bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient receptor potential cation channels in visceral sensory pathways
Authors: Blackshaw L Ashley 
Published: February 2014

The extensive literature on this subject is in direct contrast to the limited range of clinical uses for ligands of the transient receptor potential cation channels (TRPs) in diseases of the viscera. TRPV1 is the most spectacular example of this imbalance, as it is in other systems, but it is nonetheless the only TRP target that is currently targeted clinically in bladder sensory dysfunction. It is not clear why this discrepancy exists, but a likely answer is in the promiscuity of TRPs as sensors and transducers for environmental mechanical and chemical stimuli. This review first describes the different sensory pathways from the viscera, and on which nociceptive and non‐nociceptive neurones within these pathways TRPs are expressed. They not only fulfil roles as both mechano‐ and chemo‐sensors on visceral afferents, but also form an effector mechanism for cell activation after activation of GPCR and cytokine receptors. Their role may be markedly changed in diseased states, including chronic pain and inflammation. Pain presents the most obvious potential for further development of therapeutic interventions targeted at TRPs, but forms of inflammation are emerging as likely to benefit also. However, despite much basic research, we are still at the beginning of exploring such potential in visceral sensory pathways.Linked ArticlesThis article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐10
Developmental rodent models of fear and anxiety: from neurobiology to pharmacology
Authors: Ganella Despina E , Kim Jee Hyun 
Published: February 2014

Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear‐related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic ‘unlearned’ fear are poorly understood, especially beyond the period of infancy. Models using ‘learned’ fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour‐shock preferences, and then switch to more adult‐like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (includingNMDA,GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders.Linked ArticlesThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue-20
Geographic variation in animal colour polymorphisms and its role in speciation
Authors: McLean Claire A. , Stuart‐Fox Devi 
Published: February 2014

ABSTRACTPolymorphic species, in which multiple variants coexist within a population, are often used as model systems in evolutionary biology. Recent research has been dominated by the hypothesis that polymorphism can be a precursor to speciation. To date, the majority of research regarding polymorphism and speciation has focused on whether polymorphism is maintained within a population or whether morphs within populations may diverge to form separate species (sympatric speciation); however, the geographical context of speciation in polymorphic systems is likely to be both diverse and complex. In this review, we draw attention to the geographic variation in morph composition and frequencies that characterises many, if not most polymorphic species. Recent theoretical and empirical developments suggest that such variation in the number, type and frequency of morphs present among populations can increase the probability of speciation. Thus, the geographical context of a polymorphism requires a greater research focus. Here, we review the prevalence, causes and evolutionary consequences of geographic variation in polymorphism in colour‐polymorphic animal species. The prevalence and nature of geographic variation in polymorphism suggests that polymorphism may be a precursor to and facilitate speciation more commonly than appreciated previously. We argue that a better understanding of the processes generating geographic variation in polymorphism is vital to understanding how polymorphism can promote speciation.
Incidence and prediction of invasive disease and nodal metastasis in preoperatively diagnosed ductal carcinoma in situ
Authors: Osako Tomo , Iwase Takuji , Ushijima Masaru , Horii Rie , Fukami Yasuyoshi , Kimura Kiyomi , Matsuura Masaaki , Akiyama Futoshi 
Published: February 2014

For breast cancer patients with a preoperative diagnosis of ductal carcinoma in situ (DCIS), sentinel lymph node (SN) biopsy has been proposed as an axillary staging procedure in selected patients with a higher likelihood of having occult invasive lesions. With detailed histological examination of primary tumors and molecular whole‐node analysis of SNs, we aimed to validate whether this selective application accurately identifies patients with SN metastasis. The subjects were 336 patients with a preoperative needle‐biopsy diagnosis of DCIS who underwent SN biopsy using the one‐step nucleic acid amplification assay in the period 2009–2011. The incidence and preoperative predictors of upstaging to invasive disease on final pathology and SN metastasis, and their correlation, were investigated. Of the 336 patients, 113 (33.6%) had invasive disease, and 6 (1.8%) and 17 (5.0%) had macro‐ and micrometastasis in axillary nodes respectively. Of the 113 patients with invasive disease, 4 (3.5%) and 9 (8.0%) had macro‐ and micrometastasis. Predictors of invasive disease included palpability, mammographic mass, and calcifications (spread >20 mm), and intraductal solid structure, but no predictor was found for SN metastasis. Therefore, even though occult invasive disease was found at final pathology, most of the patients had no metastasis or only micrometastasis in axillary nodes. Predictors of invasive disease and SN metastasis were not completely consistent, so the selective SN biopsy for patients with a higher risk of invasive disease may not accurately identify those with SN metastasis. More accurate application of SN biopsy is required for patients with a preoperative diagnosis of DCIS.
How Well Socially Wary Preschoolers Fare Over Time Depends on Their Parasympathetic Regulation and Socialization
Authors: Hastings Paul D. , Kahle Sarah , Nuselovici Jacob M. 
Published: February 2014

Parasympathetic regulation and maternal overprotective parenting were examined in 101 children as moderators of links between preschool (M = 3.53 years) social wariness and childhood (M = 9.07 years) internalizing and anxiety problems, social skills, and scholastic performance. Across these three domains of functioning, more socially wary children were likely to manifest worse adjustment when they had low respiratory sinus arrhythmia (RSA) or highly overprotective mothers. Conversely, maternal overprotection appeared to confer benefits for preschoolers with low wariness and low RSA. These findings point to the importance of both internal self‐regulatory capacities and external support for autonomy and competence to understand and assist socially wary children and their families.
Local increase in IgE and class switch recombination to IgE in nasal polyps in chronic rhinosinusitis
Authors: Baba S. , Kondo K. , Toma‐Hirano M. , Kanaya K. , Suzukawa K. , Ushio M. , Suzukawa M. , Ohta K. , Yamasoba T. 
Published: February 2014

SummaryBackgroundChronic rhinosinusitis with nasal polyps is generally characterized by local Th2 inflammation and is categorized into two subtypes in Japan: eosinophilic chronic rhinosinusitis (similar to chronic rhinosinusitis with nasal polyps in western countries) and non‐eosinophilic chronic rhinosinusitis (characterized by Th1‐dominant inflammation).ObjectiveTo investigate local IgE production and class switch recombination to IgE in these two subtypes of chronic rhinosinusitis with nasal polyps.MethodsThe identity of IgE‐positive cells was determined using double‐immunofluorescent staining for IgE and cell‐type‐specific molecular markers. To investigate the local class switch recombination to IgE and IgE synthesis in the mucosa, we performed real‐time polymerase chain reaction to examine the mRNA expression of Th2 cytokines and class‐switch‐related molecules, including IL‐4, IL‐5, IL‐13, ε germline gene transcripts, IgE mature transcript, IgG mature transcript, RAG1, RAG2 and activation‐induced cytidine deaminase in eosinophilic polyps, non‐eosinophilic polyps and controls.ResultsThe concentrations of total IgE and number of IgE‐positive cells were significantly higher in the eosinophilic polyps compared with control and non‐eosinophilic polyps. IgE‐positive cells were predominantly mast cells in eosinophilic polyps and significantly correlated with the number of FcεR1‐positive cells in the subepithelial layer. IL‐5 and IL‐13 mRNA and ε germline gene transcripts expression levels were significantly higher in eosinophilic polyps compared with control and non‐eosinophilic polyps. In contrast, the number of plasma cells and the expression of IgG mature transcripts were increased in non‐eosinophilic polyps compared with eosinophilic polyps. RAG2 mRNA was significantly increased in both eosinophilic and non‐eosinophilic polyps compared with control mucosa.Conclusion and Clinical RelevanceThe current study suggests local class switching to IgE, production of IgE and IgE localization to the surface of mast cells in eosinophilic chronic rhinosinusitis in the Japanese population. The difference in the IgE‐related profiles between eosinophilic chronic rhinosinusitis and non‐eosinophilic chronic rhinosinusitis suggests heterogeneity in the pathogenesis of chronic rhinosinusitis with nasal polyps.
Exposure to Helicobacter pylori infection in early childhood and the risk of allergic disease and atopic sensitization: a longitudinal birth cohort study
Authors: Amberbir A. , Medhin G. , Abegaz W. E. , Hanlon C. , Robinson K. , Fogarty A. , Britton J. , Venn A. , Davey G. 
Published: February 2014

SummaryBackgroundAn inverse relation between Helicobacter pylori infection and allergic disease has been reported by a range of independent epidemiological studies, but evidence from longitudinal studies is scarce.ObjectiveWe have investigated the effects of H. pylori infection on the incidence and prevalence of allergic diseases and sensitization in a low‐income birth cohort.MethodsIn 2005/2006, a population‐based birth cohort was established in Butajira, Ethiopia, and the 1006 singleton babies born were followed up at ages 1, 3, and 5. Symptoms of allergic disease were collected using the ISAAC questionnaire, allergen skin tests performed, and stool samples analysed for H. pylori antigen and geohelminths. Multiple logistic regression was used to determine the independent effects of H. pylori measured at age 3 on the incidence of each outcome between ages 3 and 5 years (in those without the outcome at age 3), controlling for potential confounders, and to additionally assess cross‐sectional associations.ResultsA total of 863 children were followed up to age 5. H. pylori infection was found in 25% of the children at both ages 3 and 5, in 21% at age 5 but not 3, and in 17% at age 3 but not at age 5. H. pylori infection at age 3 was significantly associated with a decreased risk of incident eczema between ages 3 and 5 (adjusted OR, 95% CI, 0.31; 0.10–0.94, P = 0.02). Cross‐sectionally at age 5, H. pylori infection was inversely associated with skin sensitization (adjusted OR, 95% CI, 0.26; 0.07–0.92, P = 0.02).Conclusion and clinical relevanceThese findings provide further evidence to suggest that early‐life exposure to H. pylori may play a protective role in the development of allergy.
Interferon (IFN)-γ-mediated inflammation and the kynurenine pathway in relation to bone mineral density: the Hordaland Health Study
Authors: Apalset E M , Gjesdal C G , Ueland P M , Midttun Ø , Ulvik A , Eide G E , Meyer K , Tell G S 
Published: February 2014

SummaryThe risk of osteoporosis increases in inflammatory disorders. In cell-mediated immune activation, interferon (IFN)-γ stimulates macrophage release of neopterin and increases the activity of indoleamine 2,3-dioxygenase (IDO), thereby stimulating tryptophan degradation along the kynurenine pathway. Plasma levels of neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Several kynurenine pathway metabolites (kynurenines) possess immunomodulatory properties. The aim of this study was to investigate associations between markers of IFN-γ-mediated inflammation and kynurenines with bone mineral density (BMD). The community-based Hordaland Health Study (HUSK), with middle-aged (46–49 years) and older (71–74 years) participants, was conducted from 1998 to 2000 (n = 5312). Hip BMD in relation to neopterin, KTR and kynurenines were investigated, using linear and logistic regression analyses. In the oldest group, neopterin (P ≤ 0·019) and KTR (P ≤ 0·001) were associated inversely with BMD after multiple adjustment. Comparing the highest to the lowest quartiles, the odds ratios of low BMD (being in the lowest quintile of BMD) in the oldest cohort were for neopterin 2·01 among men and 2·34 among women (P ≤ 0·007) and for KTR 1·80 for men and 2·04 for women (P ≤ 0·022). Xanthurenic acid was associated positively with BMD in all sex and age groups while 3-hydroxyanthranilic acid was associated positively with BMD among women only (P ≤ 0·010). In conclusion, we found an inverse association between BMD and markers of IFN-γ-mediated inflammation in the oldest participants. BMD was also associated with two kynurenines in both age groups. These results may support a role of cell-mediated inflammation in bone metabolism.
Multi-functional flow cytometry analysis of CD4+ T cells as an immune biomarker for latent tuberculosis status in patients treated with tumour necrosis factor (TNF) antagonists
Authors: Sauzullo I , Scrivo R , Mengoni F , Ermocida A , Coppola M , Valesini G , Vullo V , Mastroianni C M 
Published: February 2014

SummaryAlthough monitoring tuberculosis (TB) infection during long-term treatment with tumour necrosis factor (TNF) antagonists is of great importance, no monitoring strategy has yet proved successful. Indeed, even the newly proposed interferon-gamma release assays (IGRAs) are known to produce dynamic changes in IFN-γ plasma levels, making them unreliable indicators of patients' pathological/clinical status. We used intracellular cytokine flow cytometry (ICCFC) to investigate the performance of multi-functional CD4+ T cells producing IFN-γ, interleukin (IL)-2 and/or TNF in response to Mycobacterium tuberculosis-specific antigens in subjects treated with TNF antagonists. Patients were classified into three groups based on their TB status before commencement of treatment and on IFN-γ level fluctuations evaluated by IGRA during a 36-month follow-up period. The cytokine profile of M. tuberculosis-specific CD4+ T cells showed that latent tuberculosis infection (LTBI) subjects had a higher frequency of double-positive IFN-γ+ IL-2+ CD4+ T cells and triple-positive IFN-γ+ IL-2+ TNF+ CD4+ T cells compared to those without LTBI, who showed IFN-γ-level fluctuations over time. In contrast, this latter group of patients showed similar proportions of cells producing IFN-γ alone, IL-2 alone and IL-2 in combination with TNF in response to M. tuberculosis-specific antigens. It therefore appears that patients with and without LTBI infection are characterized by different intracellular cytokine profiles. This is the first study evaluating ICCFC in patients treated with TNF antagonists, and suggests that multi-functional analysis of CD4+ T cells could be useful for ruling out TB infection in patients classified at screening as LTBI-negative but who show IGRA fluctuations under long-term TNF antagonist treatment.
Functional imaging in primary tumour‐induced osteomalacia: relative performance of FDG PET/CT vs somatostatin receptor‐based functional scans: a series of nine patients
Authors: Jadhav Swati , Kasaliwal Rajeev , Lele Vikram , Rangarajan Venkatesh , Chandra Piyush , Shah Hina , Malhotra Gaurav , Jagtap Varsha S. , Budyal Sweta , Lila Anurag R. , Bandgar Tushar , Shah Nalini S. 
Published: February 2014

AbstractContextLocalization of phosphatonin‐producing mesenchymal tumours in patients with primary tumour‐induced osteomalacia (pTIO) is challenging. Functional imaging plays an important role in the localization of these tumours.ObjectiveWe studied the relative performance of different functional imaging modalities (18F‐FDG PET/CT, 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT) in tumour localization in cases of pTIO.Design and MethodsRetrospective chart evaluation of 16 patients with confirmed TIO treated from 2006 to 2013 was conducted in a tertiary care referral centre.ResultsOf 16, nine patients had pTIO. In these nine, the positivity rates of different functional imaging modalities were 50% for 18 F‐FDG PET/CT (four of eight patients), 100% for 99Tc‐HYNIC‐TOC SPECT/CT (six of six patients) and 100% for 68Ga‐DOTATATE PET/CT (seven of seven patients). Of nine patients, six were subjected to both the 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT and all of them showed coregistration on the two scans.ConclusionsIn patients with pTIO, the somatostatin receptor‐based functional scans performed better than 18F‐FDG PET/CT in tumour localization. Amongst the somatostatin receptor‐based scans, 99Tc‐HYNIC‐TOC SPECT/CT and 68Ga‐DOTATATE PET/CT performed equally well for localization of tumours.
Graves' disease following immune reconstitution or immunomodulatory treatment: should we manage it any differently?
Authors: Weetman Anthony P. 
Published: February 2014

SummaryGraves' disease and other disorders of thyroid function may occur following treatment with novel anticancer agents or during periods of lymphocyte recovery after lymphopenia. There are three main settings for such lymphocyte reconstitution: recovery after a bone marrow or haematopoietic stem cell transplant, alemtuzumab treatment and the use of highly active antiretroviral therapy (HAART) for human immunodeficiency virus infection. The available evidence suggests that Graves' disease behaves as normal in most of these cases and should be treated conventionally, but it may follow a more favourable course in those receiving alemtuzumab or HAART. As spontaneous or drug‐induced remission may be more likely in these two settings, first‐line treatment should usually consist of an antithyroid drug.
Associations of genetic variants in/near body mass index‐associated genes with type 2 diabetes: a systematic meta‐analysis
Authors: Xi Bo , Takeuchi Fumihiko , Meirhaeghe Aline , Kato Norihiro , Chambers John C. , Morris Andrew P. , Cho Yoon Shin , Zhang Weihua , Mohlke Karen L. , Kooner Jaspal S. , Shu Xiao Ou , Pan Hongwei , Tai E Shyong , Pan Haiyan , Wu Jer‐Yuarn , Zhou Donghao , Chandak Giriraj R. ,   DIAGRAM Consortium,   AGEN‐T2D Consortium,   SAT2D Consortium
Published: February 2014

SummaryObjectiveGenome‐wide association studies have identified many obesity/body mass index (BMI)‐associated loci in Europeans and East Asians. Since then, a large number of studies have investigated the role of BMI‐associated loci in the development of type 2 diabetes (T2D). However, the results have been inconsistent. The objective of this study was to investigate the associations of eleven obesity/BMI loci with T2D risk and explore how BMI influences this risk.MethodsWe retrieved published literature from PubMed and Embase. The pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using fixed‐ or random‐effect models.ResultsIn the meta‐analysis of 42 studies for 11 obesity/BMI‐associated loci, we observed a statistically significant association of the FTO rs9939609 polymorphism (66 425 T2D cases/239 689 normoglycaemic subjects; P = 1·00 × 10−41) and six other variants with T2D risk (17 915 T2D cases/27 531 normoglycaemic individuals: n = 40 629–130 001; all P < 0·001 for SH2B1 rs7498665, FAIM2 rs7138803, TMEM18 rs7561317, GNPDA2 rs10938397, BDNF rs925946 and NEGR1 rs2568958). After adjustment for BMI, the association remained statistically significant for four of the seven variants (all P < 0·05 for FTO rs9939609, SH2B1 rs7498665, FAIM2 rs7138803, GNPDA2 rs10938397). Subgroup analysis by ethnicity demonstrated similar results.ConclusionsThis meta‐analysis indicates that several BMI‐associated variants are significantly associated with T2D risk. Some variants increase the T2D risk independent of obesity, while others mediate this risk through obesity.
Recurrent mutations of BRCA1 and BRCA2 in Poland: an update
Authors: Szwiec M. , Jakubowska A. , Górski B. , Huzarski T. , Tomiczek‐Szwiec J. , Gronwald J. , Dębniak T. , Byrski T. , Kluźniak W. , Wokołorczyk D. , Birkenfeld B. , Akbari M.R. , Narod S.A. , Lubiński J. , Cybulski C. 
Published: February 2014

AbstractThree founder alleles of BRCA1 (C61G, 4153delA, 5382insC) were reported in Poland in 2000, and these three mutations have comprised the standard testing panel used throughout the country. However, since 2000, other recurrent mutations of BRCA1 and BRCA2 have been reported. To establish if the inclusion of one or more of these mutations will increase the sensitivity of the standard test panel, we studied 1164 Polish women with unselected breast cancer diagnosed at age of 50 or below. All women were genotyped for 12 recurrent mutations of BRCA1 and BRCA2. We identified a mutation in 83 of 1164 patients (7.1%) including 61 women with one of the original three mutations (C61G, 4153delA, 5382insC) and 22 women with a different mutation (1.9%). Three new mutations (3819del5, 185delAG and 5370C>T) were seen in multiple families. By including these three mutations in the extended panel, the mutant frequency increased from 5.2 to 6.7%. Polish women with breast cancer diagnosed at age of 50 or below should be screened with a panel of six founder mutations of BRCA1 (C61G, 4153delA, 5382insC, 3819del5, 185delAG and 5370C>T).