bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking
Authors: Kosobud Ann E. K. , Wetherill Leah , Plawecki Martin H. , Kareken David A. , Liang Tiebing , Nurnberger John L. , Windisch Kyle , Xuei Xiaoling , Edenberg Howard J. , Foroud Tatiana M. , O'Connor Sean J.
Published: June 2015

Background

Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol.

Methods

One hundred and thirty‐two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single‐blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol “clamp,” during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo‐adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response.

Results

Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858.

Conclusions

Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol.
The effects of direct storage subsidies under limited rationality: a general equilibrium analysis
Authors: Femenia Fabienne
Published: June 2015

We study here the effects of a public subsidy to private storage set up at world level. To simulate the welfare effects and impacts on market fluctuations of this subsidy, we use a dynamic Computable General Equilibrium model assuming imperfect expectations. We also perform different statistical analysis based on our CGE results and show that the storage subsidy can have the undesired effect of destabilizing agricultural markets, depending on the form of economic agents’ price expectations and on the structure of the shocks impacting the agricultural production.
Cronkhite–Canada syndrome: A rare disease presenting with dermatological and gastrointestinal manifestations
Authors: Kronborg Caroline , Mahar Patrick , Howard Anne
Published: June 2015

We present a case of Cronkhite–Canada syndrome, which is a rare disease classically characterised by hyperpigmentation, alopecia and onychodystrophy associated with clinical gastrointestinal symptoms and hamartomatous gastrointestinal polyps. Management primarily involves immunosuppression and nutritional support, which led to remission in this case. The recognition of cutaneous features may lead to early diagnosis and reduce morbidity and mortality.
Retention challenge facing Australia's rural community mental health services: Service managers' perspectives
Authors: Cosgrave Catherine , Hussain Rafat , Maple Myfanwy
Published: June 2015

Objective

This paper aims to contribute to the development of a more sustainable Australian rural community mental health workforce by comparing the findings from a literature search investigating impacting factors on retention with the experiences of community mental health service managers running services in rural Australia.

Design

Semi‐structured interviews.

Setting

Public health sector, rural New South Wales.

Participants

Five community mental health managers, running services in rural Australia.

Main outcome measures

Interviews were undertaken as a pilot for a broader qualitative study investigating factors influencing the decision to stay or leave among community mental health professionals working in rural positions. The purpose of undertaking this pilot study was to test for validity and relevance of the retention phenomena and help inform the research design for the main study.

Results

Three key retention focussed themes were identified: (i) Staffing is a persistent challenge; (ii) Small remote towns pose the biggest challenge; and (iii) The decision to stay or leave is complex and multifactorial.

Conclusions

The findings of this pilot study support previous research and contribute to the understanding of influences on retention among health professionals working in rural community mental health services. Importantly, those who have worked for several years in rural positions hold important information through which to explore factors that impact retention in rural and remote regions.
Interaction of thymic stromal lymphopoietin, IL‐33, and their receptors in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps
Authors: Liao B. , Cao P.‐P. , Zeng M. , Zhen Z. , Wang H. , Zhang Y.‐N. , Hu C.‐Y. , Ma J. , Li Z.‐Y. , Song J. , Liu J.‐X. , Peng L.‐Y. , Liu Y. , Ning Q. , Liu Z.
Published: June 2015

Background

Thymic stromal lymphopoietin (TSLP), IL‐25, and IL‐33 system contribute to the initiation and development of Th2 responses. This study aimed to explore the involvement of TSLP, IL‐25, IL‐33, and their receptors in type 2 T‐helper (Th) responses in chronic rhinosinusitis with nasal polyps (CRSwNPs) and their cross‐regulation in human nasal epithelial cells (HNECs).

Methods

Immunohistochemistry, quantitative RT‐PCR, ELISA, Bio‐Plex assay, and flow cytometry were used to detect the expression of TSLP/common γ‐like TSLP receptor (TSLPR)/IL‐7 receptor α (IL‐7Rα), IL‐25/IL‐17B receptor (IL‐17RB), and IL‐33/membrane‐bound ST2 (ST2L)/soluble ST2 (sST2) in sinonasal mucosa and HNECs. HNECs cultured at an air–liquid interface were used to explore the expression in regulation of these cytokine systems.

Results

Compared with controls and noneosinophilic CRSwNP, the expression of TSLP/TSLPR/IL‐7Rα and ST2L/sST2 was significantly increased in eosinophilic CRSwNP, predominantly in epithelial cells. In contrast, the expression of IL‐33 and IL‐25/IL‐17RB was enhanced in epithelial cells in both eosinophilic and noneosinophilic CRSwNP compared to controls. The expression of TSLP, TSLPR, and ST2L was positively correlated with symptom and computer tomography scan scores in eosinophilic CRSwNP and with Th2 cytokine expression in sinonasal mucosa. The expression of ST2L was correlated with TSLP and its receptor expression. TSLP could induce ST2L expression that promoted IL‐33‐induced TSLP expression in HNECs. In addition, TSLP/TSLPR/IL‐7Rα and ST2L could be induced by Th2 cytokines, while IL‐25/IL‐17RB and IL‐33 could be upregulated by Th1/Th17 cytokines, in HNECs.

Conclusions

The positive feedback loop between TSLP, IL‐33 and their receptors, and Th2 cytokines may facilitate Th2‐skewed inflammation in eosinophilic CRSwNP.
Urinary 11β‐PGF2α and N‐methyl histamine correlate with bone marrow biopsy findings in mast cell disorders
Authors: Divekar R. , Butterfield J.
Published: June 2015

Background

The utility of measuring histamine and prostaglandin metabolites in the urine of patients with mastocytosis has not been critically examined in a large series of patients. This study examined the relationship between the extent of increase in urinary excretion of 11β‐prostaglandinF2α and N‐methyl histamine, with serum tryptase, whole blood serotonin, and bone marrow findings including morphology, percentage involvement, and abnormal mast cell phenotype.

Methods

This was a retrospective analysis of 90 patients who were continuously enrolled in the study for a period of 6 years (2008–2014). We recorded serum tryptase, whole blood serotonin, levels of urinary mast cell metabolites 11β‐prostaglandinF2α and N‐methyl histamine (NMH), and bone marrow findings.

Results

Urinary mast cell metabolites 11β‐prostaglandinF2α and N‐methyl histamine correlated with levels of serum tryptase, mast cell burden in the bone marrow, the presence of mast cell aggregates, and atypical mast cells on bone marrow biopsy. Whole blood serotonin did not have a significant correlation with the serum tryptase or mast cell burden in the bone marrow. Urinary NMH was significantly different between c‐kit D816V‐positive and c‐kit D816V‐negative patients, while 11β‐prostaglandinF2α was not. Urinary 11β‐prostaglandinF2α 24‐h excretion >3500 ng and NMH levels >400 μg/gm Cr corresponded with the high degree of bone marrow biopsies positive for atypical mast cells, the presence of aggregates, and c‐kit mutation.

Conclusions

Easily obtained and quantified urinary metabolites of histamine (greater than twice the upper limit of normal) and prostaglandin D2 (>3.4 times the upper limit of normal) correlate well with bone marrow findings of mastocytosis.
Sensitization pattern affects the asthma risk in Finnish adult population
Authors: Toppila‐Salmi S. , Huhtala H. , Karjalainen J. , Renkonen R. , Mäkelä M. J. , Wang D. Y. , Pekkanen J.
Published: June 2015

Background

There is a large global variation in the sensitization pattern and its association with allergic diseases. In temperate and tropical urban environments, mite monosensitization can be the predominant cause of allergic airway diseases, whereas in other environments, polysensitization is more typical. Sensitization to mite allergens associates with asthma. However, it is suggested that mite sensitization might play a minor role in Northern Europe. The aim of the study was to analyze how sensitization pattern affects the asthma risk in Finnish adults, with a special focus on mites.

Methods

A population‐based case–control data (N = 523) from Finnish adult asthma patients with one or two matched controls were used. Asthma was diagnosed based on a typical history of asthmatic symptoms and lung function tests. The allergic sensitization was determined based on skin prick test (SPT) of five mites, three molds, and nine other aeroallergens. Information on demographics was obtained by a questionnaire.

Results

The proportion of sensitization to any allergen was 55% in the asthma group and 39% in the control group (P = 0.001, OR 2.06, 95% CI = 1.35–3.14). Sensitization to animal dander, pollen, or Aspergillus fumigatus was associated with asthma. Polysensitization to more than one allergen types and the number of SPT‐positive reactions associated with asthma, whereas sensitization to only one allergen type was not associated with asthma.

Conclusions

The large number of sensitizations to several types of allergens distinguishes subjects with asthma. Mite sensitization had little independent association with asthma in Finland.
H1‐antihistamines for primary mast cell activation syndromes: a systematic review
Authors: Nurmatov U. B. , Rhatigan E. , Simons F. E. R. , Sheikh A.
Published: June 2015

Background

Primary mast cell activation syndromes (MCAS) are a group of disorders presenting with symptoms of mast cell mediator release.

Objectives

To assess the effectiveness and safety of orally administered H1‐antihistamines in the treatment of primary MCAS compared with placebo and other pharmacologic treatments.

Methods

We systematically searched five databases and three trial repositories and contacted an international panel of experts to identify published and unpublished trials.

Results

A total of 36 potentially relevant studies were identified. Of these, five crossover trials, enrolling a total of 71 patients (63 adults), met the eligibility criteria. All five of these studies were judged to be at moderate or high risk of bias. Two studies compared an H1‐antihistamine with placebo, two compared two different H1‐antihistamines, and one study compared H1‐ and H2‐antihistamines with oral cromolyn sodium. Four of the five randomized controlled trials were historic (reported from 1983–1993), small (enrolling 8–15 patients), and used agents and/or dosing regimens that are now less commonly used in clinical practice (i.e. azelastine, chlorpheniramine, hydroxyzine, and ketotifen). The fifth trial, which enrolled 33 adults with cutaneous and systemic mastocytosis found 4 weeks of treatment with the second‐generation H1‐antihistamine rupatadine, compared with placebo, resulted in significant improvements in quality of life, symptom control (itching, wheals and flares, flushing, tachycardia, and headache, but not gastrointestinal symptoms), and reduction in itching and whealing after standardized skin provocation to elicit Darier's sign.

Conclusions

There is an urgent need for large, well‐designed, double‐blind, placebo‐controlled randomized trials investigating the effectiveness, cost‐effectiveness, and safety of second‐generation H1‐antihistamines in treatment of primary MCAS.
Extended Analysis of At Least Partially Ordered Multi‐factor ANOVA
Authors: Rayner J. C. W. , Best D. J. , Thas O.
Published: June 2015

For multifactor experimental designs in which the levels of at least one of the factors are ordered we show how to construct components that provide a deep nonparametric scrutiny of the data. The components assess generalised correlations and the resulting tests include and extend the Page and umbrella tests. Application of the tests described is straightforward. Orthonormal polynomials on the ANOVA responses and the factors are required and the formulae needed are given subsequently. These depend on the moments of the responses and of each factor and are easily calculated. Products of at least two of these orthonormal polynomials are then used as inputs into standard ANOVA routines. For example, using the first order orthonormal polynomial on factor A and the second order orthonormal polynomial on the ANOVA response will assess if, with increasing levels of factor A there is an umbrella response with either an increase and then a decrease or a decrease and then an increase.
Screen time is independently associated with health‐related quality of life in overweight and obese adolescents
Authors: Goldfield Gary S. , Cameron Jameason D. , Murray Marisa , Maras Danijela , Wilson Angela L. , Phillips Penny , Kenny Glen P. , Hadjiyannakis Stasia , Alberga Angela S. , Tulloch Heather , Doucette Steve , Sigal Ronald J.
Published: June 2015

Aim

Excessive screen time and diminished health‐related quality of life (HRQoL) are greater problems for obese than nonobese adolescents, but no research has examined the relationship between these two variables. This study examined the association between screen time and HRQoL in overweight and obese adolescents.

Methods

A sample of 358 overweight and obese adolescents aged 14–18 years were assessed at baseline between 2005 and 2010 as part of the Canadian Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY) trial. We used the Pediatric Quality of Life (PEDS‐QL) and other self‐report measures to assess HRQoL and screen time, defined as how long the 261 females and 97 males spent viewing TV, using the computer and playing video games.

Results

After adjusting for socio‐demographic variables, adiposity, physical activity and diet, screen time duration was associated with reduced overall HRQoL (adjusted r = −0.16, ß = −0.16, p = 0.009) and psychosocial HRQoL (adjusted r = −0.16, ß = −0.18, p = 0.004), but not physical HRQoL. No differences were found between males and females.

Conclusion

Screen time was associated with reduced overall and psychosocial HRQoL in overweight and obese adolescents. Future research should determine whether reducing screen time improves overall and psychosocial HRQoL in obese adolescents.
Headache and Nausea after Treatment with High‐Dose Subcutaneous versus Intravenous Immunoglobulin
Authors: Markvardsen Lars H. , Christiansen Ingelise , Andersen Henning , Jakobsen Johannes
Published: June 2015

Treatment with intravenous immunoglobulin (IVIG) leads to transient side effects such as headache and nausea during and after the infusion. We hypothesized that subcutaneous administration of smaller doses of immunoglobulin (SCIG) given more frequently leads to less severe headache and nausea and could be an alternative in patients experiencing side effects. Fifty‐nine patients diagnosed with neurological disorders (chronic inflammatory demyelinating polyneuropathy (CIDP), multi‐focal motor neuropathy (MMN) or post‐polio syndrome) were treated with IVIG, and 27 CIDP or MMN patients with SCIG. For two consecutive weeks daily, registration of the severity of headache and nausea was registered on a visual analogue scale (VAS) from 0 to 100 mm. In the SCIG group, headache reached a peak value of 1 (0–13) mm at day 6 versus 11 (0–96) mm in the IVIG group at day 4 (p < 0.0001). For nausea, the SCIG group had a stable value of 0 (0–21) mm at all days, whereas a peak value of 3 (0–90) mm was reached at day 4 in the IVIG group (p < 0.0001). SCIG leads to less severe headache and nausea than IVIG without fluctuations of side effects in relation to the injections.
Late Holocene high precipitation events recorded in lake sediments and catchment geomorphology, Lake Vuoksjávrátje, NW Sweden
Authors: Berntsson Annika , Jansson Krister N. , Kylander Malin E. , De Vleeschouwer Francois , Bertrand Sebastien
Published: June 2015

In this paper, we show the potential of combining multi‐proxy analysis of lake sediments with catchment geomorphology to better understand palaeoenvironmental changes. Previous studies have suggested that alpine lakes in N Sweden may be highly sensitive to variations in catchment erosion and precipitation, and that this sensitivity may influence ecologically based reconstructions of past temperature changes. We analysed lake sediments covering the last 5100 years from the alpine Lake Vuoksjávrátje in NW Sweden in order to identify different erosional regimes in the lake catchment, sediment sources and lake sedimentary processes, which ultimately affect the palaeoecological record. The measured proxies include elemental geochemistry from XRF core scanning, grain size, sediment accumulation rates, fraction of terrestrial organic carbon and geomorphological mapping, supported by previously published chironomid and total organic carbon data. From the integrated results we identified time intervals when increased intensity of precipitation altered sedimentation and lake catchment erosional processes. The most prominent event occurred c. 2900 cal. a BP and is interpreted to be the result of excessive precipitation, possibly related to the climatic shift towards cooler and wetter conditions referred to as the 2.8 ka event.
Diatom response to Asian monsoon variability during the Holocene in a deep lake at the southeastern margin of the Tibetan Plateau
Authors: Li Yanling , Liu Enfeng , Xiao Xiayun , Zhang Enlou , Ji Ming
Published: June 2015

Diatom analysis was applied to a 5.56‐m‐long sediment core, spanning the last 7.8 ka, from Lake Chenghai on the southeastern margin of the Tibetan Plateau. Diatom assemblages are dominated byCyclotella rhomboideo‐elliptica,Cyclostephanos dubiusand small fragilarioid and periphytic taxa. These diatom taxa are interpreted to be sensitive to changes in trophic status and/or turbulence of the water column that are probably related to variations in precipitation and temperature induced through the Asian monsoon. High abundances ofC. dubius,Staurosirella pinnataand periphytic taxa suggest higher trophic status (mesotrophic) and stronger turbulence in the water column in the middle Holocene (7.8–4.5 kaBP). During the period of 4.5–2.3 kaBP, a decline inC. dubius,S. pinnataand periphytic taxa, and an increase inC. rhomboideo‐ellipticawith the appearance ofCyclotella ocellatasuggests a response to decreasing trophic level (more oligotrophic). After 2.3 kaBP, the persistent increases in C. rhomboideo‐ellipticaand the loss ofCyclotella ocellatamirrored a further decrease in trophic level (oligotrophic). The main changes in the diatom assemblages in the Lake Chenghai sediment core reflect direct and indirect climate forcing and in particular, the strength of monsoonal precipitation, which in turn corresponds to orbitally induced variability in Northern Hemisphere summer solar insolation since 7.8 kaBP.
Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt‐induced hypertension in mice
Authors: Krishnan S M , Dowling J K , Ling Y H , Diep H , Chan C T , Ferens D , Kett M M , Pinar A , Samuel C S , Vinh A , Arumugam T V , Hewitson T D , Kemp‐Harper B K , Robertson A A B , Cooper M A , Latz E , Mansell A , Sobey C G , Drummond G R
Published: June 2015

Background and Purpose

Inflammasomes are multimeric complexes that facilitate caspase‐1‐mediated processing of the pro‐inflammatory cytokines IL‐1β and IL‐18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL‐1β and IL‐18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis.

Experimental Approach

Wild‐type and inflammasome‐deficient ASC−/− mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real‐time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry.

Key Results

1K/DOCA/salt‐induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro‐caspase‐1, and the cytokine, pro‐IL‐1β, as well as protein levels of active caspase‐1 and mature IL‐1β. Following treatment with 1K/DOCA/salt, ASC−/− mice displayed blunted pressor responses and were also protected from increases in renal expression of IL‐6, IL‐17A, CCL2, ICAM‐1 and VCAM‐1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt‐treated mice.

Conclusions and Implications

Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL‐1β pathway as a potential therapeutic target in hypertension.

Linked Articles

This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2016.173.issue-4
‘Fish’ (Actinopterygii andElasmobranchii) diversification patterns through deep time
Authors: Guinot Guillaume , Cavin Lionel
Published: June 2015

Actinopterygii (ray‐finned fishes) andElasmobranchii (sharks, skates and rays) represent more than half of today's vertebrate taxic diversity (approximately 33000 species) and form the largest component of vertebrate diversity in extant aquatic ecosystems. Yet, patterns of ‘fish’ evolutionary history remain insufficiently understood and previous studies generally treated each group independently mainly because of their contrasting fossil record composition and corresponding sampling strategies. Because direct reading of palaeodiversity curves is affected by several biases affecting the fossil record, analytical approaches are needed to correct for these biases. In this review, we propose a comprehensive analysis based on comparison of large data sets related to competing phylogenies (including allRecent and fossil taxa) and the fossil record for both groups during theMesozoic–Cainozoic interval. This approach provides information on the ‘fish’ fossil record quality and on the corrected ‘fish’ deep‐time phylogenetic palaeodiversity signals, with special emphasis on diversification events. Because taxonomic information is preserved after analytical treatment, identified palaeodiversity events are considered both quantitatively and qualitatively and put within corresponding palaeoenvironmental and biological settings. Results indicate a better fossil record quality for elasmobranchs due to their microfossil‐like fossil distribution and their very low diversity in freshwater systems, whereas freshwater actinopterygians are diverse in this realm with lower preservation potential. Several important diversification events are identified at familial and generic levels for elasmobranchs, and marine and freshwater actinopterygians, namely in theEarly–MiddleJurassic (elasmobranchs),LateJurassic (actinopterygians),EarlyCretaceous (elasmobranchs, freshwater actinopterygians),Cenomanian (all groups) and thePaleocene–Eocene interval (all groups), the latter two representing the two most exceptional radiations among vertebrates. For each of these events along with theCretaceous‐Paleogene extinction, we provide an in‐depth review of the taxa involved and factors that may have influenced the diversity patterns observed. Among these, palaeotemperatures, sea‐levels, ocean circulation and productivity as well as continent fragmentation and environment heterogeneity (reef environments) are parameters that largely impacted on ‘fish’ evolutionary history, along with other biotic constraints.
Does the EarPopper® device improve hearing outcomes in children with persistent otitis media with effusion? A randomised single‐blinded controlled trial
Authors: Banigo A. , Hunt A. , Rourke T. , Whiteside O. , Aldren C.
Published: June 2015

Objective

To provide an independent evaluation of the efficacy and safety of the EarPopper® in improving hearing outcomes in children with otitis media with effusion (OME) and reducing the ventilation tube insertion rate.

Study Design

Randomised single‐blinded controlled trial.

Setting

The Ear Nose and Throat Department of a district general hospital (Heatherwood and Wexham Park).

Participants and Methods

Twenty‐nine children aged between 4 and 11 years diagnosed with persistent OME lasting at least 3 months with an average hearing of 25 dBHL or worse in the better ear were randomised to a treatment or control group for 7 weeks using random computer‐generated codes. Syndromic children, children with developmental delay, previous grommets and cleft palate were excluded. The audiologists were blinded at the final post‐treatment audiogram.

Results

After the seven‐week period, the mean improvement in air conduction across all frequencies was 10.9 dBHL in the treatment group (P < 0.001) and 3.6 dBHL in the control group (P = 0.201). At every frequency, the treatment group had larger improvements in air conduction, the largest being at 4 kHz where the mean air conduction in both ears improved by 14.8 dBHL. Compliance with the EarPopper® was over 90%, the only side‐effect reported being discomfort in the ears immediately after use which resolved and did not affect compliance. The ventilation tube insertion rate was 53.3% in the treatment group and 78.6% in the control group. Median follow‐up time for all patients is 47.7 months.

Conclusion

Our study shows that the EarPopper® is a safe, effective treatment option for children with hearing loss from persistent OME, and it reduces the rate of ventilation tube insertion. More studies with larger sample sizes are required to support our findings.
Tricyclic antidepressants for the treatment of tenesmus associated with rectal prolapse
Authors: Livovsky D. M. , Adler S. N. , Adar T. , Bar‐Gil Shitrit A. , Lysy J.
Published: June 2015

Aim

Tenesmus in rectal prolapse leads to a vicious circle of straining with deterioration of prolapse. The primary phenomenon triggering this may be rectal hypersensitivity. We aimed to assess whether treatment with tricyclic antidepressants (TCAs) may break the vicious circle and improve tenesmus.

Method

A retrospective review was carried out of patients with rectal prolapse and severe tenesmus who were poor surgical candidates or had refused surgery. They were treated at our tertiary centre with low dose tricyclic antidepressants.

Results

Twenty‐three (18 female) patients were included, with mean age 75.3 (±SD 14.6) years. The mean duration of symptoms was 10.8 (± 8.6) months. Full‐thickness rectal prolapse was diagnosed in 16 (70%) patients while seven (30%) had mucosal or incomplete prolapse. Ten (43%), eight (35%) and five (22%) patients were treated with nortriptyline (25 mg daily), amitriptyline (10 mg daily) and desipramine (25 mg daily). After a mean follow‐up of 9.05 (± 8.2) months, 14 (61%) patients reported significant improvement in symptoms, five (22%) had a partial response, three (13%) were lost to follow‐up and one (4%) failed to respond. The response rates for nortriptyline, desipramine and amitriptyline were 90%, 100% and 62.5%.

Conclusion

To the best of our knowledge this is the first report to address the symptomatic, conservative treatment of tenesmus in patients with rectal prolapse. TCAs may be an acceptable option for poor surgical candidates or patients refusing surgery.
Taking Natural Limits Seriously: Implications for Development Studies and the Environment
Authors: Vira Bhaskar
Published: June 2015

This article explores how thinking about ecological limits, thresholds and boundaries has evolved in the last few decades, and explores the analytical and political possibilities that emerge if development studies scholars engage with these ideas. It makes the case for an engaged political economy approach, which focuses on understanding how finite resources at a variety of scales are shared between the competing claims of different groups in society. The article suggests that, while the science of planetary limits is important, the most significant societal challenges are not about how close we are to the limits, but involve finding mechanisms to reconcile the difficult trade‐offs that inevitably arise when we consider alternative human pathways in the present and the future. Choices are ubiquitous, even when there may be no immediate ecological tipping point, and a political economy perspective focuses on the ways in which humanity prioritizes different, often irreconcilable, objectives and interests in relation to the environment. The productive consequence of this thinking for development studies is the need for a renewed focus on the key issues that define prosperity and well‐being, as well as the political and moral economy within which human society governs itself, and its relationships with nature.
Carbonic anhydrase inhibition blocks skeletogenesis and echinochrome production in Paracentrotus lividus and Heliocidaris tuberculata embryos and larvae
Authors: Zito Francesca , Koop Demian , Byrne Maria , Matranga Valeria
Published: June 2015

Carbonic anhydrases (CAs) are a family of widely distributed metalloenzymes, involved in diverse physiological processes. These enzymes catalyse the reversible conversion of carbon dioxide to protons and bicarbonate. At least 19 genes encoding for CAs have been identified in the sea urchin genome, with one of these localized to the skeletogenic mesoderm (primary mesenchyme cells, PMCs). We investigated the effects of a specific inhibitor of CA, acetazolamide (AZ), on development of two sea urchin species with contrasting investment in skeleton production, Paracentrotus lividus and Heliocidaris tuberculata, to determine the role of CA on PMC differentiation, skeletogenesis and on non‐skeletogenic mesodermal (NSM) cells. Embryos were cultured in the presence of AZ from the blastula stage prior to skeleton formation and development to the larval stage was monitored. At the dose of 8 mmol/L AZ, 98% and 90% of P. lividus and H. tuberculata embryos lacked skeleton, respectively. Nevertheless, an almost normal PMC differentiation was indicated by the expression of msp130, a PMC‐specific marker. Strikingly, the AZ‐treated embryos also lacked the echinochrome pigment produced by the pigment cells, a subpopulation of NSM cells with immune activities within the larva. Conversely, all ectoderm and endoderm derivatives and other subpopulations of mesoderm developed normally. The inhibitory effects of AZ were completely reversed after removal of the inhibitor from the medium. Our data, together with new information concerning the involvement of CA on skeleton formation, provide evidence for the first time of a possible role of the CAs in larval immune pigment cells.
Valproic acid hypersensitivity and desensitization
Authors: Toker Ori , Tal Yuval , Horev Liran , Shmoeli Dorit , Gilboa Tal
Published: June 2015

Rash, a hypersensitivity reaction, is a common cause of withdrawal from an effective antiepileptic drug (AED) in patients with epilepsy. We present a case of successful desensitization to valproic acid in a 12‐year‐old male with childhood absence epilepsy and a hypersensitivity reaction, whose epilepsy did not respond to other AEDs. Desensitization is a practical therapeutic solution for patients who develop a non‐life‐threatening hypersensitivity reaction to an AED for which there may be no substitute.
THE EFFECTS OF ASSET FORFEITURE ON POLICING: A PANEL APPROACH
Authors: Kelly Brian D. , Kole Maureen
Published: June 2015

Asset forfeiture has proven highly controversial in the United States since its expansion in 1984. Most contentious is the widespread policy that allows police agencies to keep the assets seized, which both proponents and critics assert changes police behavior. From newly developed panel data sets, we find some statistical support for the proposition that police agencies change the intensity and pattern of policing in response to forfeiture. However, in economic terms these effects are very weak and do not support the proposition that forfeiture provides vital funds and incentives for crime policing. (JEL H39, H71, K42)
Targeted ultradeep next‐generation sequencing as a method for KITD816V mutation analysis in mastocytosis
Authors: Kristensen Thomas , Broesby‐Olsen Sigurd , Vestergaard Hanne , Bindslev‐Jensen Carsten , Møller Michael Boe ,   the Mastocytosis Centre Odense University Hospital (MastOUH)
Published: June 2015

Next‐generation sequencing (NGS) is becoming increasingly used for diagnostic mutation analysis in myeloid neoplasms and may also represent a feasible technique in mastocytosis. However, detection of the KIT D816V mutation requires a highly sensitive method in most patients due to the typically low mutation levels. In this study, we established an NGS‐based KIT mutation analysis and analyzed the sensitivity of D816V detection using the Ion Torrent platform. Eighty‐two individual NGS analyses were included in the study. All samples were also analyzed using highly sensitive KIT D816V mutation‐specific qPCR. Measurements of the background level in D816V‐negative samples supported a cutoff for positivity of 0.2% in three different NGS panels. Clinical samples from patients with SM that tested positive using qPCR with a D816V allele burden >0.2% also tested positive using NGS. Samples that tested positive using qPCR with an allele burden <0.2% tested negative using NGS. We thereby demonstrate that caution should be taken when using the potentially very sensitive NGS technique for KIT D816V mutation analysis in mastocytosis, as many patients with SM have D816V mutation levels below the detection limit of NGS. A dedicated and highly sensitive KIT D816V mutation analysis therefore remains important in mastocytosis diagnostics.
Direct‐acting oral anticoagulants: pharmacology, indications, management, and future perspectives
Authors: Gómez‐Outes Antonio , Suárez‐Gea Mª Luisa , Lecumberri Ramón , Terleira‐Fernández Ana Isabel , Vargas‐Castrillón Emilio
Published: June 2015

In recent years, several direct‐acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa®, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto®, Bayer HealthCare), apixaban (Eliquis®, Bristol‐Myers Squibb), and edoxaban (Lixiana®/Savaysa®, Daiichi‐Sankyo). The new compounds have a predictable dose response and few drug–drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.
Computing reward‐prediction error: an integrated account of cortical timing and basal‐ganglia pathways for appetitive and aversive learning
Authors: Morita Kenji , Kawaguchi Yasuo
Published: June 2015

There are two prevailing notions regarding the involvement of the corticobasal ganglia system in value‐based learning: (i) the direct and indirect pathways of the basal ganglia are crucial for appetitive and aversive learning, respectively, and (ii) the activity of midbrain dopamine neurons represents reward‐prediction error. Although (ii) constitutes a critical assumption of (i), it remains elusive how (ii) holds given (i), with the basal‐ganglia influence on the dopamine neurons. Here we present a computational neural‐circuit model that potentially resolves this issue. Based on the latest analyses of the heterogeneous corticostriatal neurons and connections, our model posits that the direct and indirect pathways, respectively, represent the values of upcoming and previous actions, and up‐regulate and down‐regulate the dopamine neurons via the basal‐ganglia output nuclei. This explains how the difference between the upcoming and previous values, which constitutes the core of reward‐prediction error, is calculated. Simultaneously, it predicts that blockade of the direct/indirect pathway causes a negative/positive shift of reward‐prediction error and thereby impairs learning from positive/negative error, i.e. appetitive/aversive learning. Through simulation of reward‐reversal learning and punishment‐avoidance learning, we show that our model could indeed account for the experimentally observed features that are suggested to support notion (i) and could also provide predictions on neural activity. We also present a behavioral prediction of our model, through simulation of inter‐temporal choice, on how the balance between the two pathways relates to the subject's time preference. These results indicate that our model, incorporating the heterogeneity of the cortical influence on the basal ganglia, is expected to provide a closed‐circuit mechanistic understanding of appetitive/aversive learning.
Adolescent‐onset GABAAα1 silencing regulates reward‐related decision making
Authors: Butkovich Laura M. , DePoy Lauren M. , Allen Amanda G. , Shapiro Lauren P. , Swanson Andrew M. , Gourley Shannon L.
Published: June 2015

The GABAA receptor mediates fast, inhibitory signaling, and cortical expression of the α1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABAAα1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABAAα1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral‐mediated gene silencing of Gabra1. Adolescent‐onset Gabra1 knockdown delayed the acquisition of a cocaine‐reinforced instrumental response but spared cocaine seeking in extinction and in a cue‐induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action–outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent‐onset knockdown, although not adult‐onset knockdown, delayed the expression of goal‐directed response strategies in this task, resulting instead in inflexible habit‐like modes of response. Thus, the maturation of medial prefrontal cortex GABAAα1 systems during adolescence appears necessary for goal‐directed reward‐related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity.
The retrotrapezoid nucleus stimulates breathing by releasing glutamate in adult conscious mice
Authors: Holloway Benjamin B. , Viar Kenneth E. , Stornetta Ruth L. , Guyenet Patrice G.
Published: June 2015

The retrotrapezoid nucleus (RTN) is a bilateral cluster of neurons located at the ventral surface of the brainstem below the facial nucleus. The RTN is activated by hypercapnia and stabilises arterial Pco2 by adjusting lung ventilation in a feedback manner. RTN neurons contain vesicular glutamate transporter‐2 (Vglut2) transcripts (Slc17a6), and their synaptic boutons are Vglut2‐immunoreactive. Here, we used optogenetics to test whether the RTN increases ventilation in conscious adult mice by releasing glutamate. Neurons located below the facial motor nucleus were transduced unilaterally to express channelrhodopsin‐2 (ChR2)–enhanced yellow fluorescent protein, with lentiviral vectors that employ the Phox2b‐activated artificial promoter PRSx8. The targeted population consisted of two types of Phox2b‐expressing neuron: non‐catecholaminergic neurons (putative RTN chemoreceptors) and catecholaminergic (C1) neurons. Opto‐activation of a mix of ChR2‐expressing RTN and C1 neurons produced a powerful stimulus frequency‐dependent (5–15 Hz) stimulation of breathing in control conscious mice. Respiratory stimulation was comparable in mice in which dopamine‐β‐hydroxylase (DβH)‐positive neurons no longer expressed Vglut2 (DβHCre/0;;Vglut2fl/fl). In a third group of mice, i.e. DβH+/+;;Vglut2fl/fl mice, we injected a mixture of PRSx8‐Cre lentiviral vector and Cre‐dependent ChR2 adeno‐associated virus 2 unilaterally into the RTN; this procedure deleted Vglut2 from ChR2‐expressing neurons regardless of whether or not they were catecholaminergic. The ventilatory response elicited by photostimulation of ChR2‐positive neurons was almost completely absent in these mice. Resting ventilatory parameters were identical in the three groups of mice, and their brains contained similar numbers of ChR2‐positive catecholaminergic and non‐catecholaminergic neurons. From these results, we conclude that RTN neurons increase breathing in conscious adult mice by releasing glutamate.
Can we use peripheral tissue biopsies to diagnose Parkinson's disease? A review of the literature
Authors: Schneider S. A. , Boettner M. , Alexoudi A. , Zorenkov D. , Deuschl G. , Wedel T.
Published: June 2015

Phosphorylated α‐synuclein (phosαSYN) containing inclusions in neurons (Lewy bodies, LB) and nerve terminals (Lewy neurites, LN), the pathological hallmark of Parkinson's disease (PD), are not confined to the central nervous system, but have also been reported in peripheral tissues. However, the usefulness of αSYN/phosαSYN detection in tissues accessible to biopsies as a reliable biomarker for prodromal PD remains unclear. A systematic review of studies using biopsies of skin, olfactory and gastrointestinal (GI) tissues was conducted to evaluate the sensitivity and specificity of both αSYN and phosαSYN staining in PD patients. Data analysis was hampered by the diversity of the methods used, e.g. choice of biopsy sites, tissue processing, staining protocols and evaluation of the findings. Tissue obtained from GI tract/salivary glands (13 post‐mortem, 13 in vivo studies) yielded the highest overall sensitivity and specificity compared to skin (three post‐mortem, eight in vivo studies) and olfactory mucosa/bulb (six post‐mortem studies, one in vivo study). In contrast to phosαSYN, αSYN was more consistently detectable in peripheral tissues of healthy controls. GI tract/salivary glands appear to be the most promising candidate tissue for peripheral biopsy‐taking. phosαSYN is considered as the marker of choice to delineate pathological aggregates from normal αSYN regularly found in peripheral neural tissues. However, the sensitivity and specificity of phosαSYN are not yet acceptable for using phosαSYN as a reliable peripheral biomarker for PD in clinical routine. Further refinement regarding the interpretation of the peripheral αSYN/phosαSYN burden and the phenotypical definition of peripheral LB/LN is needed to optimize screening methods for prodromal PD.
Photoperiodic induction of prepupal diapause and its role in synchronization with host phenology in the hibiscus caterpillar, Xanthodes transversa
Authors: Shintani Yoshinori , Kawazu Kei , Hirose Yuzuru
Published: June 2015

The hibiscus caterpillar, Xanthodes transversa (Lepidoptera: Noctuidae), is a multivoltine insect that is an important pest of Malvaceae plants such as the okra, Abelmoschus esculentus, and the common rose mallow, Hibiscus mutabilis, in Japan. In the present study, the effects of photoperiod and temperature on the induction of prepupal diapause and the adaptive significance of this diapause were examined in a local population of X. transversa in Miyazaki, Kyushu, southwestern Japan. Larvae showed a long‐day photoperiodic response for controlling the induction of prepupal diapause with a critical day length between 13 and 14 h at 20 to 25°C. Under long‐day conditions larvae rapidly pupated from the sixth instar, but under short‐day conditions they entered diapause in the prepupal stage. Diapause occurrence in the field increased in late September, which was consistent with the laboratory results in terms of the photoperiodic response. Non‐diapause development after this time is maladaptive because most larvae of the next generation could not reach the critical stage (prepupae) before winter and died during early winter in outdoor experiments. Larvae suffered from a high rate of mortality when fed leaves collected late in autumn. The photoperiodic response for controlling the induction of diapause in this insect may play an important role in synchronizing the life cycle with the seasonal changes in food and temperature conditions.