bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic constraints on the recovery of sensitivity after visual pigment bleaching in retinal rods
Authors: Miyagishima Kiyoharu J. , Cornwall M. Carter , Sampath Alapakkam P.
Published: August 2009

The shutoff of active intermediates in the phototransduction cascade and the reconstitution of the visual pigment play key roles in the recovery of sensitivity after the exposure to bright light in both rod and cone photoreceptors. Physiological evidence from bleached salamander rods suggests this recovery of sensitivity occurs faster at the outer segment base compared with the tip. Microfluorometric measurements of similarly bleached salamander rods demonstrate that the reduction of all-trans retinal to all-trans retinol also occurs more rapidly at the outer segment base than at the tip. The experiments reported here were designed to test the hypothesis that these two phenomena are linked, e.g., that slowed recovery of sensitivity at the tip of outer segments is rate limited by the reduction of all-trans retinal and results from a shortage of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH), the reducing agent for all-trans retinal reduction. Extracellular measurements of membrane current and sensitivity were made from isolated salamander rods under dark-adapted and bleached conditions while intracellular NADPH concentration was varied by dialysis from a micropipette attached to the inner segment. Sensitivity at the base and tip of the outer segment was assessed before and after bleaching. After exposure to a light that photoactivates 50% of the visual pigment, rods were completely insensitive for nearly 10 minutes, after which the base recovered sensitivity and responsiveness with a time constant of ∼200 seconds, but tip sensitivity recovered more slowly with a time constant of ∼680 seconds. Dialysis of 5 mM NADPH into the rod promoted an earlier recovery and eliminated the previously observed tip/base difference. Dialysis of 1.66 mM NADPH failed to eliminate the tip/base recovery difference, suggesting the steady-state NADPH concentration in rods is ∼1 mM. These results indicate the inner segment is the primary source of reducing equivalents after pigment bleaching, with the reduction of all-trans retinal to all-trans retinol playing a key step in the recovery of sensitivity.
Different pathways for activation and deactivation in CaV1.2: a minimal gating model
Authors: Beyl Stanislav , Kügler Philipp , Kudrnac Michaela , Hohaus Annette , Hering Steffen , Timin Eugen
Published: August 2009

Point mutations in pore-lining S6 segments of CaV1.2 shift the voltage dependence of activation into the hyperpolarizing direction and significantly decelerate current activation and deactivation. Here, we analyze theses changes in channel gating in terms of a circular four-state model accounting for an activation R–A–O and a deactivation O–D–R pathway. Transitions between resting-closed (R) and activated-closed (A) states (rate constants x(V) and y(V)) and open (O) and deactivated-open (D) states (u(V) and w(V)) describe voltage-dependent sensor movements. Voltage-independent pore openings and closures during activation (A–O) and deactivation (D–R) are described by rate constants α and β, and γ and δ, respectively. Rate constants were determined for 16-channel constructs assuming that pore mutations in IIS6 do not affect the activating transition of the voltage-sensing machinery (x(V) and y(V)). Estimated model parameters of 15 CaV1.2 constructs well describe the activation and deactivation processes. Voltage dependence of the “pore-releasing” sensor movement ((x(V)) was much weaker than the voltage dependence of “pore-locking” sensor movement (y(V)). Our data suggest that changes in membrane voltage are more efficient in closing than in opening CaV1.2. The model failed to reproduce current kinetics of mutation A780P that was, however, accurately fitted with individually adjusted x(V) and y(V). We speculate that structural changes induced by a proline substitution in this position may disturb the voltage-sensing domain.
Unitary representations of rational Cherednik algebras
Authors: Etingof Pavel , Stoica Emanuel
Published: August 2009

We study unitarity of lowest weight irreducible representations of rational Cherednik algebras. We prove several general results, and use them to determine which lowest weight representations are unitary in a number of cases.

In particular, in type A, we give a full description of the unitarity locus (justified in Subsection 5.1 and the appendix written by S. Griffeth), and resolve a question by Cherednik on the unitarity of the irreducible subrepresentation of the polynomial representation. Also, as a by-product, we establish Kasatani’s conjecture in full generality (the previous proof by Enomoto assumes that the parameter

c
c

is not a half-integer).
SnoopCGH: software for visualizing comparative genomic hybridization data
Authors: Almagro-Garcia Jacob , Manske Magnus , Carret Celine , Campino Susana , Auburn Sarah , MacInnis Bronwyn L , Maslen Gareth , Pain Arnab , Newbold Christopher I , Kwiatkowski Dominic P , Clark Taane G
Published: August 2009

Summary: Array-based comparative genomic hybridization (CGH) technology is used to discover and validate genomic structural variation, including copy number variants, insertions, deletions and other structural variants (SVs). The visualization and summarization of the array CGH data outputs, potentially across many samples, is an important process in the identification and analysis of SVs. We have developed a software tool for SV analysis using data from array CGH technologies, which is also amenable to short-read sequence data.

Availability and implementation: SnoopCGH is written in java and is available from http://snoopcgh.sourceforge.net/

Contact:  jg10@sanger.ac.uk; tc5@sanger.ac.uk
Review of Pharmacological Effects of Antrodia camphorata and Its Bioactive Compounds
Authors: Geethangili Madamanchi , Tzeng Yew-Min
Published: August 2009

Antrodia camphorata is a unique mushroom of Taiwan, which has been used as a traditional medicine for protection of diverse health‐related conditions. In an effort to translate this Eastern medicine into Western‐accepted therapy, a great deal of work has been carried out on A. camphorata. This review discusses the biological activities of the crude extracts and the main bioactive compounds of A. camphorata. The list of bioactivities of crude extracts is huge, ranging from anti‐cancer to vasorelaxation and others. Over 78 compounds consisting of terpenoids, benzenoids, lignans, benzoquinone derivatives, succinic and maleic derivatives, in addition to polysaccharides have been identified. Many of these compounds were evaluated for biological activity. Many activities of crude extracts and pure compounds of A. camphorata against some major diseases of our time, and thus, a current review is of great importance. It is concluded that A. camphorata can be considered as an efficient alternative phytotherapeutic agent or a synergizer in the treatment of cancer and other immune‐related diseases. However, clinical trails of human on A. camphorata extracts are limited and those of pure compounds are absent. The next step is to produce some medicines from A. camphorata, however, the production may be hampered by problems related to mass production.
Changes of Blood Flow Volume in the Superior Mesenteric Artery and Brachial Artery with Abdominal Thermal Stimulation
Authors: Takayama Shin , Seki Takashi , Watanabe Masashi , Takashima Shigeru , Sugita Norihiro , Konno Satoshi , Takeda Takashi , Arai Hiroyuki , Yambe Tomoyuki , Yaegashi Nobuo , Yoshizawa Makoto , Maruyama Shigenao , Nitta Shin-Ichi
Published: August 2009

In traditional Chinese medicine, moxibustion is a local thermal therapy that is used for several conditions. Quantifying the effects of moxibustion therapy has been difficult because the treatment temperature depends on the physician′s experience, and the temperature distribution in the target area is not uniform. This prospective observational study aims to quantify the effect of local thermal stimulation to the abdomen. We developed a heat transfer control device (HTCD) for local thermal stimulation. Twenty‐four healthy subjects were enrolled and they underwent abdominal thermal stimulation to the para‐umbilical region with the device for 20 min. Blood flow volume in the superior mesenteric artery (SMA) and brachial artery (BA), the heart rate and the blood pressure were measured at rest, 15 min after starting thermal stimulation and 10, 20, 30 and 40 min after completing thermal stimulation. Blood flow parameters were measured by high‐resolution ultrasound. In the SMA, blood flow volume was significantly increased during thermal stimulation (P < .01), as well as at 10 min (P < .01) and 20 min (P < .05) after stimulation. In the BA, blood flow volume decreased at 40 min after stimulation (P < .01). In conclusion we could quantify the effect of local thermal stimulation with an HTCD and high‐resolution ultrasound. Thermal stimulation of the para‐umbilical region increased blood flow in the SMA 20 min after stimulation in healthy subjects.
Homeopathic Individualized Q‐Potencies versus Fluoxetine for Moderate to Severe Depression: Double‐Blind, Randomized Non‐Inferiority Trial
Authors: Adler U. C. , Paiva N. M. P. , Cesar A. T. , Adler M. S. , Molina A. , Padula A. E. , Calil H. M.
Published: August 2009

Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non‐inferiority and tolerability of individualized homeopathic medicines [Quinquagintamillesmial (Q‐potencies)] in acute depression, using fluoxetine as active control. Ninety‐one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg day−1 (up to 40 mg day−1) in a prospective, randomized, double‐blind double‐dummy 8‐week, single‐center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery & Åsberg Depression Rating Scale (MADRS) depression scores, using a non‐inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654) and 8th weeks (P = .965) of treatment. Non‐inferiority of homeopathy was indicated because the upper limit of the confidence interval (CI) for mean difference in MADRS change was less than the non‐inferiority margin: mean differences (homeopathy‐fluoxetine) were −3.04 (95% CI −6.95, 0.86) and −2.4 (95% CI −6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility of randomized controlled double‐blind trials of homeopathy in depression and indicates the non‐inferiority of individualized homeopathic Q‐potencies as compared to fluoxetine in acute treatment of outpatients with moderate to severe depression.
Paeoniae albaRadix Promotes Peripheral Nerve Regeneration
Authors: Huang Kun-Shan , Lin Jaung-Geng , Lee Han-Chung , Tsai Fuu-Jen , Bau Da-Tian , Huang Chih-Yang , Yao Chun-Hsu , Chen Yueh-Sheng
Published: August 2009

The present study providesin vitroandin vivoevaluation ofPaeoniae albaRadix (PR) on peripheral nerve regeneration. In thein vitrostudy, we found the PR caused a marked enhancement of the nerve growth factor‐mediated neurite outgrowth from PC12 cells as well as their expression of growth associated protein 43 and synapsin I. In thein vivostudy, silicone rubber chambers filled with the PR water extract were used to bridge a 10‐mm sciatic nerve defect in rats. At the conclusion of 8 weeks, regenerated nerves in the PR groups, especially at 1.25 mg ml−1had a higher rate of successful regeneration across the wide gap, relatively larger mean values of total nerve area, myelinated axon count and blood vessel number, and a significantly larger nerve conductive velocity compared to the control group (P <  .05). These results suggest that the PR extract can be a potential nerve growth‐promoting factor, being salutary in aiding the growth of injured peripheral nerve.
Nucleosomes are well positioned in exons and carry characteristic histone modifications
Authors: Andersson Robin , Enroth Stefan , Rada-Iglesias Alvaro , Wadelius Claes , Komorowski Jan
Published: August 2009

The genomes of higher organisms are packaged in nucleosomes with functional histone modifications. Until now, genome-wide nucleosome and histone modification studies have focused on transcription start sites (TSSs) where nucleosomes in RNA polymerase II (RNAPII) occupied genes are well positioned and have histone modifications that are characteristic of expression status. Using public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of Caenorhabditis elegans. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2, and H3K27me3 had evidently higher signals in internal exons than in the following introns and were clearly related to exon expression. These observations are suggestive of roles in splicing. Thus, exons are not only characterized by their coding capacity, but also by their nucleosome organization, which seems evolutionarily conserved since it is present in both primates and nematodes.
Elucidation of the ELK1 target gene network reveals a role in the coordinate regulation of core components of the gene regulation machinery
Authors: Boros Joanna , Donaldson Ian J. , O'Donnell Amanda , Odrowaz Zaneta A. , Zeef Leo , Lupien Mathieu , Meyer Clifford A. , Liu X. Shirley , Brown Myles , Sharrocks Andrew D.
Published: August 2009

Transcription factors play an important role in orchestrating the activation of specific networks of genes through targeting their proximal promoter and distal enhancer regions. However, it is unclear how the specificity of downstream responses is maintained by individual members of transcription-factor families and, in most cases, what their target repertoire is. We have used ChIP-chip analysis to identify the target genes of the ETS-domain transcription factor ELK1. Two distinct modes of ELK1 target gene selection are identified; the first involves redundant promoter binding with other ETS-domain family members; the second occurs through combinatorial binding with a second transcription factor SRF, which specifies a unique group of target genes. One of the most prominent groups of genes forming the ELK1 target network includes classes involved in core gene expression control, namely, components of the basal transcriptional machinery, the spliceosome and the ribosome. Amongst the set of genes encoding the basal transcription machinery components, are a functionally linked subset of GTFs and TAFs. Our study, therefore, reveals an unsuspected level of coordinate regulation of components of the core gene expression control machinery and also identifies two different modes of promoter targeting through binding with a second transcription factor or redundant binding with other ETS-domain family members.
Allele-specific DNA methylation in mouse strains is mainly determined by cis-acting sequences
Authors: Schilling Elmar , El Chartouni Carol , Rehli Michael
Published: August 2009

DNA methylation is a vital epigenetic mark that participates in establishing and maintaining chromatin structures and regulates gene transcription during mammalian development and cellular differentiation. Differences in epigenetic patterns between individuals may contribute to phenotypic variation and disease susceptibility; however, little is known about the extent of such variation or how different epigenetic patterns are established. Here we have compared DNA methylation profiles of macrophages from two inbred mouse strains (C57BL/6 and BALB/c) at 181 large genomic intervals that were selected based on differential gene expression patterns. Using a DNA methylation-dependent fractionation approach based on a combination of methyl-CpG immunoprecipitation and locus-wide tiling arrays, we identified several hundred differentially methylated regions, and simultaneously uncovered previously unrecognized genetic variability between both mouse strains at the studied loci. DNA sequence and methylation differences were validated by DNA sequencing and mass spectrometry analysis of bisulfite-treated DNA for a subset of regions. Importantly, we show that in F1 hybrids, the majority of strain-specific methylation patterns in somatic cells were maintained on the parental allele, regardless of their status in the male germ line. The common association of differentially methylated regions with sequence polymorphisms suggests that the genomic context determines the developmentally regulated epigenetic status at most nonimprinted regions of mammalian genomes.
‘Micro’ﬁnancial services: what do Paciﬁc people need?
Authors: Cornford Robyn
Published: August 2009

Abstract:  There are many elements in the economic and socio‐cultural context of the Paciﬁc region which distinguish it from Asia where many of the most famous models for the delivery of ‘micro’ﬁnancial services were developed. Is it possible that the rush to replicate existing models, using ‘best practice’ principles developed far from the Paciﬁc, is curtailing careful market analysis and stiﬂing experimentation and innovation in the provision of ﬁnancial services for the poor? This conference report asks readers to consider the types of ‘micro’ﬁnancial services and the methods of their delivery which may be appropriate in the Paciﬁc context, and more important, which meet the needs of people in the Paciﬁc.
5‐hydroxytryptamine signalling in irritable bowel syndrome with diarrhoea: effects of gender and menstrual status
Authors: HOUGHTON L. A. , BROWN H. , ATKINSON W. , MORRIS J. , FELL C. , WHORWELL P. J. , LOCKHART S. , KEEVIL B.
Published: August 2009

Background  Symptomatology and physiology differ between men and women and across the menstrual cycle in irritable bowel syndrome (IBS). Ovarian hormones influence 5‐hydroxytryptamine (5‐HT), an amine known to play a role in gut motor‐sensory function.

Aim  To assess the effects of gender and menstrual status on platelet‐depleted plasma (PDP) 5‐HT concentration in IBS patients with diarrhoea (IBS‐D) patients compared with healthy volunteers (HV).

Methods  Platelet‐depleted plasma 5‐HT concentrations were assessed under fasting and fed conditions in 73 IBS‐D patients (aged 18–58 years; 18 men) and 64 HV (aged 18–50 years; 24 men). Women were divided into those with low or high progesterone/oestrogen (P/O) levels.

Results  Irritable bowel syndrome patients with diarrhoea had higher PDP 5‐HT concentrations than HV under fasting (P = 0.002) and fed (P = 0.049) conditions. This was particularly related to IBS‐D men having higher PDP 5‐HT concentrations than healthy controls (P = 0.002). Moreover, PDP 5‐HT concentrations in IBS‐D women with low P/O levels were similar to healthy controls.

Conclusions  Similar to IBS‐D women with high P/O levels, IBS‐D men also have raised PDP 5‐HT concentrations. 5‐HT concentration normalizes at menses in IBS‐D women, suggesting a shift in the mechanisms responsible for abnormal 5‐HT signalling in these patients.
Review article: sleep‐related gastro‐oesophageal reflux as a distinct clinical entity
Authors: ORR W. C.
Published: August 2009

Background Many patients with chronic gastro‐oesophageal reflux disease (GERD) have frequent nighttime heartburn as well as sleep‐related gastro‐oesophageal reflux (GOR). Sleep‐related GOR has been shown to play an important role in the development of oesophagitis and other complications of GOR.

Aim To present a conceptual argument that nighttime heartburn and associated sleep‐related GOR should be recognized as a distinct clinical entity deserving special attention with regard to the diagnosis and treatment of GERD.

Methods The data presented come from surveys of GERD patients as well as from physiological studies to include studies monitoring oesophageal pH and spontaneous reflux events during polysomnographically (PSG) monitored sleep.

Results Evidence is presented to show that nighttime heartburn is prevalent and its occurrence separates patients from those who have heartburn most exclusively in the daytime. The evidence presented also supports the notion that nighttime heartburn sufferers have a more complicated disease and they have a greater risk of developing oesophagitis and other respiratory complications. The data also show that responses to acid mucosal contact are quite different during sleep compared to responses measured during the waking state.

Conclusions Nighttime heartburn and GOR represent a distinct clinical entity which deserves specific attention in the diagnosis and optimal treatment of GERD.
Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells
Authors: Lee S. , Park J‐R. , Seo M‐S. , Roh K‐H. , Park S‐B. , Hwang J‐W. , Sun B. , Seo K. , Lee Y‐S. , Kang S‐K. , Jung J‐W. , Kang K‐S.
Published: August 2009

Objectives:  Histone deacetylase (HDAC) is an important therapeutic target in cancer. Two of the main anticancer mechanisms of HDAC inhibitors are induction of terminal differentiation and inhibition of cell proliferation. To investigate the role of HDAC in maintenance of self‐renewal and cell proliferation, we treated mesenchymal stem cells (MSCs) that originated from adipose tissue or umbilical cord blood with valproic acid (VPA) and sodium butyrate (NaBu).

Materials and methods:  Human MSCs were isolated from mammary fat tissue and cord blood. We performed MTT assay and flow cytometry‐based cell cycle analysis to assess self‐renewal of MSCs. In vitro differentiation assays into osteogenic, adipogenic, neurogenic and chondrogenic lineages were conducted to investigate MSC multipotency. Immunocytochemistry, Western blot and reverse transcription‐polymerase chain reaction were used to interrogate molecular pathways.

Results:  VPA and NaBu flattened the morphology of MSCs and inhibited their growth. VPA and NaBu activated the transcription of p21CIP1/WAF1 by increasing the acetylation of histone H3 and H4 and eventually blocked the cell cycle at G2/M phase. The expression level of p16INK4A, a cdk inhibitor that is closely related to cellular senescence, was not changed by HDAC inhibitor treatment. We performed controlled differentiation into bone, fat, cartilage and nervous tissue to elucidate the role of HDAC in the pluripotency of MSC to differentiate into functional tissues. VPA and NaBu decreased the efficiency of adipogenic, chondrogenic, and neurogenic differentiation as visualized by specific staining and reverse transcription‐polymerase chain reaction. In contrast, osteogenic differentiation was elevated by HDAC inhibitor treatment.

Conclusion:  HDAC activity is essential for maintaining the self‐renewal and pluripotency of MSCs.
A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide‐induced granulocytopaenia
Authors: Scholz M. , Ackermann M. , Engel C. , Emmrich F. , Loeffler M. , Kamprad M.
Published: August 2009

Objectives: Recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre‐select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G‐CSF derivatives filgrastim and pegfilgrastim in mice.

Methods: Healthy CD‐1 mice and those with cyclophosphamide‐induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G‐CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.

Results: Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.

Conclusion: Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G‐CSF application.
Allergen‐specific antibody and cytokine responses, mast cell reactivity and intestinal permeability upon oral challenge of sensitized and tolerized mice
Authors: Perrier C. , Thierry A.‐C. , Mercenier A. , Corthésy B.
Published: August 2009

Background
Food allergy has reached an epidemic level in westernized countries and although central mechanisms have been described, the variability associated with genetic diversity underscores the still unresolved complexity of these disorders.

Objective
To develop models of food allergy and oral tolerance, both strictly induced by the intestinal route, and to compare antigen‐specific responses.

Methods
BALB/c mice were mucosally sensitized to ovalbumin (OVA) in the presence of the mucosal adjuvant cholera toxin, or tolerized by intra‐gastric administrations of OVA alone. Antibody titres and cytokines were determined by ELISA, and allergic status was determined through several physiologic parameters including decline in temperature, diarrhoea, mast cell degranulation and intestinal permeability.

Results
OVA‐specific antibodies (IgE, IgGs and IgA in serum and feces) were produced in sensitized mice exclusively. Upon intra‐gastric challenge with OVA, sensitized mice developed anaphylactic reactions associated with a decline of temperature, diarrhoea, degranulation of mast cells, which were only moderately recruited in the small intestine, and increased intestinal permeability. Cytokines produced by immune cells from sensitized mice included T‐helper type 2 cytokines (IL‐5, IL‐13), but also IL‐10, IFN‐γ and IL‐17. In contrast, all markers of allergy were totally absent in tolerized animals, and yet the latter were protected from subsequent sensitization, demonstrating that oral tolerance took place efficiently.

Conclusion
This work allows for the first time an appropriate comparison between sensitized and tolerized BALB/c mice towards OVA. It highlights important differences from other models of allergy, and thus questions some of the generally accepted notions of allergic reactions, such as the protective role of IFN‐γ, the importance of antigen‐specific secretory IgA and the role of mucosal mast cells in intestinal anaphylaxis. In addition, it suggests that IL‐17 might be an effector cytokine in food allergy. Finally, it demonstrates that intestinal permeability towards the allergen is increased during challenge.

Cite this as: C. Perrier, A.‐C. Thierry, A. Mercenier and B. Corthésy, Clinical & Experimental Allergy, 2010 (40) 153–162.
Digested Ara h 1 has sensitizing capacity in Brown Norway rats
Authors: Bøgh K. L. , Kroghsbo S. , Dahl L. , Rigby N. M. , Barkholt V. , Mills E. N. C. , Madsen C. B.
Published: August 2009

Background
Food allergies are a public health issue of growing concern, with peanuts in particular being associated with severe reactions. The peanut allergen, Ara h 1, belongs to the cupin plant food allergen family, which, unlike other structural families, appears to be broken down rapidly following gastrointestinal digestion.

Objective
Using Ara h 1 as a model allergen, the ability of digested protein to sensitize has been investigated.

Methods
Ara h 1 was purified from whole roasted peanuts. Intact Ara h 1 was digested in an in vitro model, simulating the human gastrointestinal digestion process. Digestion products were analysed for peptide sizes and their ability to aggregate. Brown Norway (BN) rats, used as an animal model, were immunized with purified intact Ara h 1 or the gastrointestinal digestion products thereof. The sensitizing capacity was evaluated by analyses of specific antibody (IgG1, IgG2a and IgE) responses and ability to trigger mediator release of rat basophilic leukaemia (RBL)‐2H3 cells.

Results
The present study showed that Ara h 1 was broken down, resulting in peptide fragments of sizes <2.0 kDa, of which approximately 50% was in aggregated complexes of Mr up to 20 kDa. Ara h 1 digesta were shown to have sensitizing capacity in BN rats, being capable of inducing specific IgG and IgE antibodies. The IgE response was functional, having the capacity to induce specific degranulation of RBL cells.

Conclusion
From this study, it can be concluded that lability of a food allergen to gastrointestinal digestion does not necessarily abrogate its allergenic sensitizing potential.
Comparison of skin prick tests with specific serum immunoglobulin E in the diagnosis of fungal sensitization in patients with severe asthma
Authors: O'Driscoll B. R. , Powell G. , Chew F. , Niven R. M. , Miles J. F. , Vyas A. , Denning D. W.
Published: August 2009

Background
It has been shown that patients with allergic bronchopulmonary aspergillosis (ABPA) and patients with severe asthma with fungal sensitization (SAFS) can benefit from antifungal therapy. It is not known whether allergy skin prick tests (SPT) or specific IgE tests are more sensitive in the identification of patients who are sensitized to fungi and who are therefore candidates for antifungal therapy.

Objectives
To compare SPT and specific serum IgE tests for fungal sensitization in patients with severe asthma.

Methods
We have undertaken SPT and specific serum IgE tests to six fungi (Aspergillus fumigatus, Candida albicans, Penicillium notatum, Cladosporium herbarum, Alternaria alternata and Botrytis cineria) and specific serum IgE test for Trichophyton in 121 patients with severe asthma (British Thoracic Society/SIGN steps 4 and 5).

Results
Sixty‐six percent of patients were sensitized to one or more fungi based on SPT and/or specific serum IgE results. Positivity to SPT and/or specific serum IgE was as follows: A. fumigatus 45%, C. albicans 36%, P. notatum 29%, C. herbarum 24%, A. alternata 22%, B. cineria 18%, Trichophyton 17% (specific serum IgE only). Concordance between the tests was 77% overall but only 14–56% for individual fungi. Twenty‐nine (24%) patients were sensitized to a single fungus and seven (6%) were sensitized to all seven fungal species. Fifty percent of patients were sensitized to fungal and non‐fungal extracts, 21% were sensitized only to non‐fungal extracts, 16% were sensitized only to fungal extracts and 13% had no positive tests.

Conclusion
This study is consistent with previous reports that fungal sensitization is common in patients with severe asthma. At present, it remains necessary to undertake both SPT and specific serum IgE testing to identify all cases of fungal sensitization. This may be important in the identification of patients with ABPA and SAFS who may benefit from antifungal therapy.
Basophil responsiveness in patients with insect sting allergies and negative venom‐specific immunoglobulin E and skin prick test results
Authors: Korosec P. , Erzen R. , Silar M. , Bajrovic N. , Kopac P. , Kosnik M.
Published: August 2009

Background
Current guidelines do not adequately address the question of how best to manage patients with a convincing history of insect allergy, but negative venom‐specific IgE and skin test results.

Methods
Forty‐seven patients out of a total of 1219 (4%), with a positive history of sting allergy, were recruited over a period of 4.5 years. All recruited patients had a convincing history of a severe or a life‐threatening anaphylactic reaction of Mueller grade II–IV (median grade III) after Hymenoptera sting, but negative venom‐specific IgE and skin prick test results. Diagnostic work‐up was prospectively followed by the CD63 basophil activation test and by intradermal skin testing. A control group of 25 subjects was also assessed.

Results
Thirty‐five out of 47 (75%) patients demonstrated a positive basophil CD63 response after stimulation with bee and/or wasp venom. Intradermal venom skin tests were performed for 37 patients, 17 (46%) of whom showed positive results. Out of 20 patients who demonstrated negative intradermal test results, 12 patients showed a positive CD63 response (60%). In contrast, out of 9 patients who showed a negative CD63 response, only one was detected by intradermal testing (11%). In the control group, only two out of 25 (4%) subjects displayed a positive basophil response and/or intradermal test.

Conclusion
Here we show that, in complex cases with inconclusive diagnostic results, the CD63 activation test could be particularly useful and more sensitive than intradermal skin testing.
Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice
Authors: Bommireddy R , Bueno O F , Martin J , Ormsby I , Chen H , Gard C , Molkentin J D , Boivin G P , Babcock G F , Doetschman T
Published: August 2009

Transforming growth factor (TGF) β1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca2+]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1−/− thymocytes, and because calcineurin Aβ (CNAβ)-deficient mice do not reject allogenic tumours, we have generated Tgfb1−/−Cnab−/− mice to address whether CNAβ deficiency prevents T cell activation and inflammation in Tgfb1−/− mice. Here we show that in Tgfb1−/−Cnab−/− mice inflammation is reduced significantly relative to that in Tgfb1−/− mice. However, both CD4+ and CD8+ T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNAβ decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1−/− T cells can undergo activation in the absence of CNAβ, probably by using the other isoform of calcineurin (CNAα) in a compensatory manner. CNAβ-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer.
Lateral velocity variation related correction in asymptotic true‐amplitude one‐way propagators
Authors: Cao Jun , Wu Ru‐Shan
Published: August 2009

It was mathematically proved that the asymptotic true‐amplitude one‐way wave equation could provide the same amplitude as the full‐wave equation in heterogeneous lossless media in the sense of high‐frequency asymptotics. Much work has been done on the vertical velocity variation related amplitude correction term but the lateral velocity variation related term has not received much attention, even being excluded in some asymptotic true‐amplitude one‐way propagator formulations. Here we analyse the effects of different amplitude correction terms in the asymptotic true‐amplitude one‐way propagator, especially the effect related to the lateral velocity variation, by comparing the wavefield amplitude from the one‐way propagator with that from full‐wave modelling. We derive a dual‐domain wide‐angle screen type asymptotic true‐amplitude one‐way propagator and evaluate two implementations of the amplitude correction. Numerical examples show that the lateral velocity variation related correction term can play a significant role in the asymptotic true‐amplitude one‐way propagator. Optimization of the expansion coefficients in the asymptotic true‐amplitude one‐way propagator can improve both the amplitude and phase accuracy for wide‐angle waves.
Contrasting phylogeographical patterns for springtails reflect different evolutionary histories between the Antarctic Peninsula and continental Antarctica
Authors: McGaughran Angela , Torricelli Giulia , Carapelli Antonio , Frati Francesco , Stevens Mark I. , Convey Peter , Hogg Ian D.
Published: August 2009

Aim We examined the genetic structure among populations and regions for the springtailsCryptopygus antarcticus antarcticusandGomphiocephalus hodgsoni(Collembola) to identify potential historical refugia and subsequent colonization routes, and to examine population growth/expansion and relative ages of population divergence.

Location Antarctic Peninsula forC. a. antarcticus; Antarctic continent (southern Victoria Land) forG. hodgsoni.

Methods Samples were collected from 24 and 28 locations across the Antarctic Peninsula and southern Victoria Land regions forC. a. antarcticusandG. hodgsoni, respectively. We used population genetic, demographic and nested clade analyses based on mitochondrial DNA (cytochromecoxidase subunit I and subunit II).

Results Both species were found to have population structures compatible with the presence of historical glacial refugia on Pleistocene (2 Ma–present) time‐scales, followed by post‐glacial expansion generating contemporary geographically isolated populations. However,G. hodgsonipopulations were characterized by a fragmented pattern with several ‘phylogroups’ (likely ancestral haplotypes present in high frequency) retaining strong ancestral linkages among present‐day populations. Conversely,C. a. antarcticushad an excess of rare haplotypes with a much reduced volume of ancestral lineages, possibly indicating historical founder/bottleneck events and widespread expansion.

Main conclusions We infer that these differences reflect distinct evolutionary histories in each locality despite the resident species having similar life‐history characteristics. We suggest that this has predominantly been influenced by variation in the success of colonization events as a result of intrinsic historical glaciological differences between the Antarctic Peninsula and continental Antarctic environments.
Explosive evolution of an ancient group of Cyphophthalmi (Arachnida: Opiliones) in the Balkan Peninsula
Authors: Murienne Jérôme , Karaman Ivo , Giribet Gonzalo
Published: August 2009

Aim  To investigate the phylogeny of the genus Cyphophthalmus in the Balkan Peninsula and to test the current recognition of ‘phyletic lines’ and phylogenetic groups proposed in previous studies in order to elucidate the biogeographical history of the region.

Location  Europe, Balkan Peninsula, Adria microplate.

Methods  Two mitochondrial (cytochrome c oxidase subunit I and 16S rRNA) and two nuclear (28S rRNA and 18S rRNA) markers were used to infer the phylogenetic history of the group. Molecular dating with relaxed molecular clocks was used to elucidate the relative time of diversification within the genus Cyphophthalmus and its constituent lineages.

Results  Our analyses confirm the monophyly of the genus Cyphophthalmus, and that of the Aegean and gjorgjevici lineages, whereas the ‘Dinaric lineage’ appears paraphyletic.

Main conclusions  We show that the genus Cyphophthalmus is an old endemic from the Balkan biogeographical region, which gave origin to at least three main lineages. Those lineages have diversified within overlapping ranges. According to our molecular dating, they have also diversified within the same timeframe. The Dinaric Alps, although presenting a large number of species, cannot be inferred as the centre of origin of the group. Instead, the biogeographical evolution of the genus could be related to the palaeogeographic history of the Adria microplate.
Phylogeography of the Guinea multimammate mouse (Mastomys erythroleucus): a case study for Sahelian species in West Africa
Authors: Brouat Carine , Tatard Caroline , Bâ Khalilou , Cosson Jean‐François , Dobigny Gauthier , Fichet‐Calvet Elisabeth , Granjon Laurent , Lecompte Emilie , Loiseau Anne , Mouline Karine , Piry Sylvain , Duplantier Jean‐Marc
Published: August 2009

Aim  To investigate the phylogeographical structure of the Guinea multimammate mouse, Mastomys erythroleucus (Temminck, 1853), a widespread murid rodent in sub‐Saharan (Sahel and Sudan) savannas, for a better understanding of the impacts of geographical and historical factors on the evolutionary history of this species, in the context of the growing database of phylogeographical studies of African savanna mammal species.

Location  Sahel and Sudan savannas, Africa.

Methods  We sequenced the whole cytochrome b gene in 211 individuals from 59 localities distributed from Senegal to Ethiopia. Sequence data were analysed using both phylogenetic (several rooted tree‐construction methods, median‐joining networks) and population genetic methods (spatial analyses of molecular variance, mismatch distributions).

Results  Haplotypes were distributed into four major monophyletic groups corresponding to distinct geographical regions across a west–east axis. Diversification events were estimated to have occurred between 1.16 and 0.18 Ma.

Main conclusions  Vicariance events related to the fragmentation of savanna habitats during the Pleistocene era may explain the phylogeographical patterns observed. Genetic structure was consistent with a role of major Sahelian rivers as significant barriers to west–east dispersal. Recent demographic expansions probably occurred during arid phases of the Holocene with the southward expansion of savannas.
How many buffalo does it take to change a savanna? A response to Bowman et al. (2008)
Authors: Petty Aaron M. , Werner Patricia A.
Published: August 2009

Bowman et al. (Journal of Biogeography, 2008, 35, 1976–1988) aimed to explain observed increases in woody cover on floodplains and savannas of Kakadu National Park using estimates of buffalo (Bubalus bubalis) density as a causal variable. They found that buffalo were a minor model variable and concluded that buffalo are ‘not a major driver of floodplain and eucalypt dynamics’. However, the authors mislabelled the historical density of buffalo on their site, citing a period as high density instead of low density. Further, their results were not contextualized within the substantial body of scientific and historical evidence of the buffalo’s strong influence on vegetation in Kakadu. The authors instead postulated three unanalysed drivers of observed patterns of change: fire regime, rainfall and atmospheric CO2. We suggest that further analyses of change in woody vegetation should make use of accurate historical records of grazers as well as available data sets on fire history.
Failure to detect deaf‐blindness in a population of people with intellectual disability
Authors: Fellinger J. , Holzinger D. , Dirmhirn A. , Van Dijk J. , Goldberg D.
Published: August 2009

Background Early identification of deaf‐blindness is essential to ensure appropriate management. Previous studies indicate that deaf‐blindness is often missed. We aim to discover the extent to which deaf‐blindness in people with intellectual disability (ID) is undiagnosed.

Method A survey was made of the 253 residents of an institute offering residential and occupational facilities for people with IDs. Data are included for the 224 individuals who were able to complete both auditory and visual assessments. Otoacoustic emissions were used to screen for hearing impairment; those who did not pass were assessed by behavioural audiometry. Visual acuity was assessed with one of the following: EH‐Optotypes, LH‐Optotypes, Teller Acuity Cards, Cardiff Acuity Cards or the Stycar Ball Vision Test.

Results Prior to the study hearing impairment had been diagnosed in 12.5% of the 224 subjects, and visual impairment in 17%. Upon completion of the study these figures rose to 46% and 38.4% respectively. Deaf‐blindness was diagnosed in 3.6% of the subjects before, and in 21.4% after, the study. Most (87.5%) of the deaf‐blind individuals had profound ID.

Conclusion Deaf‐blindness is most often not identified either by standard medical screening or by care staff. Individuals with this disability, however, require provision of special kinds of care. Four categories of deaf‐blindness are proposed, according to the severity of sensory impairment in each modality. The tests used in this study are non‐invasive and are appropriate for individuals with ID and children. Early and periodic screening for visual and hearing impairment in individuals with ID is recommended.
Dysfunctional beliefs and attitudes about sleep in children
Authors: GREGORY ALICE M. , COX JENNY , CRAWFORD MEGAN R. , HOLLAND JESSICA , HARAVEY ALLISON G. ,   The Steps Team
Published: August 2009

The objective of the study was to determine whether associations between dysfunctional beliefs and attitudes about sleep and sleep disturbance are evident in children. Cross‐sectional data were collected from 123 children aged 8–10 years (49% boys). The participants came from ethnically diverse backgrounds from two inner‐city schools in London, UK. Children completed the Sleep Self‐Report (SSR) and the Dysfunctional Beliefs and Attitudes about Sleep (DBAS) questionnaire (which was adapted for use with children). Parents completed the Child Sleep Habits Questionnaire (CSHQ). The total DBAS score was associated with sleep disturbances defined as total SSR score (β = 0.40, P < 0.001, r2 = 0.15), the SSR insomnia items (β = 0.29, P < 0.01, r2 = 0.08) and the total CSHQ score (β = 0.22, P < 0.05, r2 = 0.04). Some dysfunctional beliefs about sleep predicted sleep disturbance to a greater extent than others. For example, when controlling for the other DBAS subscales, the ‘control and predictability of sleep’ subscale, but not the ‘sleep requirements expectations’ subscale, predicted total SSR score and SSR insomnia items. Given this preliminary evidence that dysfunctional beliefs and attitudes about sleep appear to be associated with sleep difficulties in children, future work is needed to further developmentally adapt a version of the DBAS appropriate for use with children.
Plexiform neurofibromas in neurofibromatosis type 1
Authors: Sehgal Virendra N. , Srivastava Govind , Aggarwal Ashok K. , Oberai Rakesh
Published: August 2009

Plexiform neurofibroma developing in neurofibromatosis type 1 is a fascinating overture whereby diagnosis is primarily based on clinical characteristics, the details of which are outlined. Nonetheless, it is imperative to establish a clear‐cut clinical status vis‐á‐vis the adjoining tissues. Magnetic resonance imaging (MRI) may provide an additional supplement to the diagnosis and an aid to further management of the condition.