection. Currently, screening focuses upon high‐risk individuals only.
Family demands, social support and caregiver burden in Taiwanese family caregivers living with mental illness: the role of family caregiver gender
Authors: Hsiao Chiu‐Yueh
Published: September 2010

Aim.  The purpose of this study was to assess gender effects on family demands, social support and caregiver burden as well as to examine contributing factors of caregiver burden in caring for family members with mental illness.

Background.  Providing continued care and support for people with mental illness is demanding and challenging. Findings of earlier caregiving studies on the role of caregiver gender in response to caregiver burden and caregiving‐related factors have been inconsistent. Little research has been undertaken to examine gender effect on family demands, social support and caregiver burden in Taiwanese family caregivers of individuals with mental illness.

Design.  Cross‐sectional, descriptive correlation design.

Methods.  Data from 43 families, including at least one male and female family caregiver in each family, were analysed using descriptive statistics, principal component analysis and mixed linear modelling. Demographic data, Perceived Stress Scale, Perceived Social Support and Caregiver Burden Scale‐Brief were used to collect data.

Results.  Female family caregivers perceived less social support and experienced higher degrees of caregiver burden compared with male family caregivers. In contrast, no significant gender effect was associated with family demands. Family caregivers with greater family demands and less social support experienced higher degrees of caregiver burden.

Conclusions.  The results reinforced those of previously published studies that caregiver burden is highly prevalent among female family caregivers. Caregiver gender appears to be highly valuable for explaining family demands, social support and caregiver burden.

Relevance to clinical practice.  Health care professionals should continue to collaborate with family caregivers to assess potential gender effects on available support and design gender‐specific interventions to alleviate caregiver burden.
A medication reconciliation form and its impact on the medical record in a paediatric hospital
Authors: Bédard Pascal , Tardif Lyne , Ferland Alexandre , Bussières Jean‐François , Lebel Denis , Bailey Benoit , Girard Marc , Lachaîne Jean
Published: September 2010

Objectives  The objective of this study was to evaluate the quality of medication information available in medical charts before and after the implementation of a medication reconciliation form.

Patients and methods  This study is a retrospective chart review of patients under 18 years who were taking two medications or more at home and were admitted to a paediatric hospital for more than 24 hours and discharged from a general paediatrics, infectious disease, gastroenterology or pneumology ward over two 20‐week periods (pre‐ and post‐implementation). Each week, 10 medical records were randomly chosen and reviewed. The quality of the medication information was measured on admission (dose, route of administration and frequency) and on discharge (dose, route of administration, frequency and duration of treatment). The proportion of medications that fully met these criteria was compared between the groups using the chi‐squared test.

Results  Information was analysed for a total of 3275 medications in the pre‐implementation group, vs. 3240 medications in the post‐implementation group. Baseline characteristics were similar in both groups. On admission, the quality of medication information was comparable between the pre‐ and post‐implementation groups (29.1 vs. 29.3%, respectively; P = 0.86). However, on discharge, an improvement in the quality of information was observed in the post‐implementation group (51.7 vs. 65.2%; P < 0.001).

Conclusion  Our study demonstrated that the forms used in the reconciliation process, in particular the discharge prescription, could increase the quality of the information related to drug use in medical charts. We believe that medication reconciliation forms should be widely used by all the health care professional teams involved in the drug history or prescription process.
Translation, adaptation and validation of instruments or scales for use in cross‐cultural health care research: a clear and user‐friendly guideline
Authors: Sousa Valmi D. , Rojjanasrirat Wilaiporn
Published: September 2010

Rationale, aims and objectives  The diversity of the population worldwide suggests a great need for cross‐culturally validated research instruments or scales. Researchers and clinicians must have access to reliable and valid measures of concepts of interest in their own cultures and languages to conduct cross‐cultural research and/or provide quality patient care. Although there are well‐established methodological approaches for translating, adapting and validating instruments or scales for use in cross‐cultural health care research, a great variation in the use of these approaches continues to prevail in the health care literature. Therefore, the objectives of this scholarly paper were to review published recommendations of cross‐cultural validation of instruments and scales, and to propose and present a clear and user‐friendly guideline for the translation, adaptation and validation of instruments or scales for cross‐cultural health care research.

Methods  A review of highly recommended methodological approaches to translation, adaptation and cross‐cultural validation of research instruments or scales was performed. Recommendations were summarized and incorporated into a seven‐step guideline. Each one of the steps was described and key points were highlighted. Example of a project using the proposed steps of the guideline was fully described.

Conclusions  Translation, adaptation and validation of instruments or scales for cross‐cultural research is very time‐consuming and requires careful planning and the adoption of rigorous methodological approaches to derive a reliable and valid measure of the concept of interest in the target population.
Adrenal incidentalomas and cardiometabolic morbidity: an emerging association with serious clinical implications
Authors: Peppa M. , Koliaki C. , Raptis S. A.
Published: September 2010

Abstract.  Peppa M, Koliaki C, Raptis SA (Athens University Medical School, Attikon University Hospital, Haidari, Athens; Hellenic National Diabetes Center for the Prevention, Research and Treatment of Diabetes Mellitus and its Complications (H.N.D.C), Athens, Greece). Adrenal incidentalomas and cardiometabolic morbidity: an emerging association with serious clinical implications (Review). J Intern Med 2010; 268: 555–566.

Adrenal incidentalomas (AIs) represent adrenal masses that are incidentally discovered whilst investigating symptoms and signs unrelated to adrenal pathology. The onset and natural course of AIs are unknown, and the possible underlying cardiometabolic abnormalities have not been examined in depth. A growing body of clinical and experimental evidence supports the notion that both functioning and, paradoxically, nonfunctioning AIs are associated with a partially expressed or even full‐blown metabolic syndrome (MS) phenotype, through yet unclear mechanisms. Subtle, subclinical or even profound adrenal hormone excess and an increased proinflammatory state might explain to some extent the development of MS disturbances. The emerging association between AIs and MS appears to be important in determining the optimal clinical management of these patients and raises speculation about the exact mechanisms of this interesting cause–effect relationship.
The case against customised birthweight standards
Authors: Hutcheon Jennifer A. , Zhang Xun , Platt Robert W. , Cnattingius Sven , Kramer Michael S.
Published: September 2010

Hutcheon JA, Zhang X, Platt RW, Cnattingius S, Kramer MS. The case against customised birthweight standards. Paediatric and Perinatal Epidemiology 2010.

Customised birthweight standards are widely recognised to improve the prediction of adverse perinatal outcomes compared with conventional birthweight‐for‐gestational‐age charts. However, their apparent benefits are more likely to have been derived from their incorporation of intrauterine‐based (EFW) reference values at preterm ages than their adjustment for maternal characteristics. Although maternal characteristics are able to explain population‐level differences in birthweight, they are not strong enough predictors for individual‐level prediction of birthweight. With maternal characteristics accounting for only a small per cent of the total factors influencing birthweight, the best estimate of an infant's birthweight remains close to the population average, explaining the ineffectiveness of adjusting for maternal characteristics. Given that customised percentiles are also unable to distinguish between pathological and physiological influences of maternal characteristics on birthweight, customising birthweight percentiles for maternal characteristics has little justification.
Cadmium uptake and sequestration kinetics in individual leaf cell protoplasts of the Cd/Zn hyperaccumulator Thlaspi caerulescens
Authors: LEITENMAIER BARBARA , KÜPPER HENDRIK
Published: September 2010

Hyperaccumulators store accumulated metals in the vacuoles of large leaf epidermal cells (storage cells). For investigating cadmium uptake, we incubated protoplasts obtained from leaves of Thlaspi caerulescens (Ganges ecotype) with a Cd‐specific fluorescent dye. A fluorescence kinetic microscope was used for selectively measuring Cd‐uptake and photosynthesis in different cell types, so that physical separation of cell types was not necessary. Few minutes after its addition, cadmium accumulated in the cytoplasm before its transport into the vacuole. This demonstrated that vacuolar sequestration is the rate‐limiting step in cadmium uptake into protoplasts of all leaf cell types. During accumulation in the cytoplasm, Cd‐rich vesicle‐like structures were observed. Cd uptake rates into epidermal storage cells were higher than into standard‐sized epidermal cells and mesophyll cells. This shows that the preferential heavy metal accumulation in epidermal storage cells, previously observed for several metals in intact leaves of various hyperaccumulator species, is due to differences in active metal transport and not differences in passive mechanisms like transpiration stream transport or cell wall adhesion. Combining this with previous studies, it seems likely that the transport steps over the plasma and tonoplast membranes of leaf epidermal storage cells are driving forces behind the hyperaccumulation phenotype.
Sarcoptes scabieivar.canisrefractory to ivermectin treatment in two dogs
Authors: Terada Yuri , Murayama Nobuo , Ikemura Hiroshi , Morita Tatsushi , Nagata Masahiko
Published: September 2010

A 10‐year‐old castrated male Shih Tzu presented with severe generalized pruritus. Skin scrapings revealed the presence ofSarcoptes scabieivar.canis. A Yorkshire terrier in the same household simultaneously developed pruritus due to scabies. Both dogs were treated with 300 μg/kg ivermectin, at first orally and then subcutaneously at 14 day intervals. However, live mites were still found on day 35, and the skin condition deteriorated in both dogs. These findings suggested that theS. scabieiin these dogs was clinically refractory to ivermectin. The pruritus in both dogs rapidly and completely disappeared following topical fipronil administration. This appears to be the first report of canine scabies refractory to ivermectin treatment.
Human leukocyte antigen (HLA) and single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)‐alpha ‐238 and ‐308 as genetic markers of susceptibility to psoriasis and severity of the disease in a long‐term follow‐up Brazilian study
Authors: Magalhães Renata Ferreira , Biral Ana Cristina , Pancoto João Alexandre Trés , Donadi Eduardo Antonio , Mendes‐Júnior Celso Texeira , Magna Luís Antonio , Kraemer Maria Helena
Published: September 2010

Background  The strongest genetic marker for psoriasis is Cw*06. Polymorphisms in the tumor necrosis factor (TNF)‐alpha promoter region, especially replacement of guanine with adenine in positions ‐238 and ‐308 are related to higher TNF‐alpha production and higher risk for psoriasis in Caucasoid populations, not found in Asians. We performed a case‐control study of 69 patients with psoriasis type I and 70 controls, characterized clinical progression along 10‐years of follow‐up in mild or severe disease and determined HLA class I, II, and TNF single nucleotide polymorphisms (SNPs) ‐238 and ‐308 polymorphisms to demonstrate whether these polymorphisms may be genetic risk for susceptibility to psoriasis or severity of the disease in Brazilians.

Methods  Polymorphisms were identified using PCR/SSP. Alleles, genotypes, and haplotypes frequencies were compared using Fisher’s test.

Results  More severe disease was found in male patients. It may be suggested that alleles B*37, Cw*06, Cw*12, and DRB1*07 were associated with severe disease course, while B*57 with mild disease. No statistical difference was found between the patients and controls regarding polymorphisms frequencies in TNF SNPs. This study pointed to a higher TNF‐238 G/G genotype frequency (OR: 3.21; CI: 1.06–9.71; P = 0.04) in the group with severe disease.

Conclusions  Polymorphisms in the TNF‐alpha SNPs do not seem to be a more important genetic risk factor for psoriasis than the already known Cw*06 in Brazilian patients, but these markers may be related to clinical manifestations.