bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular and plasma steady‐state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre‐treated HIV‐infected patients
Authors: Ter Heine Rob , Mulder Jan Willem , Van Gorp Eric C. M. , Wagenaar Jiri F. P. , Beijnen Jos H. , Huitema Alwin D. R.
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre‐treated for HIV‐infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents.

WHAT THIS STUDY ADDS

• We investigated the steady‐state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment.

AIM To study the steady‐state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre‐treated patients.

METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC‐MS/MS assay and pharmacokinetic analysis was performed using non‐linear mixed effect modelling.

RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l−1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%.

CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK–PD relationships in the therapeutic concentration range, when compared with other non‐nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI‐naive patients, but not in patients with HIV harbouring PI resistance.
Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients
Authors: Ruf Peter , Kluge Michael , Jäger Michael , Burges Alexander , Volovat Constantin , Heiss Markus Maria , Hess Jürgen , Wimberger Pauline , Brandt Birgit , Lindhofer Horst
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The trifunctional antibody catumaxomab is a highly effective anti‐cancer therapeutic that is administered to patients suffering from malignant ascites intraperitoneally (i.p.) in microgram (µg) doses. So far, no clinical pharmacokinetic data are available.

WHAT THIS STUDY ADDS

• Catumaxomab attains effective local concentrations in the ascites fluid and shows low systemic exposure with an acceptable safety profile confirming the appropriateness of the i.p. application scheme.

AIMS Catumaxomab is the first EMEA approved trifunctional anti‐EpCAM×anti‐CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti‐drug antibody (ADA) development.

METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 µg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored.

RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml−1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (Cmax) of 403 pg ml−1. The mean elimination half‐life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter‐individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model.

CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate.
Detection of exhaled hydrogen sulphide gas in healthy human volunteers during intravenous administration of sodium sulphide
Authors: Toombs Christopher F. , Insko Michael A. , Wintner Edward A. , Deckwerth Thomas L. , Usansky Helen , Jamil Khurram , Goldstein Brahm , Cooreman Michael , Szabo Csaba
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Hydrogen sulphide (H2S) is a biological mediator and a potential therapeutic agent. In animal studies, the metabolism and pharmacokinetics of H2S have been characterized.

WHAT THIS STUDY ADDS

• This study is first to demonstrate the pharmacokinetics of an intravenously administered H2S formulation in humans, and to characterize the exhaled H2S response in humans.

INTRODUCTION Hydrogen sulphide (H2S) is an endogenous gaseous signaling molecule and potential therapeutic agent. Emerging studies indicate its therapeutic potential in a variety of cardiovascular diseases and in critical illness. Augmentation of endogenous sulphide concentrations by intravenous administration of sodium sulphide can be used for the delivery of H2S to the tissues. In the current study, we have measured H2S concentrations in the exhaled breath of healthy human volunteers subjected to increasing doses sodium sulphide in a human phase I safety and tolerability study.

METHODS We have measured reactive sulphide in the blood via ex vivo derivatization of sulphide with monobromobimane to form sulphide‐dibimane and blood concentrations of thiosulfate (major oxidative metabolite of sulphide) via ion chromatography. We have measured exhaled H2S concentrations using a custom‐made device based on a sulphide gas detector (Interscan).

RESULTS Administration of IK‐1001, a parenteral formulation of Na2S (0.005–0.20 mg kg−1, i.v., infused over 1 min) induced an elevation of blood sulphide and thiosulfate concentrations over baseline, which was observed within the first 1–5 min following administration of IK‐1001 at 0.10 mg kg−1 dose and higher. In all subjects, basal exhaled H2S was observed to be higher than the ambient concentration of H2S gas in room air, indicative of on‐going endogenous H2S production in human subjects. Upon intravenous administration of Na2S, a rapid elevation of exhaled H2S concentrations was observed. The amount of exhaled H2S rapidly decreased after discontinuation of the infusion of Na2S.

CONCLUSION Exhaled H2S represents a detectable route of elimination after parenteral administration of Na2S.
Correlates of spontaneous reporting of adverse drug reactions within primary care: the paradox of low prescribers who are high reporters
Authors: Cox Anthony R. , Anton Christopher , McDowell Sarah E. , Marriott John F. , Ferner Robin E.
Published: February 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Under‐reporting of adverse drug reactions to regulatory authorities is common, and there is concern about falling numbers of general practitioner reports.

• Although previous work has suggested high prescribers are less interested in pharmacovigilance, a recent examination of reporting to the Yellow Card scheme has suggested ADR reporting is correlated with high prescribing rates.

• This study aimed to examine influences on the reporting of ADRs to the Yellow Card scheme in primary care.

WHAT THIS STUDY ADDS

• High prescribing rates within primary care are correlated with low ADR reporting rates.

• Several Primary Care Trust characteristics related to general practitioners, such as increased proportions of single‐handed general practitioners and larger list sizes, are associated with low ADR reporting rates.

AIM(S) To examine Primary Care Trust (PCT) demographics influencing general practitioner (GP) involvement in pharmacovigilance.

METHODS PCT adverse drug reaction (ADR) reports to the Yellow Card scheme between April 2004 and March 2006 were obtained for the UK West Midlands region. Reports were analysed by all drugs, and most commonly reported drugs (‘top drugs’). PCT data, adjusted for population size, were aggregated. Prescribing statistics and other characteristics were obtained for each PCT, and associations between these characteristics and ADR reporting rates were examined.

RESULTS During 2004–06, 1175 reports were received from PCTs. Two hundred and eighty (24%) of these reports were for 14 ‘top drugs’. The mean rate of reporting for PCTs was 213 reports per million population. A total of 153 million items were prescribed during 2004–06, of which 33% were ‘top drugs’. Reports for all drugs and ‘top drugs’ were inversely correlated with the number of prescriptions issued per thousand population (rs=−0.413, 95% CI −0.673, −0.062, P < 0.05, and r=−0.420, 95% CI −0.678, −0.071, P < 0.05, respectively). Reporting was significantly negatively correlated with the percentages of male GPs within a PCT, GPs over 55 years of age, single‐handed GPs within a PCT, the average list size of a GP within a PCT, the overall deprivation scores and average QOF total points. ADR reports did not correlate significantly with the proportion of the population over 65 years old.

CONCLUSIONS Some PCT characteristics appear to be associated with low levels of ADR reporting. The association of low prescribing areas with high ADR reporting rates replicates previous findings.
Add‐on montelukast to inhaled corticosteroids protects against excessive airway narrowing
Authors: Ulrik C. S. , Diamant Z.
Published: February 2010

Rationale
Excessive airway narrowing in response to broncho‐active stimuli is a predictor for severe exacerbations in asthma. Leukotriene receptor antagonists (LTRAs) have complementary properties to inhaled corticosteroids (ICS) on asthma control.

Objectives
The LTRA montelukast may provide an additional protection against excessive airway narrowing. We tested the add‐on effects of montelukast on the maximal response plateau and PD20 to inhaled methacholine in asthmatics on a stable dose of ICS.

Methods
Thirty‐one patients with allergic asthma [14M/17F, 19–50 years, forced expiratory volume in 1 s (FEV1) >70% pred., PD20 <3.9 μmol methacholine], with a twice documented response plateau to methacholine, were randomized in a double‐blind (montelukast 10 mg or matching placebo once daily), 12‐week parallel study. Bronchoprovocation tests with methacholine (0.03–256 μmol or 40% decline in FEV1) were repeated every 4 weeks and after wash‐out. The main study objectives were changes from baseline in maximal FEV1 decline at the response plateau (i.e. >2 post‐dose FEV1 values within 5%) and PD20 to methacholine after 12 weeks' treatment.

Results
Neither treatment affected baseline FEV1 (P=0.62). Compared with placebo, montelukast significantly decreased the maximal response plateau to methacholine (mean difference 9.4%; 95% confidence interval 3.9–15.7; P<0.005), improved the FEV1 decline (mean change in FEV1 decline was 2.1% [montelukast] and −0.8% [placebo], respectively, P<0.05), and increased PD20 methacholine (mean change in PD20 of 5.3 [montelukast] and 1.4 [placebo] doubling doses, respectively, P<0.001).

Conclusion
Add‐on montelukast to ICS has disease‐modifying effects in adults with persistent asthma, and hence reduces the risk of excessive airway narrowing (NCT 00913328).

Cite this as: C. S. Ulrik and Z. Diamant, Clinical & Experimental Allergy, 2010 (40) 576–581.
Fine needle aspiration cytology and flow cytometry immunophenotyping of non‐Hodgkin lymphoma: can we do better?
Authors: Zeppa P. , Vigliar E. , Cozzolino I. , Troncone G. , Picardi M. , De Renzo A. , Grimaldi F. , Pane F. , Vetrani A. , Palombini Lucio
Published: February 2010

P. Zeppa, E. Vigliar, I. Cozzolino, G. Troncone, M. Picardi, A. De Renzo, F. Grimaldi, F. Pane, A. Vetrani and L. Palombini Fine needle aspiration cytology and flow cytometry immunophenotyping of non‐Hodgkin lymphoma: can we do better?

Objective:  To evaluate the diagnostic efficiency of fine needle aspiration cytology/flow cytometry (FNAC/FC) in the diagnosis and classification of non‐Hodgkin lymphoma (NHL) in a series of 446 cases and to compare the results with those of previous experiences to evaluate whether there had been an improvement in FNAC/FC diagnostic accuracy.

Methods:  FNAC/FC was used to analyse 446 cases of benign reactive hyperplasia (BRH), NHL and NHL relapse (rNHL) in 362 lymph nodes and 84 extranodal lesions. When a diagnosis of NHL was reached, a classification was attempted combining FC data and cytological features. Sensitivity, specificity and positive and negative predictive values (PPV and NPV) of FNAC/FC in the diagnosis and classification of NHL were calculated and compared with those available in the literature.

Results:  FNAC/FC provided a diagnosis of NHL and rNHL in 245 cases and of BRH in 188 cases. In nine cases, the diagnosis was ‘suggestive of NHL’ (sNHL) and in four cases was inadequate. Histology and clinical follow‐up confirmed 102 cases of NHL and detected one false positive. In 18 cases of BRH diagnosed by FNAC/FC, histological examination revealed 14 BRH and four NHL (false negatives). All nine cases diagnosed as sNHL were confirmed by histology. Including sNHL cases as false negatives, statistical analysis showed 94.9% sensitivity, 99.4% specificity, 99.6% PPV and 93.4% NPV in the diagnosis of NHL. A specific subtype was diagnosed in 125 cases and confirmed in 67 of 70 cases that had histological biopsies. Statistical analysis did not demonstrate significant improvements between the present series and previous studies either in diagnosis or in classification of NHL.

Conclusions:  FNAC/FC is a fundamental tool in the diagnosis and classification of NHL but the exiguity of diagnostic material and other technical and clinical limitations will probably continue to limit further improvement of the technique.
Carbon decomposition processes in a peat from the Australian Alps
Authors: Grover S. P. P. , Baldock J. A.
Published: February 2010

Carbon dioxide emissions and the mass loss of peat incubatedin situwere measured in peat soils in the Australian Alps. The carbon chemistry of incubated peats was characterized using13C nuclear magnetic resonance (NMR).In situdecomposition decreased as a function of increasing alkyl carbon content of the initial organic matter, providing direct evidence of the oft‐cited link between substrate quality and decomposition rates. More mass loss occurred in the bog peat samples than in the dried peat samples. However, at the peat surface, the amount of CO2emitted was not significantly different between bog peat and dried peat. Carbon inputs, and therefore the sink or source status, of these peats are yet to be quantified.
The concerted action of bZip and cMyb transcription factors FlbB and FlbD induces brlA expression and asexual development in Aspergillus nidulans
Authors: Garzia Aitor , Etxebeste Oier , Herrero‐García Erika , Ugalde Unai , Espeso Eduardo A.
Published: February 2010

Fungi are capable of generating diverse cell types through developmental processes that stem from hyphae, acting as pluripotent cells. The formation of mitospores on emergence of hyphae to the air involves the participation of transcription factors, which co‐ordinate the genesis of new cell types, eventually leading to spore formation.

In this investigation, we show that bZip transcription factor FlbB, which has been attributed to participate in transducing the aerial stimulus signal, activates the expression of c‐Myb transcription factor FlbD. Both factors then jointly activate brlA, a C2H2 zinc finger transcription factor, which plays a central role in spore formation. This sequence of regulatory events resembles developmental control mechanisms involving c‐Myb and bZip counterparts in metazoans and plants.
A bacterial elongation factor G homologue exclusively functions in ribosome recycling in the spirochaete Borrelia burgdorferi
Authors: Suematsu Takuma , Yokobori Shin‐ichi , Morita Hiroyuki , Yoshinari Shigeo , Ueda Takuya , Kita Kiyoshi , Takeuchi Nono , Watanabe Yoh‐ichi
Published: February 2010

Translation elongation factor G (EF‐G) in bacteria plays two distinct roles in different phases of the translation system. EF‐G catalyses the translocation of tRNAs on the ribosome in the elongation step, as well as the dissociation of the post‐termination state ribosome into two subunits in the recycling step. In contrast to this conventional view, it has very recently been demonstrated that the dual functions of bacterial EF‐G are distributed over two different EF‐G paralogues in human mitochondria. In the present study, we show that the same division of roles of EF‐G is also found in bacteria. Two EF‐G paralogues are found in the spirochaete Borrelia burgdorferi, EF‐G1 and EF‐G2. We demonstrate that EF‐G1 is a translocase, while EF‐G2 is an exclusive recycling factor. We further demonstrate that B. burgdorferi EF‐G2 does not require GTP hydrolysis for ribosome disassembly, provided that translation initiation factor 3 (IF‐3) is present in the reaction. These results indicate that two B. burgdorferi EF‐G paralogues are close relatives to mitochondrial EF‐G paralogues rather than the conventional bacterial EF‐G, in both their phylogenetic and biochemical features.
Thymineless death is associated with loss of essential genetic information from the replication origin
Authors: Sangurdekar Dipen P. , Hamann Bree L. , Smirnov Dmitri , Srienc Friedrich , Hanawalt Philip C. , Khodursky Arkady B.
Published: February 2010

Thymine starvation results in a terminal cellular condition known as thymineless death (TLD), which is the basis of action for several common antibiotics and anticancer drugs. We characterized the onset and progression of TLD in Escherichia coli and found that DNA damage is the only salient property that distinguishes cells irreversibly senesced under thymine starvation from cells reversibly arrested by the nucleotide limitation. The damage is manifested as the relative loss of genetic material spreading outward from the replication origin: the extent of TLD correlates with the progression of damage. The reduced lethality in mutants deficient in the RecFOR/JQ repair pathway also correlates with the extent of damage, which explains most of the observed variance in cell killing. We propose that such spatially localized and persistent DNA damage is the consequence of transcription‐dependent initiation of replication in the thymine‐starved cells and may be the underlying cause of TLD.
Novel essential residues of Hda for interaction with DnaA in the regulatory inactivation of DnaA: unique roles for Hda AAA+ Box VI and VII motifs
Authors: Nakamura Kenta , Katayama Tsutomu
Published: February 2010

Escherichia coli ATP–DnaA initiates chromosomal replication. For preventing extra‐initiations, a complex of ADP–Hda and the DNA‐loaded replicase clamp promotes DnaA‐ATP hydrolysis, yielding inactive ADP–DnaA. However, the Hda–DnaA interaction mode remains unclear except that the Hda Box VII Arg finger (Arg‐153) and DnaA sensor II Arg‐334 within each AAA+ domain are crucial for the DnaA‐ATP hydrolysis. Here, we demonstrate that direct and functional interaction of ADP–Hda with DnaA requires the Hda residues Ser‐152, Phe‐118 and Asn‐122 as well as Hda Arg‐153 and DnaA Arg‐334. Structural analyses suggest intermolecular interactions between Hda Ser‐152 and DnaA Arg‐334 and between Hda Phe‐118 and the DnaA Walker B motif region, in addition to an intramolecular interaction between Hda Asn‐122 and Arg‐153. These interactions likely sustain a specific association of ADP–Hda and DnaA, promoting DnaA‐ATP hydrolysis. Consistently, ATP–DnaA and ADP–DnaA interact with the ADP–Hda‐DNA–clamp complex with similar affinities. Hda Phe‐118 and Asn‐122 are contained in the Box VI region, and their hydrophobic and electrostatic features are basically conserved in the corresponding residues of other AAA+ proteins, suggesting a conserved role for Box VI. These findings indicate novel interaction mechanisms for Hda–DnaA as well as a potentially fundamental mechanism in AAA+ protein interactions.
Mutational analysis of the S21 pinholin
Authors: Pang Ting , Park Taehyun , Young Ry
Published: February 2010

Lambdoid phage 21 has the prototype pinholin‐SAR endolysin lysis system, which is widely distributed among phages. Its prototype pinholin, S2168, triggers at an allele‐specific time to form small, heptameric lesions, or pinholes, in the cytoplasmic membrane, thus initiating lysis. S2168 has two transmembrane domains, TMD1 and TMD2. Only TMD2 is required for the formation of pinholes, whereas TMD1 acts as an inhibitor of TMD2 and must be externalized to the periplasm in the lytic pathway. Previously we provided evidence that S2168 first accumulates as inactive dimers with both transmembrane domains embedded in the bilayer. Here we analyse an extensive collection of S21 mutants to identify residues and domains critical to the function and regulation of the pinholin. Evidence is presented indicating that, within the inactive dimer, TMD1 acts in trans as an inhibitor of the lethal function of TMD2. A wide range of phenotypes, from absolute lysis defectives to accelerated lysis triggering, are observed for mutations mapping to each topological domain. The pattern of phenotypes allows the generation of a model for the structure of the inactive dimer. The model identifies the faces of the two transmembrane domains involved in intramolecular and intermolecular interactions, as well as interaction with the lipid.
Stem cell collection in unmanipulated HLA‐haploidentical/mismatched related transplantation with combined granulocyte‐colony stimulating factor‐mobilised blood and bone marrow for patients with haematologic malignancies: the impact of donor characteristics and procedural settings
Authors: Zhang C. , Chen X.‐H. , Zhang X. , Gao L. , Gao L. , Kong P.‐Y. , Peng X.‐G. , Sun A.‐H. , Gong Y. , Zeng D.‐F. , Wang Q.‐Y.
Published: February 2010

Unmanipulated haploidentical/mismatched related transplantation with combined granulocyte‐colony stimulating factor‐mobilised peripheral blood stem cells (G‐PBSCs) and granulocyte‐colony stimulating factor‐mobilised bone marrow (G‐BM) has been developed as an alternative transplantation strategy for patients with haematologic malignancies. However, little information is available about the factors predicting the outcome of peripheral blood stem cell (PBSC) collection and bone marrow (BM) harvest in this transplantation. The effects of donor characteristics and procedure factors on CD34+ cell yield were investigated. A total of 104 related healthy donors received granulocyte‐colony stimulating factor (G‐CSF) followed by PBSC collection and BM harvest. Male donors had significantly higher yields compared with female donors. In multiple regression analysis for peripheral blood collection, age and flow rate were negatively correlated with cell yield, whereas body mass index, pre‐aphaeresis white blood cell (WBC) and circulating immature cell (CIC) counts were positively correlated with cell yields. For BM harvest, age was negatively correlated with cell yields, whereas pre‐BM collection CIC counts were positively correlated with cell yield. All donors achieved the final product of ≥6 ×106 kg−1 recipient body weight. This transplantation strategy has been shown to be a feasible approach with acceptable outcomes in stem cell collection for patients who received HLA‐haploidentical/mismatched transplantation with combined G‐PBSCs and G‐BM. In donors with multiple high‐risk characteristics for poor aphaeresis CD34+ cell yield, BM was an alternative source.
Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly
Authors: Guenova E. , Volz T. , Eichner M. , Hoetzenecker W. , Caroli U. , Griesinger G. , Burow G. , Mitev V. , Biedermann T.
Published: February 2010

To cite this article: Guenova E, Volz T, Eichner M, Hoetzenecker W, Caroli U, Griesinger G, Burow G, Mitev V, Biedermann T. Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly. Allergy 2010; 65: 919–923.

Background:  Epidemiologic studies suggest that elderly people are more prone to develop severe anaphylactic reactions. However, the exact cause for this phenomenon remains unclear.

Aims of the study:  To study the role of the serum tryptase as a diagnostic parameter for individual risk evaluation and its impact on the severity of allergic reactions in elderly people.

Methods:  Two hundred and seventy‐four consecutive patients visiting the Department of Dermatology, Tübingen, Germany, who were diagnosed with honeybee or wasp venom allergy, were included in the study.

Results:  Sting reaction severity increased with increased age and tryptase levels (P = 0.001 and P = 0.0003, respectively). Furthermore, we find not only a general increment in tryptase levels in elderly people (P = 0.0001) but also a continuous increase in tryptase concentrations even below the cut‐off (11.4 μg/l) with increasing age (P = 0.0026).

Conclusions:  Our data confirm serum tryptase as a risk factor for severe anaphylactic reaction to hymenoptera stings. Furthermore, we give first evidence that basal serum tryptase levels increase continuously with age and being an indicator for either increased mast cell load or reactivity this can at least partly be responsible for the observed aggravated allergic reactions in elderly people. As those patients are at increased risk for life‐threatening anaphylactic reactions, it should be considered to adjust VIT especially in elderly patients with elevated tryptase levels as recommended for patients with mastocytosis by increasing venom doses during VIT and by considering its life‐long continuation.
IPF: new insight on pathogenesis and treatment
Authors: Harari S. , Caminati A.
Published: February 2010

To cite this article: Harari S, Caminati A. IPF: new insight on pathogenesis and treatment. Allergy 2010; 65: 537–553.

Recent years have seen a robust influx of exciting new observations regarding the mechanisms that regulate the initiation and progression of pulmonary fibrosis but the pathogenesis remains poorly understood. The search for an alternative hypothesis to unremitting, chronic inflammation as the primary explanation for the pathophysiology of idiopathic pulmonary fibrosis (IPF) derives, in part, from the lack of therapeutic efficacy of high‐dose immunosuppressive therapy in patients with IPF. The inflammatory hypothesis of IPF has since been challenged by the epithelial injury hypothesis, in which fibrosis is believed to result from epithelial injury, activation, and/or apoptosis with abnormal wound healing. This hypothesis suggests that recurrent unknown injury to distal pulmonary parenchyma causes repeated epithelial injury and apoptosis. The resultant loss of alveolar epithelium exposes the underlying basement membrane to oxidative damage and degradation. Emerging concepts suggest that IPF is the result of epithelial–mesenchymal interaction. The initiation of this fibrotic response may depend upon genetic factors and environmental triggers; the role of Th1 or Th2 cell‐derived cytokines may also be important. This process appears to be unique to usual interstitial pneumonia/IPF. It is clear that IPF is a heterogeneous disease with variations in pathology, high‐resolution computed tomography findings, and patterns of progression. Idiopathic pulmonary fibrosis is a complex disorder, and no unifying hypothesis has been identified at present that explains all the abnormalities.
Mast cell adhesion to bronchial smooth muscle in asthma specifically depends on CD51 and CD44 variant 6
Authors: Girodet P.‐O. , Ozier A. , Trian T. , Begueret H. , Ousova O. , Vernejoux J.‐M. , Chanez P. , Marthan R. , Berger P. , Tunon de Lara J. M.
Published: February 2010

To cite this article: Girodet P‐O, Ozier A, Trian T, Begueret H, Ousova O, Vernejoux J‐M, Chanez P, Marthan R, Berger P, Tunon de Lara JM. Mast cell adhesion to bronchial smooth muscle in asthma specifically depends on CD51 and CD44 variant 6. Allergy 2010; 65: 1004–1012.

Background:  Mast cells infiltrate the bronchial smooth muscle (BSM) in asthmatic patients, but the mechanism of mast cell adhesion is still unknown. The adhesion molecules CD44 (i.e. hyaluronate receptor) and CD51 (i.e. vitronectin receptor) are widely expressed and bind to many extracellular matrix (ECM) proteins. The aims of the study are (i) to identify the role of ECM in mast cell adhesion to BSM and (ii) to examine the role of CD51 and CD44 in this adhesion.

Methods:  Human lung mast cells, human mast cell line (HMC‐1), and BSM cells from control donors or asthmatic patients were cultured in the presence/absence of various cytokines. Mast cell–BSM interaction was assessed using 3H‐thymidine‐pulsed mast cells, confocal immunofluorescence, or electron microscopy. Adhesion molecules expression and collagen production on both cell types were evaluated by quantitative RT‐PCR, western blot, and flow cytometry.

Results:  Mast cell adhesion to BSM cells mostly involved type I collagen of the ECM. Such an adhesion was increased in normal BSM cells under inflammatory condition, whereas it was maximal in asthmatic BSM cells. Blockade of either CD51 or CD44 significantly decreased mast cell adhesion to BSM. At the molecular level, protein and the transcriptional expression of type I collagen, CD51 or CD44 remained unchanged in asthmatic BSM cells or in mast cells/BSM cells under inflammatory conditions, whereas that of CD44 variant isoform 6 (v6) was increased.

Conclusions:  Mast cell–BSM cell adhesion involved collagen, CD44, and CD51, particularly under inflammatory conditions. CD44v6 expression is increased in asthmatic BSM cells.
Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma
Authors: Fonseca J. A. , Nogueira‐Silva L. , Morais‐Almeida M. , Azevedo L. , Sa‐Sousa A. , Branco‐Ferreira M. , Fernandes L. , Bousquet J.
Published: February 2010

To cite this article: Fonseca JA, Nogueira‐Silva L, Morais‐Almeida M, Azevedo L, Sa‐Sousa A, Branco‐Ferreira M, Fernandes L, Bousquet J. Validation of a questionnaire (CARAT10) to assess rhinitis and asthma in patients with asthma. Allergy 2010; 65: 1042–1048.

Background and aim:  The Control of Allergic Rhinitis and Asthma Test (CARAT) was developed to be used in the concurrent management of these diseases, as recommended by the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines. However, it was necessary to statistically identify and remove redundant questions and to evaluate the new version’s factor structure, internal consistency and concurrent validity.

Methods:  In this cross‐sectional study 193 adults with allergic rhinitis and asthma from 15 outpatient clinics in Portugal were included. The CARAT questionnaire was reduced using descriptive analysis, exploratory factor analysis and internal consistency. Spearman’s correlations were used to compare the CARAT scores with a medical evaluation and other measures of control, including the Asthma Control Questionnaire and symptoms’ visual analogue scales. The performance against physician rating of control was summarized using the area under the curve (AUC) from receiver operating characteristic analysis. In addition, CARAT was compared with the physician’s decision to reduce, maintain or increase treatment.

Results:  The reduced version has 10 questions and 2 factors (CARAT10). The Cronbach’s alpha was 0.85. All correlation coefficients of CARAT10 and factors with the different measures of control met the a priori predictions, ranging from 0.58 to 0.79. The AUC was 0.82. For the physician’s decision groups of reduce, maintain or increase treatment, the mean (IC95%) scores of CARAT10 were 24 (21.4;26.6), 21 (19.4;21.9) and 15 (13.6;16.5), respectively.

Conclusion:  CARAT10 has high internal consistency and good concurrent validity, making it useful to compare groups in clinical studies.
Economic evaluation of BDP/formoterol fixed vs two single inhalers in asthma treatment
Authors: Brüggenjürgen B. , Ezzat N. , Kardos P. , Buhl R.
Published: February 2010

To cite this article: Brüggenjürgen B, Ezzat N, Kardos P, Buhl R. Economic evaluation of BDP/formoterol fixed vs two single inhalers in asthma treatment. Allergy 2010; 65: 1108–1115.

Background:  Asthma treatment costs are substantial, the largest proportion being incurred by medications. Combination therapy with inhaled corticosteroids (ICS) and long‐acting beta2‐agonists (LABA) is recommended in patients not adequately controlled by ICS alone. Aim of this study was to compare costs and health outcomes of a fixed ICS–LABA combination of beclomethasone dipropionate (BDP) and formoterol fumarate (FF) vs the same drugs delivered via separate inhalers in Germany.

Methods:  A cost‐minimization analysis, a cost‐effectiveness analysis, as well as a threshold analysis were undertaken. Efficacy results were obtained from a recent clinical trial. Cost inputs include medical costs, physician costs, and hospital admission costs. Medical costs, health outcomes, and treatment costs were also varied to assess their impact on results.

Results:  Beclomethasone dipropionate/FF fixed combination was less costly compared to BDP + FF delivered as separate inhalers, costs totaling €525 and €637, respectively, over a 24‐week treatment period. The incremental cost‐effectiveness ratio was €−9.77 per additional day free of asthma symptoms. Equal cost‐effectiveness ratios would still be obtained at a price of the fixed combination increased by 3.4‐fold.

Conclusion:  A cost‐minimization analysis as well as a cost‐effectiveness analysis for Germany based on different product price calculations show that BDP/FF fixed combination is superior to BDP + FF delivered via separate inhalers.
Linear and Stable Dominance Hierarchies in Cooperative Carrion Crows
Authors: Chiarati Elisa , Canestrari Daniela , Vera Rubén , Marcos José M. , Baglione Vittorio
Published: February 2010

Cooperatively breeding birds typically form cohesive and stable groups that live year‐round in all purpose territories where competition for resources is likely to arise. Understanding how group members negotiate over resources is crucial because conflicts may disrupt the stability of the group and may ultimately hinder cooperation. However, social relationships within the group have been largely neglected so far. Here we investigated how cooperatively breeding carrion crows (Corvus corone corone) share a food source, by observing dyadic interactions in 29 territories that contained retained offspring of the breeding pair and/or immigrants. We found that crows formed linear and stable dominance hierarchies, which were stronger for males than females. We suggest that this difference mirrors the level of competition for resources other than food, such as reproduction and territory inheritance, which is higher in males than females. Interestingly, immigrant males dominated male offspring, suggesting that, for the resident breeder, which is the alpha member of the group, the benefits of an association with an immigrant overcome the costs of having his sons pushed down in the hierarchy. Our study uncovered the key factors that determine hierarchical relationships among cooperatively breeding crows and highlighted the need of focussing on social interactions in every context of group living to fully explain the dynamic of cooperation at the nest.
Synthetic feeding stimulants enhance insecticide activity against western corn rootworm larvae, Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae)
Authors: Bernklau E. J. , Bjostad L. B. , Hibbard B. E.
Published: February 2010

In bioassays, the addition of a synthetic feeding stimulant blend improved the efficacy of the insecticide thiamethoxam against neonate western corn rootworm, Diabrotica virgifera virgifera LeConte, larvae. In 4‐h bioassays, the concentration of thiamethoxam required for 50% mortality (LC50) was 2800 pg/ml for the insecticide alone, but was reduced to 0.0075 pg/ml when the synthetic feeding stimulant blend was added (more than a 100,000‐fold difference). Dilutions of thiamethoxam and tefluthrin (ranging from 0 pg/ml to 10 μg/ml) were tested in behavioural bioassays alone and in conjunction with a feeding stimulant blend containing 30 : 4 : 4 : 1 mg/ml glucose : fructose : sucrose : linoleic acid. Larvae were placed on insecticide‐treated filter paper disks in an arena that allowed them to leave the treated area at will. In 30‐min bioassays, and in 4‐h bioassays, significantly more larvae fed on thiamethoxam‐treated disks when the feeding stimulant blend was present for every concentration of insecticide tested. Larvae fed readily on disks treated with tefluthrin when the feeding stimulants were added, but the feeding stimulant blend did not affect the activity of tefluthrin insecticide at any concentration tested.
Genetic variation for bulb size, soluble solids content and pungency in the Spanish sweet onion variety Fuentes de Ebro. Response to selection for low pungency
Authors: Mallor C. , Balcells M. , Mallor F. , Sales E.
Published: February 2010

With no figures and 4 tables

The cultivar ‘Fuentes de Ebro’ is a long‐day onion grown in the northeast of Spain, which is characterized by its succulence and low pungency. However, to match the market demand the size, pungency, and storability need to be improved. We have evaluated these quality‐related bulb traits in 15 grower’s open‐pollinated lines of this cultivar. Phenotypic variation observed for bulb weight, size and soluble solids content was significantly affected by location, growing season and line, while pungency depended on line and plot location. We found higher levels of genetic variation for bulb size and pungency than for soluble solids content, and significant phenotypic correlations indicated that milder onion tend to show larger size and lower soluble solids content. After one cycle of selection, we have obtained progeny with significantly lower pungency levels, and therefore, we estimated a realized heritability of 0.67. As conclusion, it is feasible to obtain a sweet cultivar after some selection cycles in the ‘Fuentes de Ebro’ onion, although considering indirect consequences in size and soluble solids content.
Genetics of flowering time in chickpea in a semi‐arid environment
Authors: Hegde V. S.
Published: February 2010

With 1 figure and 3 tables

Time of flowering is an important component of adaptation and productivity of chickpea (Cicer arietinum L.) in semi‐arid environments characterized by terminal drought and heat stress. Genetics of flowering time was studied in late × early, early × late and early × early crosses under field conditions to obtain additional information on the number of genes involved and their allelic relationships. Results have shown that duplicate dominant genes with cumulative but unequal effect govern flowering time in chickpea. A genotype with two dominant alleles in homozygous or heterozygous conditions at both loci (Efl1,Efl2) control late flowering (41 days and above). A genotype with a dominant allele in homozygous or heterozygous condition at one of the loci and homozygous recessive allele at the other (Efl1,efl2) control earliness (26–40 days) and a genotype with homozygous recessive alleles at both loci (efl1,efl2) is responsible for super‐earliness (<25 days). Influence of maternal genetic factors on the inheritance of flowering time was non‐significant in chickpea.
A dramatic response to a single dose of infliximab as rescue therapy in acute generalized pustular psoriasis of von Zumbusch associated with a neutrophilic cholangitis
Authors: Chandran Nisha Suyien , Chong Wei‐Sheng
Published: February 2010

Generalized pustular psoriasis of von Zumbusch is an unstable, inflammatory form of psoriasis, with the hallmark of neutrophil infiltration in cutaneous as well as extracutaneous lesions. It is often recalcitrant, making treatment difficult. Tumour necrosis factor‐α antagonists including infliximab have been used with success in treating recalcitrant cases. We report a case of a 48‐year‐old Chinese female patient with a long‐standing history of poorly controlled generalized pustular psoriasis which was resistant to multiple therapies. During a severe flare, a single dose of infliximab resulted in rapid clearing of cutaneous lesions, together with resolution of liver function abnormalities that are likely secondary to neutrophilic cholangitis. Subsequent maintenance therapy with acitretin allowed remission of pustular disease for 7 months. This demonstrates the efficacy of single‐dose infliximab for both cutaneous lesions and systemic hepatic involvement in generalized pustular psoriasis.
A case of multiple angiomas without any angiokeratomas in a female heterozygote with Fabry disease
Authors: Mirceva Vesna , Hein Rüdiger , Ring Johannes , Möhrenschlager Matthias
Published: February 2010

Fabry disease is a rare, X‐chromosome‐linked lysosomal storage disease caused by a deficient α‐galactosidase A enzyme. The disease manifests primarily in affected hemizygous males and to some extent in heterozygous females (‘carrier’). A 45‐year‐old female Fabry disease patient without angiokeratomas but with numerous angiomas is presented. Her leukocyte α‐galactosidase A activity was reduced (0.35 nmol/min/mg protein; normal range: 0.4–1). The analysis of her α‐galactosidase A gene (exon 1–7) showed the transition c.427 G>A. An intrafamilial follow‐up search detected a reduced leukocyte α‐galactosidase A activity in her father, who suffered exclusively from coronary heart disease. Our case report underlines the possible wide range of clinical signs in Fabry disease patients, sometimes complicated by missing typical lesions (e.g. angiokeratomas). In oligosymptomatic Fabry disease cases, genetic analysis is recommended.
Cutaneous heterotopic bronchogenic tissue in the scapular area
Authors: Adım Şaduman Balaban , Başkan Emel Bülbül , Sarıcaoğlu Hayriye , Elezoğlu Bahar
Published: February 2010

Cutaneous bronchogenic anomalies are very rare lesions, and most of them present as cysts and/or sinus tracts in the subcutaneous layer. We report a 15‐year‐old boy who presented with a crusted and papillomatous plaque over the right scapular region. Histopathological examination of this plaque revealed pseudostratified ciliated columnar epithelium with papillary invaginations that included mucinous material. The lesion had no cyst or sinus formation and was bordered with smooth muscle bundles in stroma.
Sporotrichoid Mycobacterium marinum infection of the face following a cat scratch
Authors: Phan Tai Anh , Relic John
Published: February 2010

Mycobacterium marinum infections in humans uncommonly affect the face and are not known to be associated with cat scratches. We describe a 24‐year‐old woman who presented with a 3‐month history of multiple tender, occasionally discharging cystic nodules involving the left side of her face in a sporotrichoid distribution. She had suffered a cat scratch to her left lower eyelid 3 weeks before the onset of the eruption and owned multiple tropical fish tanks. She was systemically well and had no lymphadenopathy. She had a background history of a 4.5‐mm‐thick nodular melanoma of her temple treated by wide local excision and negative sentinel lymph node biopsy 4 years prior. Skin biopsies showed multiple variably sized granulomas surrounded by thick cuffs of lymphocytes involving the superficial and deep dermis with no organisms seen on Ziehl–Neelsen, peroidic acid‐Schiff and methenamine silver stains. Laboratory investigations showed a mildly raised erythrocyte sedimentation rate but normal full blood count and C‐reactive protein. Fluid from the left cheek grew an acid‐fast bacillus identified as Mycobacterium marinum. The skin eruption cleared after 5‐month treatment with oral clarithromycin 500 mg twice daily and rifampicin 600 mg daily.
Hyaluronidase allergy: A rare cause of periorbital inflammation
Authors: Borchard Kate , Puy Robert , Nixon Rosemary
Published: February 2010

Hyaluronidase is a bovine or ovine testicular protein that is used as an adjunct to co‐administered medicaments and fluids to enhance their dispersion and absorption through the degradation of hyaluronan. While it is a known potential allergen, there are few reports of hyaluronidase hypersensitivity. A 56‐year‐old lady presented 8 hours post glaucoma surgery with ipsilateral lacriminorrhoea, periorbital erythema, oedema, proptosis, pruritis and conjunctival chemosis. Right ocular motility was restricted and visual acuity was reduced. The reaction settled with oral corticosteroids and antihistamines. Hyaluronidase allergy was confirmed on skin prick testing. Hyaluronidase allergy is rare. In the few cases reported, reactions occurred at various doses and were acute (intraoperative), early (within hours), intermediate (within days) or delayed (within weeks). Anaphylaxis has also been described. Primary sensitization appears to be a prerequisite for most reactions. The variability in onset of symptoms and the response to skin testing would suggest that type I and type IV hypersensitivity may both contribute to this response. In this case, the timing fitted with a late phase type 1 reaction. This case shows that despite being less common than haemorrhage for acute reactions and infection for delayed reactions, allergy can account for orbital inflammation following ophthalmic surgery.
Amoebiasis cutis: Clinical suspicion is the key to early diagnosis
Authors: Verma Ghanshyam K , Sharma Nand Lal , Shanker Vinay , Mahajan Vikram K , Kaushik Rajani , Verma Santwana , Jindal Nidhi
Published: February 2010

Amoebiasis cutis is a rare manifestation of Entamoeba histolytica, primarily an intestinal pathogen, which occurs as a complication of amoebic dysentery. Primary cutaneous amoebiasis occurs from contamination of pre‐existing wounds. A high degree of clinical suspicion and demonstration of trophozoites from lesions are important for making an early diagnosis lest these patients should suffer significant morbidity. A HIV‐negative and otherwise healthy 40‐year‐old man presented with a well‐defined, indurated, painful, progressively enlarging plaque with overlying ulcers and pus discharging sinuses involving buttocks, perianal/perineal area and part of the left thigh of 3 years' duration. A wide array of investigations was unhelpful but demonstration of Entamoeba histolytica trophozoites in wet‐drop preparation from the ulcer margin was diagnostic. The trophozoites were also visualized both in H&E and periodic acid Schiff‐stained histological sections. Resolution of lesion was observed 2 weeks after treatment with oral metronidazole 800 mg three times a day and wound care.