bluuebunny/crossref_metadata_2025 huggingface dataset:
Right ventricle dimensions and function in response to acute hypoxia in healthy human subjects
Authors: Netzer N. C. , Strohl K. P. , Högel J. , Gatterer H. , Schilz R.
Published: June 2016

Aim

Acute hypoxia produces acute vasoconstriction in the pulmonary circulation with consequences on right ventricular (RV) structure and function. Previous investigations in healthy humans have been restricted to measurements after altitude acclimatization or were interrupted by normoxia. We hypothesized that immediate changes in RV dimensions in healthy subjects in response to normobaric hypoxia differ without the aforementioned constraints.

Methods

Transthoracic echocardiography was performed in 35 young, healthy subjects exposed to 11% oxygen, as well as six controls under sham hypoxia (20.6% oxygen, single blind) first at normoxia and after 30, 60, 100, 150 min of hypoxia or normoxia respectively. A subgroup of 15 subjects continued with 3‐min cycling exercise in hypoxia with subsequent evaluation followed by an assessment 1 min at rest while breathing 4 L min−1 oxygen.

Results

During hypoxia, there was a significant linear increase of all RV dimensions (RVD1 + 29 mm, RVD2 + 42 mm, RVD3 + 41 mm, RVOT + 13 mm, RVEDA + 18 mm, P < 0.01) in the exposure group vs. the control group. In response to hypoxia, right ventricular systolic pressure (RVSP) showed a modest increase in hypoxia at rest (+7.3 mmHg, P < 0.01) and increased further with physical effort (+11.8 mmHg, P < 0.01). After 1 min of oxygen at rest, it fell by 50% of the maximum increase.

Conclusion

Acute changes in RV morphology occur quickly after exposure to normobaric hypoxia. The changes were out of proportion to a relatively low‐estimated increase in pulmonary pressure, indicating direct effects on RV structure. The results in healthy subjects are basis for future clinically oriented interventional studies in normobaric hypoxia.
Relationship between the stockperson's attitudes and dairy productivity in Japan
Authors: Fukasawa Michiru , Kawahata Masatoshi , Higashiyama Yumi , Komatsu Tokushi
Published: June 2016

The aim of this study is to identify the factors that comprise farmer attitudes toward dairy cows and jobs in Japan, and examine the relationship between these attitudes and dairy productivity. At first, we executed a questionnaire survey to determine factors that comprise attitudes of farmers toward their jobs and dairy cows, and three factors were extracted. These were named as ‘Positive beliefs to cows’, ‘Negative beliefs to cows’ and ‘Job satisfaction’, respectively. Second, we examined the relationships between attitude and dairy productivity in 35 dairy farms. The positive beliefs scores correlated positively both with milk yield and milk urea nitrogen concentration. We found there to be three farm groups by cluster analysis using three attitude score. The group B farms showed significantly higher positive beliefs scores and job satisfaction scores; on the other hand, the group C farms showed significantly lower positive beliefs scores and higher negative belief scores. The milk yield in group B was significantly higher than that in group C. This study showed that Japanese farmers' attitudes toward cows considerably resemble those seen in previous studies in Western cultures. Positive attitudes toward cows could enhance stockmanship, and could improving animal welfare and productivity.
Prospective dose selection and acceleration of paliperidone palmitate 3‐month formulation development using a pharmacometric bridging strategy
Authors: Samtani Mahesh N. , Nandy Partha , Ravenstijn Paulien , Remmerie Bart , Vermeulen An , Russu Alberto , D'hoore Peter , Baum Ellen Z. , Savitz Adam , Gopal Srihari , Hough David
Published: June 2016

Aims

To prospectively select the dose of the paliperidone palmitate 3‐month (PP3M) formulation, using a pharmacometric bridging strategy based on the paliperidone palmitate 1‐month (PP1M) formulation previously approved for schizophrenia treatment.

Methods

Pharmacokinetic (PK) data from a 6‐month interim analysis of a single dose PP3M Phase I clinical trial was integrated with a previously developed PP1M population‐PK model. The model was updated to incorporate formulation as a covariate on absorption parameters and to explore the most critical design element of the Phase III study: the PP1M‐to‐PP3M dose multiplier for patients switching formulations. Plasma paliperidone concentrations were measured at predetermined intervals during Phase III, enabling comparison of the multiple‐dose PK between PP1M and PP3M. Exposure matching was assessed graphically to determine whether paliperidone plasma concentrations from the two formulations overlapped.

Results

Prospective steady‐state PK simulations revealed that a 3.5 multiple of the PP1M dose would yield a corresponding PP3M dose with comparable exposure. The prospective pharmacometric simulation and observed Phase III PK data agreed closely. Phase III results confirmed the hypothesis that efficacy of PP3M was noninferior to that of PP1M. The similarity in exposures between the two formulations was likely a key determinant of the equivalent efficacy between the two products observed in the Phase III study.

Conclusions

Successful prospective PP3M Phase III clinical trial dose selection was achieved through the use of pharmacometric bridging, without conducting a Phase II study and using only limited Phase I data for PP3M. We estimate that this strategy reduced development time by 3–5 years and may be applicable to other drug development projects.
Physical Exercise and Brain Mitochondrial Fitness: The Possible Role Against Alzheimer's Disease
Authors: Bernardo T.C. , Marques‐Aleixo I. , Beleza J. , Oliveira P.J. , Ascensão A. , Magalhães J.
Published: June 2016

Exercise is one of the most effective strategies to maintain a healthy body and mind, with particular beneficial effects of exercise on promoting brain plasticity, increasing cognition and reducing the risk of cognitive decline and dementia in later life. Moreover, the beneficial effects resulting from increased physical activity occur at different levels of cellular organization, mitochondria being preferential target organelles. The relevance of this review article relies on the need to integrate the current knowledge of proposed mechanisms, focus mitochondria, to explain the protective effects of exercise that might underlie neuroplasticity and seeks to synthesize these data in the context of exploring exercise as a feasible intervention to delay cognitive impairment associated with neurodegenerative conditions, particularly Alzheimer disease.
Mechanism responsible for D‐transposition of the great arteries: Is this part of the spectrum of right isomerism?
Authors: Nakajima Yuji
Published: June 2016

D‐transposition of the great arteries (TGA) is one of the most common conotruncal heart defects at birth and is characterized by a discordant ventriculoarterial connection with a concordant atrioventricular connection. The morphological etiology of TGA is an inverted or arrested rotation of the heart outflow tract (OFT, conotruncus), by which the aorta is transposed in the right ventral direction to the pulmonary trunk. The rotational defect of the OFT is thought to be attributed to hypoplasia of the subpulmonic conus, which originates from the left anterior heart field (AHF) residing in the mesodermal core of the first and second pharyngeal arches. AHF, especially on the left, at the early looped heart stage (corresponding to Carnegie stage 10–11 in the human embryo) is one of the regions responsible for the impediment that causes TGA morphology. In human or experimentally produced right isomerism, malposition of the great arteries including D‐TGA is frequently associated. Mutations in genes involving left–right (L–R) asymmetry, such as NODAL, ACTRIIB and downstream target FOXH1, have been found in patients with right isomerism as well as in isolated TGA. The downstream pathways of Nodal‐Foxh1 play a critical role not only in L–R determination in the lateral plate mesoderm but also in myocardial specification and differentiation in the AHF, suggesting that TGA is a phenotype in heterotaxia as well as the primary developmental defect of the AHF.
Four‐unit fixed dental prostheses replacing the maxillary incisors supported by two narrow‐diameter implants – a five‐year case series
Authors: Moráguez Osvaldo , Vailati Francesca , Grütter Linda , Sailer Irena , Belser Urs C.
Published: June 2016

Objectives

(1) To determine the survival rate of 10 four‐unit fixed dental prostheses (FDPs) replacing the four maxillary incisors, supported by 20 narrow‐diameter implants (NDIs), (2) to assess the incidence of mechanical and biological complications, and (3) to evaluate bone level changes longitudinally after final FDP insertion.

Materials and methods

Ten patients (six women, four men), mean age 49.4 ± 12.6 years, were treated with a four‐unit anterior maxillary FDP (six screw‐retained; four cemented). Biological parameters, eventual technical complications, radiographic measurements, and study casts were assessed at 1 (baseline), 3, and 5 years after implant placement. A multilevel logistic regression test was performed on clinical parameters and bone level changes (significance level P < 0.05).

Results

The 5‐year implant and FDP survival rate was 100%. Mean modified plaque index (mPI) values were 0.03 and 0.02 at 3 and 5 years, significantly lower when compared to mPI (0.11 ± 0.31) at 1 year. Mean modified sulcus bleeding index (mSBI) was 0.08, 0.08, and 0.15 over time. Probing depth (PD) values were 1.57, 1.64, and 2.03 mm. Statistically significant differences were found between 1 vs. 5 year (P = 0.0003) and 3 vs. 5 year (P = 0.001). Keratinized mucosa (3.65 mm) remained stable during observation period. DIB mean values were 2.01 ± 0.34, 2.13 ± 0.13, and 2.17 ± 0.38 mm. Patient satisfaction based on visual analog scale revealed favorable fulfillment of overall treatment and esthetic expectations.

Conclusions

Two NDIs supporting a four‐unit FDP to replace the four missing maxillary incisors may be considered a predictable treatment modality.
DOES THE RIGHT TO CHOOSE MATTER FOR DEFINED CONTRIBUTION PLANS?
Authors: Wong Kin Ming , Tsang Kwok Ping
Published: June 2016

We find that sensitivity of fund flows and fund performance are both related to participants' right to choose their investments in defined contribution plans. Under the Mandatory Provident Fund system of Hong Kong, both employers and employees are required to contribute to a retirement account. Originally, employees' investment choices were restricted to a subset of funds chosen by their employers. The system was later modified so that employees are allowed to invest in any fund within the system. We present evidence that flows of fund have become more sensitive to past fund performance after this policy change, and that average fund performance in the system has also improved. Based on the improvement in fund performance, we estimate the accumulated cost of the lack of choice to be around 10% of the current total asset value of the system. (JEL G14, G18)
Physiological and biological predictors of length of stay and recovery in adults with acute asthma: An observational cohort study
Authors: Jones Thomas L. , Owen Jonathon , Elliott Scott , Brown Thomas , Reynish Dominic , Mistry Heena , Kerley Sumita , Matti Salah , Shute Janis K. , Chauhan Anoop J.
Published: June 2016

Introduction

Asthma is a prevalent, chronic disease associated with significant risk to patients and cost to healthcare systems. Accurate estimates of length of stay and recovery are important for patient information, physician prognostication, and management of inpatient beds.

Objectives

To assess factors affecting length of stay and time to recovery in adults with acute asthma.

Methods

We prospectively recruited adult asthmatic non‐smokers admitted with an asthma exacerbation. Participants were assessed for demographics, symptoms, medications, bloods including blood count, clotting status, and cytokines. Results were analyzed for correlation and subsequently in a regression model.

Results

One hundred twenty‐six participants were recruited of which 75.4% were female. Mean age was 40.0 and mean length of stay was 3.98 days. Length of stay was associated with lower APTT ratio (1 pg/mL (P = 0.04).

Conclusion

Older participants with lower FEV1 and supplemental oxygen requirements are likely to remain in hospital longer. Activation of the “intrinsic” clotting pathway correlates with an increased length of stay as does a raised serum AST. Detectable IL‐12 in plasma correlates with slower recovery and this may be due to poor response to corticosteroids.
Effect of perioperative systemic steroid treatment on patients with obstructive lung disease undergoing elective abdominal surgery
Authors: Lee Hyun Woo , Lee Jung Kyu , Oh So Hee , Kim Deog Kyeom , Chung Hee Soon , Heo Eun Young
Published: June 2016

Introduction

Chronic obstructive pulmonary disease is an independent risk factor of postoperative pulmonary complications (PPCs). It is unknown whether a perioperative systemic corticosteroid would be beneficial in patients with obstructive airway disease.

Objectives

The present study was conducted to determine the effect of a perioperative systemic corticosteroid on PPCs in patients who showed airway obstruction in preoperative spirometry.

Methods

Retrospective medical record reviews were performed on records from January 2010 to December 2011 in a referral hospital. We analyzed the data of patients who were referred to pulmonologists before elective abdominal surgery and had a prebronchodilator FEV1/FVC of <70%. We compared the PPCs between the steroid group and the non‐steroid group.

Results

A total of 270 patients were referred to pulmonologists and, of these, 86 had a FEV1/FVC of <70% in the preoperative spirometry. In the 30 patients in the steroid group, the mean FEV1 was 52.2% and half of these had previously used a bronchodilator. Use of a perioperative systemic corticosteroid was significantly associated with reduced incidence of PPCs in the multivariate logistic regression with adjustment by propensity score (adjusted odds ratio = 0.036, 95% confidence interval [CI] = 0.003–0.505; P = 0.014).

Conclusion

In our retrospective study we showed that those treated with steroids had better outcomes. However, future prospective and randomized controlled trials are needed.
Atorvastatin enhances kainate‐induced gamma oscillations in rat hippocampal slices
Authors: Li Chengzhang , Wang Jiangang , Zhao Jianhua , Wang Yali , Liu Zhihua , Guo Fang Li , Wang Xiao Fang , Vreugdenhil Martin , Lu Cheng Biao
Published: June 2016

Atorvastatin has been shown to affect cognitive functions in rodents and humans. However, the underlying mechanism is not fully understood. Because hippocampal gamma oscillations (γ, 20–80 Hz) are associated with cognitive functions, we studied the effect of atorvastatin on persistent kainate‐induced γ oscillation in the CA3 area of rat hippocampal slices. The involvement of NMDA receptors and multiple kinases was tested before and after administration of atorvastatin. Whole‐cell current‐clamp and voltage‐clamp recordings were made from CA3 pyramidal neurons and interneurons before and after atorvastatin application. Atorvastatin increased γ power by ~ 50% in a concentration‐dependent manner, without affecting dominant frequency. Whereas atorvastatin did not affect intrinsic properties of both pyramidal neurons and interneurons, it increased the firing frequency of interneurons but not that of pyramidal neurons. Furthermore, whereas atorvastatin did not affect synaptic current amplitude, it increased the frequency of spontaneous inhibitory post‐synaptic currents, but did not affect the frequency of spontaneous excitatory post‐synaptic currents. The atorvastatin‐induced enhancement of γ oscillations was prevented by pretreatment with the PKA inhibitor H89, the ERK inhibitor U0126, or the PI3K inhibitor wortmanin, but not by the NMDA receptor antagonist D‐AP5. Taken together, these results demonstrate that atorvastatin enhanced the kainate‐induced γ oscillation by increasing interneuron excitability, with an involvement of multiple intracellular kinase pathways. Our study suggests that the classical cholesterol‐lowering agent atorvastatin may improve cognitive functions compromised in disease, via the enhancement of hippocampal γ oscillations.
DevS/DosS sensor is bifunctional and its phosphatase activity precludes aerobic DevR/DosR regulon expression in Mycobacterium tuberculosis
Authors: Kaur Kohinoor , Kumari Priyanka , Sharma Saurabh , Sehgal Snigdha , Tyagi Jaya Sivaswami
Published: June 2016

Two‐component systems, comprising histidine kinases and response regulators, empower bacteria to sense and adapt to diverse environmental stresses. Some histidine kinases are bifunctional; their phosphorylation (kinase) and dephosphorylation (phosphatase) activities toward their cognate response regulators permit the rapid reversal of genetic responses to an environmental stimulus. DevR–DevS/DosR–DosS is one of the best‐characterized two‐component systems of Mycobacterium tuberculosis. The kinase function of DevS is activated by gaseous stress signals, including hypoxia, resulting in the induction of ~ 48‐genes DevR dormancy regulon. Regulon expression is tightly controlled and lack of expression in aerobic Mtb cultures is ascribed to the absence of phosphorylated DevR. Here we show that DevS is a bifunctional sensor and possesses a robust phosphatase activity toward DevR. We used site‐specific mutagenesis to generate substitutions in conserved residues in the dimerization and histidine phosphotransfer domain of DevS and determined their role in kinase/phosphatase functions. In vitro and in vivo experiments, including a novel in vivo phosphatase assay, collectively establish that these conserved residues are critical for regulating kinase/phosphatase functions. Our findings establish DevS phosphatase function as an effective control mechanism to block aerobic expression of the DevR dormancy regulon. Asp‐396 is essential for both kinase and phosphatase functions, whereas Gln‐400 is critical for phosphatase function. The positive and negative functions perform opposing roles in DevS: the kinase function triggers regulon induction under hypoxia, whereas its phosphatase function prevents expression under aerobic conditions. A finely tuned balance in these opposing activities calibrates the dormancy regulon response output.
Factors affecting parents’ choices of functional foods targeted for children
Authors: Annunziata Azzurra , Vecchio Riccardo , Kraus Artur
Published: June 2016

In recent years the link between diet and disease has become well established, with studies increasingly pointing to the role of diet in disease prevention, as well as its ability to prevent chronic diseases affecting children. As a consequence, there are ever more functional products specifically targeting children, marketed in terms of the benefits conferred on children's health as well as their potential in reducing the risk of disease. The current study aims to explore factors affecting parents’ choices of suitable FFs for their children. The questions addressed in this paper concern how FFs for children are perceived by their parents and what driving factors affect their willingness to purchase FFs. The results from a web survey conducted in southern Italy on a sample of 365 parents of children aged from 1 to 10 years reveal that parents have a strong interest in functional nutrition for their children, even if their level of familiarity with these products is still low. Furthermore, multivariate analysis shows that the buying frequency of FFs targeting children is influenced by several variables, beyond socio‐demographics, generally related to parents’ nutritional knowledge, and trust and familiarity with FFs. The paper provides some practical indications for both policy makers and marketers to build different strategies to improve communication on the nutritional and health benefits of FFs for children.
The influence of source attractiveness on self‐perception and advertising effectiveness for 6‐ to 7‐year‐old children
Authors: Van de Sompel Dieneke , Vermeir Iris
Published: June 2016

The objective of this article is to examine the effects of using attractive peer models in advertising for 6‐ to 7‐year‐old children. This age is important in children's development, as children of that age are not yet fully aware of the persuasive intent of advertising, are more focused on perceptual than on cognitive information in ads and are more focused on irrelevant rather than relevant ad information. More insights are therefore needed about whether attractive advertising models influence self‐perception and advertising effectiveness of children this young, in order to help policy makers, parents and advertisers understand these effects. Two experimental studies are presented in which children are exposed to ads with peer models. Results show that when children of 6‐ to 7‐year‐old rate advertising models as being more attractive, advertising effectiveness raises, but children's perceived self‐worth and children's perceived physical attractiveness are unaffected. We conclude that 6‐ to 7‐year‐old children use model attractiveness as a perceptual cue to rate ads but are not yet using comparisons with these models to evaluate themselves.
Spawning of coral reef invertebrates and a second spawning season for scleractinian corals in the central Red Sea
Authors: Bouwmeester Jessica , Gatins Remy , Giles Emily Clark , Sinclair‐Taylor Tane Hemi , Berumen Michael Lee
Published: June 2016

Recent coral spawning observations in the central Red Sea show that most scleractinian species release their gametes in the spring, with a majority of species spawning in April. There is, however, a lack of reproductive data for several other coral species, as well as a general lack of data for other invertebrates. Here, we document the detailed timing of spawning for 13 scleractinian coral species, one sea anemone, and six echinoderms from an inshore reef off the coast of Thuwal, Saudi Arabia, in the spring between April and June 2014. Furthermore, inferred from the presence of mature gametes, we report the month of spawning for three additional coral species in the spring. Seven scleractinian coral species were inferred to release their gametes in a second reproductive season, in the autumn, between September and November. This is the first report of a second spawning season in the Arabian region. Biannual spawning has so far been reported on the Great Barrier Reef, in Western Australia, in Indonesia, in Malaysia, in Palau, in Thailand, in Taiwan, and in Western Samoa.
Predictors of long‐term drug survival for infliximab in psoriasis
Authors: Magis Q. , Jullien D. , Gaudy‐Marqueste C. , Baumstark K. , Viguier M. , Bachelez H. , Guibal F. , Delaporte E. , Karimova E. , Montaudié H. , Boye T. , Aubin F. , Beylot‐Barry M. , Richard M.‐A. ,   the “Groupe de Recherche sur le Psoriasis de la Société Française”
Published: June 2016

Background

Limited information is available regarding factors associated with long‐term drug survival of infliximab for psoriasis in real life.

Objectives

The main aim pf this study was to identify predictors of long‐term (>12 months) drug survival among patients treated with infliximab for psoriasis in a real‐world clinical setting.

Methods

Retrospectively collected data, relating to disease, patient characteristics and treatment procedures, in a multicentre observational cohort of patients with moderate‐to‐severe plaque psoriasis treated with infliximab at eight university hospitals, 120 of whom maintained a response to infliximab for more than 12 months, were compared with prospectively collected data in the same centres from 54 patients who experienced secondary loss of response within a 12‐month period.

Results

Mean duration of drug survival of infliximab in patients with long‐term drug survival was 41.12 months ± 20.64 SD vs. 8.5 months ± 2.43 SD in patients with a secondary loss of response. Multivariate analysis identified greater disease severity at treatment onset (PASI score >12) (OR = 5.18, 95% CI: 1.60–16.77, P = 0.006), high levels of initial psoriasis clearance (PASI‐90 reduction or equivalent) (OR = 18.50, 95% CI: 4.56–74.45, P = 0.0001) and combination with methotrexate (OR = 13.15, 95% CI: 1.46–118.79, P = 0.022) as independent predictors of long‐term drug survival and sustained efficacy of infliximab.

Conclusion

Positive predictors for long‐term drug survival of infliximab in real life were identified. Their impact on treatment management should be addressed in further prospective trials.
Ecological genetics of sediment browsing behaviour in a planktonic crustacean
Authors: Arbore R. , Andras J.P. , Routtu J. , Ebert D.
Published: June 2016

Zooplankton can display complex habitat selection behaviours that influence the way they interact with their environments. Some species, although primarily pelagic, can exploit sediment‐borne particles as a food source or use sediments as a refuge from pelagic predation. However, this strategy may increase the exposure to other risks such as benthic predation and infection from sediment‐borne parasite transmission stages. The evolution of habitat selection behaviour in these species is thus expected to be influenced by multiple and possibly contrasting selective forces. Here, we study the browsing behaviour of the water flea Daphnia magna on bottom sediments. First, we demonstrated genetic variation for sediment browsing among D. magna genotypes from natural populations sampled across a broad geographic range. Next, we used an F2 recombinant panel to perform a QTL analysis and identified three regions in the D. magna genome contributing to variation in browsing behaviour. We also analysed the correlation between our data and previously published data on the phototactic behaviour of genotypes from the same F2 panel. Clonal means of the two behavioral traits were not correlated, suggesting that they may evolve independently. Browsing behaviour is likely to be a relevant component of habitat selection in D. magna, and its study may help to incorporate the interactions with the sediment into eco‐evolutionary models of this key freshwater species.
Hardness does not affect the physiological responses of wild and domestic strains of diploid and triploid rainbow trout Oncorhynchus mykiss to short‐term exposure to pH 9.5
Authors: Thompson W. A. , Rodela T. M. , Richards J. G.
Published: June 2016

This study examined the effects of water hardness on the physiological responses associated with high pH exposure in multiple strains of diploid and triploid rainbow trout Oncorhynchus mykiss. To accomplish this, three wild strains and one domesticated strain of diploid and triploid O. mykiss were abruptly transferred from control soft water (City of Vancouver dechlorinated tap water; pH 6·7; [CaCO3] < 17·9 mg l−1) to control soft water (handling control), high pH soft water (pH 9·5; [CaCO3] < 17·9 mg l−1), or high pH hard water (pH 9·5; [CaCO3] = 320 mg l−1) followed by sampling at 24 h for physiological measurements. There was a significant effect of ploidy on loss of equilibrium (LOE) over the 24 h exposure, with only triploid O. mykiss losing equilibrium at high pH in both soft and hard water. Furthermore, exposure to pH 9·5 resulted in significant decreases in plasma sodium and chloride, and increases in plasma and brain ammonia with no differences between soft and hard water. There was no significant effect of strain on LOE, but there were significant differences between strains in brain ammonia and plasma cortisol. Overall, there were no clear protective effects of hardness on high pH exposure in these strains of O. mykiss.
Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity
Authors: Han Murui , Chang JuOae , Kim Jonghan
Published: June 2016

The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic anemia. While iron plays an important role in neural function, the behavioral consequences of DMT1 deficiency are largely unexplored. The goal of this study was to define the neurobehavioral and neurochemical phenotypes of homozygous Belgrade (b/b) rats that carry DMT1 mutation and explore potential mechanisms of these phenotypes. The b/b rats (11–12 weeks old) and their healthy littermate heterozygous (+/b) Belgrade rats were subject to elevated plus maze tasks. The b/b rats spent more time in open arms, entered open arms more frequently and traveled more distance in the maze than +/b controls, suggesting increased impulsivity. Impaired emotional behavior was associated with down‐regulation of GABA in the hippocampus in b/b rats. Also, b/b rats showed increased GABAA receptor α1 and GABA transporter, indicating altered GABAergic function. Furthermore, metal analysis revealed that b/b rats have decreased total iron, but normal non‐heme iron, in the brain. Interestingly, b/b rats exhibited unusually high copper levels in most brain regions, including striatum and hippocampus. Quantitative PCR analysis showed that both copper importer copper transporter 1 and exporter copper‐transporting ATPase 1 were up‐regulated in the hippocampus from b/b rats. Finally, b/b rats exhibited increased 8‐isoprostane levels and decreased glutathione/glutathione disulfide ratio in the hippocampus, reflecting elevated oxidative stress. Combined, our results suggest that copper loading in DMT1 deficiency could induce oxidative stress and impair GABA metabolism, which promote impulsivity‐like behavior.

image

Iron‐copper model: Mutations in the divalent metal transporter 1 (DMT1) decrease body iron status and up‐regulate copper absorption, which leads to copper loading in the brain and consequently increases metal‐induced oxidative stress. This event disrupts GABAergic neurotransmission and promotes impulsivity‐like behavior. Our model provides better understanding of physiological risks associated with imbalanced metal metabolism in mental function and, more specifically, the interactions with GABA and redox control in the treatment of emotional disorders.
Parenchyma–stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF‐β/BMP4 in ameloblastoma
Authors: Takebe Yuichiro , Tsujigiwa Hidetsugu , Katase Naoki , Siar Chong Huat , Takabatake Kiyofumi , Fujii Masae , Tamamura Ryo , Nakano Keisuke , Nagatsuka Hitoshi
Published: June 2016

Background

Tumor parenchyma–stromal interactions affect the properties of tumors and their dynamics. Our group previously showed that secreted frizzled related protein (sFRP)‐2 impairs bone formation and promotes bone invasion in ameloblastoma. However, the effects of the secreted growth factors CCN2, TGF‐β, and BMP4 on stromal tissues in ameloblastoma remain unclear.

Materials and results

Thirty‐five paraffin‐embedded ameloblastoma cases, ameloblastoma‐derived cell lines (AM‐1), and primary cultures of ameloblastoma stromal fibroblasts (ASF) were used. Immunohistochemistry, MTT assay, Western blotting, and RT‐PCR were performed on these samples. Parenchyma–stromal CCN2 overexpression correlated significantly with fibrous‐type stroma, but not with myxoid‐type stroma, suggesting a role of CCN2 in fibrosis (P < 0.05). Recombinant CCN2 induction of enhanced ASF proliferation in AM‐1 medium supports this view. Conversely, BMP4 and TGF‐β were expressed in myxoid‐type fibroblasts, but little expression was found in parenchyma. RANKL‐positive and CD68‐positive stromal cell populations were significantly greater in myxoid‐type tumor areas than in fibrous‐type tumor areas, while a higher Ki‐67 labeling index was recorded in ameloblastoma with fibrous‐type stroma. These data suggest that stromal properties influence bone resorption‐related activities and growth rates, respectively.

Conclusions

These results suggest that the effects of secreted growth factors are governed by ameloblastoma parenchyma–stromal interactions. CCN2 promotes fibrogenesis independent of TGF‐β signaling. Absence of CCN2 expression is associated with a phenotypic switch to a myxoid‐type microenvironment that is conducive for TGF‐β/BMP4 signaling to promote osteoclastogenesis.
Brazilian multicenter study of association between polymorphisms in CRISPLD2 and JARID2 and non‐syndromic oral clefts
Authors: Messetti Ana Camila , Machado Renato Assis , de Oliveira Carine Ervolino , Martelli‐Júnior Hercílio , de Almeida Reis Silvia Regina , Moreira Helenara Salvati Bertolossi , Persuhn Darlene Camati , Wu Tao , Coletta Ricardo D.
Published: June 2016

Background

Variants in the cysteine‐rich secretory protein LCCL domain containing 2 gene (CRISPLD2) and in the jumonji, AT‐rich interaction domain 2 gene (JARID2) were previously shown to influence non‐syndromic oral cleft susceptibility. Herein, we performed a case−control study to examine the potential association of single‐nucleotide polymorphisms (SNPs) in CRISPLD2 and JARID2 with non‐syndromic cleft lip and/or palate (NSCL/P) in the Brazilian population. Given the ethnicity‐dependent genetic predisposition to NSCL/P, we performed a structured analysis taking into account the genomic ancestry variation of each individual.

Methods

Four SNPs in CRISPLD2 (rs1546124, rs8061351, rs2326398, and rs4783099) and four in JARID2 (rs915344, rs2299043, rs2237138, and rs2076056), that were previously reported to be associated with NSCL/P, were genotyped in 785 Brazilian patients with NSCL/P (549 with cleft lip with or without cleft palate‐NSCL ± P, and 236 with cleft palate only‐NSCPO) and 693 unaffected Brazilian controls. Genomic ancestry was assessed with a set of 40 biallelic short insertion/deletion variants previously validated as ancestry informative markers of the Brazilian population.

Results

After adjustment of ancestry variations, allelic analysis revealed marginal associations between the CRISPLD2 rs4783099 T allele and increased risk for NSCPO (OR: 1.31, 95% CI: 1.05–1.62, P = 0.01) and between JARID2 rs2237138 and decreased NSCL ± P risk (OR: 0.80, 95% CI: 0.67–0.97, P = 0.02). Haplotype analysis indicated a lack of association between JARID2 haplotypes and non‐syndromic oral cleft risk.

Conclusions

Our results suggest that CRISPLD2 rs4783099 may represent a risk factor for NSCPO while JARID2 rs2237138 shows a protective effect against NSCL ± P in the Brazilian population.
STABLE ECONOMIC AGGLOMERATION PATTERNS IN TWO DIMENSIONS: BEYOND THE SCOPE OF CENTRAL PLACE THEORY
Authors: Ikeda Kiyohiro , Murota Kazuo , Takayama Yuki
Published: June 2016

This paper elucidates which agglomeration patterns exist in two‐dimensional economic space and how such patterns appear stably. Hexagonal lattices, that with and that without a boundary, are advanced, respectively, as practical and theoretical spatial platforms of economic activities. Agglomeration patterns on these lattices include hexagons in central place theory, but also encompass megalopolis and racetrack‐shaped decentralization. As the transport cost decreases, stable economic agglomeration undergoes the formation of the smallest hexagon and transition to patterns with larger market areas, often undergoing downtown decay but finally leading to a megalopolis. Formulas for break points are provided in an economic geography model.
Off-label and unlicensed medicines to hospitalised children in Norway
Authors: Teigen Arna , Wang Siri , Truong Bich Thuy , Bjerknes Kathrin
Published: June 2016

Objectives

The aim of this study was to investigate the use of off-label (OL) and unlicensed (UL) medicines to hospitalised children in Norway, to add to the current knowledge on use of medicines in this vulnerable patient group.

Methods

The study was performed as a cross-sectional prospective study. Medication was classified as on- or off-label based on the comparison with the SmPC regarding age, indication, dosage, route of administration and handling of the product. UL products were classified as imported or pharmacy produced.

Key findings

More than 90% of children receiving medicines in our study were given OL or UL medicines. More patients received OL (83%) than UL (59%). Route of administration was the most frequently observed OL category. The vast majority of the OL prescriptions were for ‘off-patent’ products. One-third of products prescribed were UL.

Conclusions

The study confirms that medicines to children in hospital to a significant degree are being used outside or without authorisation, in spite of recent paediatric regulatory initiatives. More data are still needed on efficacy and safety of medicines used in children, data to be incorporated in the SmPC. In addition, suitable formulations are needed to ensure optimal dosing and adherence without risky manipulations.
Textural and Sensory Attributes of Steamed Bread Fortified with High‐Amylose Maize Starch
Authors: Wang Sunan , Khamchanxana Pasongsin , Zhu Fan , Zhu Cheng , Pan Jiarong
Published: June 2016

Chinese steamed bread (CSB) is a staple food item produced through steaming fermented dough. High‐amylose maize starch (HAMS) is a natural source of resistant starch and dietary fiber. The feasibility of using HAMS with 80% amylose content to formulate northern style CSB was reported. Adding HAMS (up to 10%) had minimal influences on the color and texture of CSB. Specific volume and spread ratio of CSB were reduced by 10 − 20% and 10 − 13%, respectively. Increasing HAMS concentration from 2 to 10% decreased the staling rate of CSB by 8 − 48%. CSB with and without HAMS had a 3‐day mould‐free shelf‐life. Sensory evaluation showed that the overall acceptability of CSB containing HAMS (up to 6%) were comparable with control. Organoleptic, textural, and shelf life properties of CSB with 2% HAMS substitution were similar to the control.

Practical Applications

Adding HAMS could improve the shelf life of CSB without negatively affecting the sensory acceptability. The results of this study suggest the possibility of expanding the HAMS application and CSB in functional food market. The findings provide some insights for industrial research and development using resistant starch for healthy steamed cereal products.
A partial metabolic pathway enables group b streptococcus to overcome quinone deficiency in a host bacterial community
Authors: Franza Thierry , Delavenne Emilie , Derré‐Bobillot Aurélie , Juillard Vincent , Boulay Mylène , Demey Emmanuelle , Vinh Joelle , Lamberet Gilles , Gaudu Philippe
Published: June 2016

Aerobic respiration metabolism in Group B Streptococcus (GBS) is activated by exogenous heme and menaquinone. This capacity enhances resistance of GBS to acid and oxidative stress and improves its survival. In this work, we discovered that GBS is able to respire in the presence of heme and 1,4‐dihydroxy‐2‐naphthoic acid (DHNA). DHNA is a biosynthetic precursor of demethylmenaquinone (DMK) in many bacterial species. A GBS gene (gbs1789) encodes a homolog of the MenA 1,4‐dihydroxy‐2‐naphthoate prenyltransferase enzyme, involved in the synthesis of demethylmenaquinone. In this study, we showed that gbs1789 is involved in the biosynthesis of long‐chain demethylmenaquinones (DMK‐10). The Δgbs1789 mutant cannot respire in the presence of heme and DHNA, indicating that endogenously synthesized DMKs are cofactors of the GBS respiratory chain. We also found that isoprenoid side chains from GBS DMKs are produced by the protein encoded by the gbs1783 gene, since this gene can complement an Escherichia coli ispB mutant defective for isoprenoids chain synthesis. In the gut or vaginal microbiote, where interspecies metabolite exchanges occur, this partial DMK biosynthetic pathway can be important for GBS respiration and survival in different niches.
Engagement practices that join scientific methods with community wisdom: designing a patient‐centered, randomized control trial with a Pacific Islander community
Authors: McElfish Pearl Anna , Goulden Peter A , Bursac Zoran , Hudson Jonell , Purvis Rachel S , Kim Yeary Karen H , Aitaoto Nia , Kohler Peter O
Published: June 2016

This article illustrates how a collaborative research process can successfully engage an underserved minority community to address health disparities. Pacific Islanders, including the Marshallese, are one of the fastest growing US populations. They face significant health disparities, including extremely high rates of type 2 diabetes. This article describes the engagement process of designing patient‐centered outcomes research with Marshallese stakeholders, highlighting the specific influences of their input on a randomized control trial to address diabetes. Over 18 months, an interdisciplinary research team used community‐based participatory principles to conduct patient‐engaged outcomes research that involved 31 stakeholders in all aspects of research design, from defining the research question to making decisions about budgets and staffing. This required academic researcher flexibility, but yielded a design linking scientific methodology with community wisdom.
How foraging allometries and resource dynamics could explain Bergmann's rule and the body‐size diet relationship in mammals
Authors: Brown Joel S. , Kotler Burt P. , Porter Warren P.
Published: June 2016

Two dramatic large scale patterns characterize body size in mammalian herbivores. One is Bergmann's rule that notes that mammals tend to increase in body size at higher latitudes. The other is the inverse relationship between herbivore body size and diet quality. Here, we present a model that may explain both. We start by noting that searching for and handling resources are fundamental activities for feeding mammals. We note that if with body size, encounter probability increases less favorably and handling time more favorably than metabolic costs, then body size represents a tradeoff between search efficiency (favors smaller body size) and handling efficiency (favors larger). If so, then optimal body size increases with both temperature and the conspicuousness of the food, but decreases with food quality. For this to happen there must be food limitation where the herbivores influence food standing crop. Lower energetic foraging costs (lower latitude, lower seasonality and/or higher temperatures) or higher food quality result in lower standing crops of food. A lower standing crop of food favors searching efficiency and, hence, smaller body sizes. Factors that increase the standing crop of food favor handling efficiency and larger body sizes. Simply maximizing net profit from foraging or foraging efficiency that are often assumed to help explain Bergmann's rule do not predict either Bergmann's rule nor the inverse relationship between food quality and body size. With the inclusion of consumer–resource dynamics, fitness maximization predicts both. Testing the model's predictions invites empirical research into the allometries of foraging parameters relating to search and handling.
PRAGMATIC MUNICIPALISM: LOCAL GOVERNMENT SERVICE DELIVERY AFTER THE GREAT RECESSION
Authors: KIM YUNJI , WARNER MILDRED E.
Published: June 2016

Since the Great Recession, some have argued that local governments have become ‘austerity machines’ that cut and privatize services and undermine unions. We conducted a national survey of US municipalities in 2012 to examine how service provision level and delivery methods are related to local stress and capacity, controlling for community need and place characteristics. We find that local governments are balancing the pressures of stress with community needs. They use alternative revenue sources and service delivery methods (privatization and cooperation) to maintain services. Unionization is not a barrier to innovation. Further, we find that ethnically diverse suburbs are providing more services than other suburbs, thus acting more like metro core cities. We find that the Great Recession has not dramatically shifted local government behaviour to a ‘new normal’ of fiscal austerity. Instead, we find municipalities practising ‘pragmatic municipalism’ to maintain their public role.
Group Selling, Product Durability, and Consumer Behavior
Authors: He Yuhong , Ray Saibal , Yin Shuya
Published: June 2016

Firms producing complementary goods often strategically form groups and jointly sell their products to better coordinate their decisions. For consumer durables, decisions about such collaboration might be complicated due to two factors. Because of their durability and presence of used goods markets, such products engender “future” price competition between new and used goods. On the other hand, consumers of such products might be forward‐looking and patient, both of which affect their purchasing behavior. In this study, we study how the above product and consumer characteristics interact to affect the group selling decisions of complementary firms. We do so through a two‐period model consisting of a value chain with two upstream manufacturers and a downstream retailer. When consumers are relatively impatient and reluctant to wait to buy later, group selling by manufacturers will take place only when the end product is relatively perishable, that is, product durability is low. However, if consumers are patient, that is, willing to wait, collaboration happens only when the end product is quite durable; for relatively perishable products the manufacturers sell their products separately. We also comment on how our results are affected by factors like manufacturers directly selling to end consumers or there being multiple opportunities to decide whether or not to use group selling strategy.
To Preannounce or Not: New Product Development in a Competitive Duopoly Market
Authors: Klastorin Ted , Mamani Hamed , Zhou Yong‐Pin
Published: June 2016

In this study, we consider the issue of preannouncing or not preannouncing the development of a new product. Our research is motivated by contrasting views in the literature and varying actions observed in practice. We develop and analyze a game theoretic model that examines the effect of a firm's preannouncement of its product development. Our model is based on a durable goods duopoly market with profit‐maximizing firms. The first firm is an innovator who initially begins developing the product; the second firm is an imitator that begins developing a competing product as soon as it becomes aware of the innovator's product. We assume that consumers are rationally expectant and purchase at most one unit of the product when they have maximum positive utility surplus that is determined by the characteristics of the product, the consumer's marginal utility, and the consumer's discounted utility for future expected products. The innovator firm can release information about its product when it begins developing the product or can guard information about its product until it introduces the product into the market. Our analysis and numerical tests show that, under some conditions, the innovator firm can benefit by preannouncing its product and giving the imitator firm additional time to differentiate its product. We discuss these conditions and their implications for new product development efforts.
Tax Evasion and the Business Environment in Uganda
Authors: Mawejje Joseph , Okumu Ibrahim Mike
Published: June 2016

This paper examines the interaction between the different indicators of the business environment and tax evasion. First, we develop a simple theoretical model linking tax evasion to the business environment. Second, we test the model predictions using the World Bank Enterprise Survey data for Uganda. Findings indicate that the extent of tax evasion is associated with bureaucratic bribery, the quality and efficiency of the legal systems, and the inadequate provision of public capital. Our results are robust to alternative estimation strategy, choice of instruments, treatment of outliers, and missing data.