bluuebunny/crossref_metadata_2025 huggingface dataset:
Balance between autophagic pathways preserves retinal homeostasis
Authors: Rodríguez‐Muela Natalia , Koga Hiroshi , García‐Ledo Lucía , de la Villa Pedro , de la Rosa Enrique J. , Cuervo Ana María , Boya Patricia
Published: March 2013

Aging contributes to the appearance of several retinopathies and is the largest risk factor for aged‐related macular degeneration, major cause of blindness in the elderly population. Accumulation of undegraded material as lipofuscin represents a hallmark in many pathologies of the aged eye. Autophagy is a highly conserved intracellular degradative pathway that plays a critical role in the removal of damaged cell components to maintain the cellular homeostasis. A decrease in autophagic activity with age observed in many tissues has been proposed to contribute to the aggravation of age‐related diseases. However, the participation of different autophagic pathways to the retina physiopathology remains unknown. Here, we describe a marked reduction in macroautophagic activity in the retina with age, which coincides with an increase in chaperone‐mediated autophagy (CMA). This increase in CMA is also observed during retinal neurodegeneration in the Atg5flox/flox; nestin‐Cre mice, a mouse model with downregulation of macroautophagy in neuronal precursors. In contrast to other cell types, this autophagic cross talk in retinal cells is not bi‐directional and CMA inhibition renders cone photoreceptor very sensitive to stress. Temporal and cell‐type‐specific differences in the balance between autophagic pathways may be responsible for the specific pattern of visual loss that occurs with aging. Our results show for the first time a cross talk of different lysosomal proteolytic systems in the retina during normal aging and may help the development of new therapeutic intervention for age‐dependent retinal diseases.
The Alcohol Deprivation Effect: Marked Inhibition by Anticatalase Gene Administration into the Ventral Tegmental Area in Rats
Authors: Tampier Lutske , Quintanilla María Elena , Karahanian Eduardo , Rivera‐Meza Mario , Herrera‐Marschitz Mario , Israel Yedy
Published: March 2013

Background

Animals that have chronically consumed alcohol and are subsequently deprived of it markedly increase their intake above basal levels when access to alcohol is reinstated. Such an effect, termed the alcohol deprivation effect (ADE), has been proposed to reflect (i) an obsessive–compulsive behavior, (ii) craving, or (iii) an increased reinforcing value of ethanol (EtOH). It has been reported that acetaldehyde, a highly reinforcing metabolite of EtOH, is generated in the brain by the action of catalase. Recent studies show that the administration of an anticatalase (shRNA)‐encoding lentiviral vector into the brain ventral tegmental area (VTA) of naïve rats virtually abolishes (85 to 95%) their EtOH intake. It is hypothesized that the antireinforcing effect of the anticatalase vector will also inhibit the ADE.

Methods

Two‐month‐old Wistar‐derived UChB alcohol drinker rats were offered free access to water and 10 and 20% EtOH for 67 days. Thereafter, the animals were deprived of EtOH for 15 days and were subsequently offered access to the EtOH solutions. At the start of the deprivation period, animals were microinjected a single dose of an anticatalase (or control) vector into the VTA. EtOH intake was measured on the first hour of EtOH re‐exposure as well as on a 24‐hour basis for 7 days.

Results

A marked ADE was observed when EtOH intake was measured on the first hour or 24 hours following EtOH re‐exposure, compared to the corresponding controls. The administration of the anticatalase vector reduced ADE by 60 to 80% (p < 0.001) on the first hour and by 63 to 80% (p < 0.001) on the initial 24 hours of EtOH re‐exposure (first and second ADE, respectively) without changing the total fluid intake, indicating a specific effect on EtOH drinking.

Conclusions

Ethanol intake associated with ADE—a binge‐like drinking behavior—is markedly inhibited by the administration of an anticatalase vector into the VTA, which blocks the conversion of EtOH into acetaldehyde, strongly suggesting that the marked increased EtOH intake that follows an alcohol deprivation period is mediated by acetaldehyde and its reinforcing metabolite.
A hierarchy of predictors for dementia‐free survival in old‐age: results of the AgeCoDe study
Authors: Luck T. , Riedel‐Heller S. G. , Luppa M. , Wiese B. , Bachmann C. , Jessen F. , Bickel H. , Weyerer S. , Pentzek M. , König H.‐H. , Prokein J. , Eisele M. , Wagner M. , Mösch E. , Werle J. , Fuchs A. , Brettschneider C. , Scherer M. , Breitner J. C. S. , Maier W.
Published: March 2013

Objective

Progression from cognitive impairment (CI) to dementia is predicted by several factors, but their relative importance and interaction are unclear.

Method

We investigated numerous such factors in the AgeCoDe study, a longitudinal study of general practice patients aged 75+. We used recursive partitioning analysis (RPA) to identify hierarchical patterns of baseline covariates that predicted dementia‐free survival.

Results

Among 784 non‐demented patients with CI, 157 (20.0%) developed dementia over a follow‐up interval of 4.5 years. RPA showed that more severe cognitive compromise, revealed by a Mini‐Mental State Examination (MMSE) score < 27.47, was the strongest predictor of imminent dementia. Dementia‐free survival time was shortest (mean 2.4 years) in such low‐scoring patients who also had impaired instrumental activities of daily living (iADL) and subjective memory impairment with related worry (SMI‐w). Patients with identical characteristics but without SMI‐w had an estimated mean dementia‐free survival time of 3.8 years, which was still shorter than in patients who had subthreshold MMSE scores but intact iADL (4.2–5.2 years).

Conclusion

Hierarchical patterns of readily available covariates can predict dementia‐free survival in older general practice patients with CI. Although less widely appreciated than other variables, iADL impairment appears to be an especially noteworthy predictor of progression to dementia.
Saving Private Business Enterprises
Authors: Jo Tae‐Hee
Published: March 2013

This article develops an argument from a heterodox microeconomic perspective that the business enterprise and the state have to control market institutions in order to protect the vested interests of the ruling class. Market governance by the business enterprise and market regulation by the state are in this regard purposeful and necessary actions to save private business enterprises vis‐à‐vis fundamental instability inherent in the capitalist system.
Three Modes of Competition in the Marketplace
Authors: Redmond William
Published: March 2013

Competition is often thought of a fairly obvious thing, a rivalry. In a market context the meaning of competition is usually taken to be a rivalry among the sellers. The article seeks to broaden this view by considering other competitive relationships in the marketplace. Using the simplifying assumption that there are only two types of market actors, sellers and consumers, there are three possible types of relationships or interdependencies among these actors in a market. In competitive terms this includes the familiar competition among sellers but there is also the possibility of competition between sellers and consumers, as well as competition among consumers. The article outlines essential characteristics of the three modes. Implications of multi‐mode competition for market performance and welfare are discussed.
Reducing caesarean section rates – No easy task
Authors: Roberts Christine L. , Algert Charles S. , Todd Angela L. , Morris Jonathan M.
Published: March 2013

To identify the greatest potential for reducing overall caesarean delivery rates, we used longitudinally linked data for women with consecutive births 2001–2009 to examine the likely impact of hypothetical risk‐based scenarios. Among women with a first birth, singleton, vertex‐presenting fetus at term, increasing the vaginal birth rate following induction of labour by 20% potentially has greatest impact, with a 12.1% relative decrease in the overall caesarean rate. The potential relative decrease in other scenarios ranged from 0.8 to 5.9%.
The Pediatric Symptom Checklist as screening tool for neurological and psychosocial problems in a paediatric cohort of patients with coeliac disease
Authors: Terrone Gaetano , Parente Iolanda , Romano Alfonso , Auricchio Renata , Greco Luigi , Del Giudice Ennio
Published: March 2013

Aim

To screen for neurological and behavioural disorders in a paediatric cohort of patients with coeliac disease (CD) in order to detect possible differences related to compliance with gluten‐free diet (GFD).

Methods

We recruited a cohort of 139 patients divided into three groups: A (40 patients with newly diagnosed CD), B (54 patients with CD in remission after GFD) and C (45 patients with potential CD). Patients first underwent a screening neurological visit, detecting signs associated with CD, and then were evaluated with Pediatric Symptom Checklist (PSC), a psychosocial screen for cognitive, emotional and behavioural problems.

Results

In the group B as compared to group A, there was a statistically significant decrease (p < 0.05) in the incidence of chronic fatigue, headache and inattention. The same applied to patients compliant to GFD vs. non‐compliant. Potential coeliacs turning into overt CD had a higher incidence of headache and inattention compared with potential coeliacs showing normal mucosa. The PSC mean score in group A was statistically higher than in group B.

Conclusion

Gluten‐free diet had a positive impact on neuropsychiatric symptoms. We suggest the use of PSC in the routine follow‐up of coeliacs in order to allow an early detection of psychosocial problems.
The assessment of genetic diversity within and among the eight subpopulations of Japanese Black cattle using 52 microsatellite markers
Authors: Nishimaki Takahiro , Ibi Takayuki , Tanabe Yoshihiro , Miyazaki Yoshiyuki , Kobayashi Naohiko , Matsuhashi Tamako , Akiyama Takayuki , Yoshida Emi , Imai Kazumi , Matsui Mayu , Uemura Keiichi , Watanabe Naoto , Fujita Tatsuo , Saito Yosuke , Komatsu Tomohiko , Yamada Takahisa , Mannen Hideyuki , Sasazaki Shinji , Kunieda Tetsuo
Published: March 2013

Japanese Black cattle are at risk for genetic homogeneity due to intensive use of a few sires. Therefore, assessment of the actual genetic diversity of this breed is important for future breeding plans. In the present study, we investigated the genetic diversity within and among eight subpopulations of Japanese Black cattle using 52 microsatellite markers. The parameters for genetic diversity of Japanese Black cattle were comparable to those of other cattle breeds, suggesting that the relatively high genetic diversity of the breed. However, upon comparison among the eight subpopulations, the Hyogo subpopulation showed markedly low genetic diversity. The results of the pairwise FST values, phylogenetic network and structure analysis indicated that the Hyogo population has remarkably high level of genetic differentiation from other populations, while Yamagata, Niigata, Hiroshima and Kagawa populations have low levels of genetic differentiation. Furthermore, multidimensional scaling plots indicated that individuals in some subpopulations were separated from individuals in the other subpopulations. We conclude that while the overall genetic diversity of Japanese Black cattle is still maintained at a relatively high level, that of a particular subpopulation is significantly reduced, and therefore the effective population size of the breed needs to be controlled by correct mating strategies.
Changes in the bacterial community and composition of fermentation products during ensiling of wiltedItalian ryegrass and wilted guinea grass silages
Authors: Li Yanbing , Nishino Naoki
Published: March 2013

To gain further insights into temperate and tropical grass ensiling, fermentation products and bacterial communities were examined at both the initial and late stages of ensiling of wiltedItalian ryegrass and wilted guinea grass silages. 2,3‐Butanediol and ethanol fermentation were observed in wiltedItalian ryegrass silage. Enterobacteria such asRahnellasp. andEnterobactersp. may have been involved in fermentation; however, alcohol production was intensified after the silage enterobacterial community overwhelmed the pre‐ensiled enterobacterial community.Pediococcusspp. appeared in silage stored for 4 months, when a significant increase in lactic acid content was seen compared with that at 2 months. Prolonged storage enhanced acetic acid fermentation in wilted guinea grass silage. The disappearance ofEnterococcus sulfureusand appearance ofLactobacillus plantarummay have been associated with the increased acetic acid content. Although many species of enterobacteria were found in common between the pre‐ensiled crop and silages of Italian ryegrass and guinea grass, marked differences were seen in the type of fermentation from the initial stages. These results indicate that the bacterial community of pre‐ensiled crops may be immediately replaced by one that is adapted to ensiling environments, although metabolic changes may continue over the course of ensiling.
Duration of action of a topical anaesthetic formulation for pain management of mulesing in sheep
Authors: Lomax S , Sheil M , Windsor PA
Published: March 2013

Objective

To investigate the effect of topical anaesthesia on ‘mothering up’ of lambs after mulesing and marking, and for pain alleviation over a 24‐h period.

Design

Two separate trials were performed on Merino lambs undergoing the mules procedure for flystrike prevention, to assess the efficacy of immediate postoperative topical anaesthetic wound dressing containing lignocaine (hydrochloride) 40.6 g/L, bupivacaine (hydrochloride) 4.5 g/L, adrenaline (tartrate) 24.8 mg/L and cetrimide 5.0 g/L in a gel base (Bayer Animal Health, Gordon, NSW, Australia).

Methods

In both trials, lambs were assigned to one of three treatment regimens: control, mules procedure with topical anaesthetic (0.5 mL/kg) and mules procedure without topical anaesthetic treatment. Parameters measured included body weight, assessment of skin and wound sensitivity to light touch and pain stimulation, behavioural responses and time to mother up and to feed.

Results

In both trials there was rapid (1 min) and prolonged (up to 24 h) wound analgesia as shown by lower scores for light touch (P < 0.001) and pain responses (P < 0.001), with absent or significantly diminished primary and secondary hyperalgesia (P ≤ 0.05) and significant reduction in pain‐related behaviours (P < 0.001) in treated versus untreated lambs.

Conclusion

Significant pain alleviation and improved recovery can be achieved in lambs for at least 24 h after mulesing through the use of topical anaesthesia. It is suggested that the haemostatic action of adrenalin, together with inhibition of the inflammatory cascade and the barrier effect of the gel within the product, may explain the prolonged anaesthesia up to 24 h observed in the present study. These results suggest that topical anaesthesia has the capacity to dramatically improve the welfare of lambs undergoing mulesing.
Enantiomer Selective Glucuronidation of the Non‐Steroidal Pure Anti‐Androgen Bicalutamide by Human Liver and Kidney: Role of the Human UDP‐Glucuronosyltransferase (UGT)1A9 Enzyme
Authors: Grosse Laurent , Campeau Anne‐Sophie , Caron Sarah , Morin Frédéric‐Alexandre , Meunier Kim , Trottier Jocelyn , Caron Patrick , Verreault Mélanie , Barbier Olivier
Published: March 2013

Bicalutamide (Casodex®) is a non‐steroidal pure anti‐androgen used in the treatment of localized prostate cancer. It is a racemate drug, and its activity resides in the (R)‐enantiomer, with little in the (S)‐enantiomer. A major metabolic pathway for bicalutamide is glucuronidation catalysed by UDP‐glucuronosyltransferase (UGT) enzymes. While (S)bicalutamide is directly glucuronidated, (R)bicalutamide requires hydroxylation prior to glucuronidation. The contribution of human tissues and UGT isoforms in the metabolism of these enantiomers has not been extensively investigated. In this study, both (R) and/or (S)bicalutamide were converted into glucuronide (‐G) derivatives after incubation of pure and racemic solutions with microsomal extracts from human liver and kidney. Intestinal microsomes exhibited only low reactivity with these substrates. Km values of liver and kidney samples for (S)bicalutamide glucuronidation were similar, and lower than values obtained with the (R)‐enantiomer. Among the 16 human UGTs tested, UGT1A8 and UGT1A9 were able to form both (S) and (R)bicalutamide‐G from pure or racemic substrates. UGT2B7 was also able to form (R)bicalutamide‐G. Kinetic parameters of the recombinant UGT2B7, UGT1A8 and UGT1A9 enzymes support a predominant role of the UGT1A9 isoform in bicalutamide metabolism. Accordingly, (S)bicalutamide inhibited the ability of human liver and kidney microsomes to glucuronidate the UGT1A9 probe substrate, propofol. In conclusion, the present study provides the first comprehensive analysis of in vitro bicalutamide glucuronidation by human tissues and UGTs and identifies UGT1A9 as a major contributor for (R) and (S) glucuronidation in the human liver and kidney.
Neurocognitive features in subgroups of bipolar disorder
Authors: Aminoff Sofie Ragnhild , Hellvin Tone , Lagerberg Trine Vik , Berg Akiah Ottesen , Andreassen Ole A , Melle Ingrid
Published: March 2013

Objective

To examine which subgroups of DSM‐IV bipolar disorder (BD) [BD type I (BD‐I) or BD type II (BD‐II), and subgroups based on history of psychosis, presenting polarity, and age at onset] differentiate best regarding neurocognitive measures.

Methods

A total of 199 patients with BD were characterized by clinical and neurocognitive features. The distribution of subgroups in this sample was: BD‐I, 64% and BD‐II, 36%; 60% had a history of psychosis; 57% had depression as the presenting polarity; 61% had an early onset of BD, 25% had a mid onset, and 14% had a late onset. We used multivariate regression analyses to assess relationships between neurocognitive variables and clinical subgroups.

Results

Both BD‐I diagnosis and elevated presenting polarity were related to impairments in verbal memory, with elevated presenting polarity explaining more of the variance in this cognitive domain (22.5%). History of psychosis and BD‐I diagnosis were both related to impairment in semantic fluency, with history of psychosis explaining more of the variance (11.6%).

Conclusion

Poor performance in verbal memory appears to be associated with an elevated presenting polarity, and poor performance in semantic fluency appears to be associated with a lifetime history of psychosis.
Mood‐dependent changes of serum lithium concentration in a rapid cycling patient maintained on stable doses of lithium carbonate
Authors: Rittmannsberger Hans , Malsiner‐Walli Gertraud
Published: March 2013

Objective

Serum lithium levels may be influenced by mood state. We report on a 58‐year‐old female patient suffering from rapid cycling bipolar disorder. Her serum lithium levels varied greatly, despite stable medication.

Methods

The patient was observed over a one‐year period.

Results

The patient received a stable medication of lithium carbonate (450 mg), valproate (1500 mg), and clozapine (200 mg). Investigating mood and serum lithium levels over one year revealed six manic and six depressive phases. The mean lithium serum level was 0.67 mmol/L in the depressive states, 0.39 mmol/L in the manic states (t = 4.11, p = 0.001 versus depression), and 0.40 mmol/L in the euthymic states (t = 3.58, p = 0.003 versus depression). Noncompliance was ruled out. The patient gained up to 8 kg during manic phases, accompanied by pretibial edema.

Conclusions

Changes in serum lithium concentration are probably not caused by altered lithium, but by water metabolism. During mania, body water increases, leading to dilution and therefore a reduction in serum lithium levels. As there is no proof for any other known cause of hypervolemia, we propose the hypothesis that the increase in body water is due to a variant of idiopathic edema.
Oncogenic properties of sphingosine kinases in haematological malignancies
Authors: Wallington‐Beddoe Craig T. , Bradstock Kenneth F. , Bendall Linda J.
Published: March 2013

The sphingosine kinases (SphKs) have relatively recently been implicated in contributing to malignant cellular processes with particular interest in the oncogenic properties of SPHK1. Whilst SPHK1 has received considerable attention as a putative oncoprotein, SPHK2 has been much more difficult to study, with often conflicting data surrounding its role in cancer. Initial studies focused on non‐haemopoietic malignancies, however a growing body of literature on the role of sphingolipid metabolism in haemopoietic malignancies is now emerging. This review provides an overview of the current state of knowledge of the SphKs and the bioactive lipid sphingosine 1‐phosphate (S1P), the product of the reaction they catalyse. It then reviews the current literature regarding the roles of S1P and the SphKs in haemopoietic malignancies and discusses the compounds currently available that modulate sphingolipid metabolism and their potential and shortcomings as therapeutic agents for the treatment of haematological malignancies.
Public voices from anonymous corridors: The public face of the public service in a Westminster system
Authors: Grube Dennis
Published: March 2013

Under the traditions of the Westminster system, prime ministers and ministers give countless public speeches each year, while their loyal public service quietly and anonymously carries out the daily business of public administration. Current practice suggests that this traditional picture no longer holds true. In the 21st century, bureaucratic leaders are prepared to give public speeches on their own authority – adopting a “public face” as contributors to public debate. This article examines the extent to which key bureaucratic leaders in Canada have adopted an independent public face through public speeches, and how the Canadian experience compares to other Westminster jurisdictions. It argues that contemporary Canadian practice has taken a middle road between independent policy advocacy and quiet anonymity.
Management improvement in the Canadian public service, 1999–2010
Authors: Charko Phil
Published: March 2013

This article surveys management improvement initiatives in the federal public service during the 2000s and assesses their progress. It reviews eight key areas: management accountability; expenditure management; financial management; human resource management; grants and contributions management; project management and capital investment; internal audit; and processes to sustain public service values and ethics. Although not all of the initiatives have been equally successful, this article argues that general improvement has been realized. The article also considers factors behind the successes, arguing that improvements typically arise from a combination of political, organizational, cultural and economic factors including public service leadership and support at the political level. Recent budget pressures may affect the sustainability of continuing management improvement, but elements for moving forward are clear.
“Man plans,God laughs”:Canada's national strategy for protecting critical infrastructure
Authors: Quigley Kevin
Published: March 2013

Critical Infrastructure Protection seeks to enhance the physical and cyber‐security of key public and private assets and mitigate the effects of natural disasters, industrial accidents and terrorist attacks. In 2009, severalCanadian governments published theNational Strategy and Action Plan for Critical Infrastructure(NS&AP), a framework for governments and the owners and operators of critical infrastructure – largely in the private sector – to collaborate on the security and increased resiliency ofCanada's critical assets. Drawing on the social science risk literature, audits, and a three‐year research and education project, this article argues that the strategy of relationship building, collaborative risk management and information sharing is under‐developed and limited by market competition, incompatible institutional cultures, and legal, logistical and political constraints. TheNS&APshould better delineate risks and identify how governments can work with industry, and acknowledge the paradox between trust and transparency, the role of small‐ and medium‐sized enterprise, and how risk management processes can vary.
Lifestyle correlates of self‐reported sleep duration among Saudi adolescents: a multicentre school‐based cross‐sectional study
Authors: Al‐Hazzaa H. M. , Musaiger A. O. , Abahussain N. A. , Al‐Sobayel H. I. , Qahwaji D. M.
Published: March 2013

Background

Lifestyle factors are important determinants of adequate sleep among adolescents. However, findings on sleep duration relative to lifestyle factors are conflicting. Therefore, this study examined the association of self‐reported sleep duration with physical activity, sedentary behaviours and dietary habits among Saudi adolescents.

Methods

A multicentre school‐based cross‐sectional study was conducted in three major cities in Saudi Arabia. The sample included 2868 secondary‐school students (51.9% girls) aged 15–19 years, randomly selected using a multistage stratified cluster sampling technique. In addition to anthropometric measurements, sleep duration, physical activity, sedentary behaviours and dietary habits were assessed using self‐reported questionnaire.

Results

Several lifestyle factors were associated with sleep duration in adolescents. While controlling for some potential confounders, the findings showed that high screen time [>5 h/day; adjusted odds ratio (aOR) = 1.505, 95% confidence interval (CI) = 1.180–1.920, P = 0.001] and low (aOR = 1.290, 95% CI = 1.064–1.566, P = 0.010) to medium (aOR = 1.316, 95% CI = 1.075–1.611, P = 0.008) physical activity levels were significantly related to daily sleep of 8 h or longer. Furthermore, having low intake of breakfast (<3 day/week compared with 5 days or more per week) decreased the odd of having adequate sleep duration by a factor of 0.795 (95% CI = 0.667–0.947, P < 0.010).

Conclusions

Short sleep duration (<8 h/day) among Saudi adolescents 15–19 year olds was significantly associated with several lifestyle factors. Intervention programs aiming for improving sleeping habits among adolescents need to consider such potential association of lifestyle variables with sleep duration.
Professionals' understanding of partnership with parents in the context of family support programmes
Authors: van Houte Sabine , Bradt Lieve , Vandenbroeck Michel , Bouverne‐De Bie Maria
Published: March 2013

Partnership has become a dominant concept in current thinking about the parent–professional relationship within a variety of interventions aimed at child welfare, including family support practice. However, despite the burgeoning policy and research attention, the meaning of partnership in practice remains unclear. Based on interviews with professionals in a family support intervention in Flanders (the Dutch‐speaking part of Belgium), this paper offers an insight into professionals' daily interactions with parents. The analysis reveals a tension between professionals' commitment towards parents on the one hand, and the way professionals take up this commitment in an expert role on the other. Consequences for professionals' relationships in child and family welfare interventions are discussed, as well as some implications for the realization of proper partnerships that acknowledge the power imbalances that exist in such partnerships.
Familial clustering and genetic heterogeneity in Meniere's disease
Authors: Requena T. , Espinosa‐Sanchez J.M. , Cabrera S. , Trinidad G. , Soto‐Varela A. , Santos‐Perez S. , Teggi R. , Perez P. , Batuecas‐Caletrio A. , Fraile J. , Aran I. , Martin E. , Benitez J. , Pérez‐Fernández N. , Lopez‐Escamez J.A.
Published: March 2013

The aims of this study were to estimate the prevalence of familial cases in patients with Meniere's disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology‐Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs) and offspring (λo) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16–48 and 4–12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.
Mechanical Property Assessment of Bone Healing around a Titanium–Zirconium Alloy Dental Implant
Authors: Anchieta Rodolfo B. , Baldassarri Marta , Guastaldi Fernando , Tovar Nick , Janal Malvin N. , Gottlow Jan , Dard Michel , Jimbo Ryo , Coelho Paulo G.
Published: March 2013

Background

It has been reported that titanium–zirconium alloy with 13–17% zirconium (TiZr1317) implants show higher biomechanical stability and bone area percentage relative to commercially pure titanium (cpTi) grade 4 fixtures.

Purpose

This study aimed to determine whether the higher stability for TiZr1317 implants is associated with higher mechanical properties of remodeling bone in the areas around the implants.

Materials and Methods

This study utilized 36 implants (n = 18: TiZr1317, n = 18: cpTi), which were placed in the healed ridges of the mandibular premolar and first molar of 12 mini pigs (n = 3 implants/animal). After 4 weeks in vivo, the samples were retrieved, and resin‐embedded histologic sections of approximately 100 μm in thickness were prepared. In order to determine the nanomechanical properties, nanoindentation (n = 30 tests/specimen) was performed on the bone tissue of the sections under wet conditions with maximum load of 300 μN (loading rate: 60 μN/s).

Results

The mean (± standard deviation) elastic modulus (E) and hardness (H) for the TiZr1317 group were 2.73 ± 0.50 GPa and 0.116 ± 0.017 GPa, respectively. For the cpTi group, values were 2.68 ± 0.51 GPa and 0.110 ± 0.017 GPa for E and H, respectively. Although slightly higher mechanical properties values were observed for the TiZr1317 implants relative to the cpTi for both elastic modulus and hardness, these differences were not significant (E = p > 0.75; H = p > 0.59).

Conclusions

The titanium–zirconium alloy used in this study presented similar degrees of nanomechanical properties to that of the cpTi implants.
Vitamin D3 Induces IDO+ Tolerogenic DCs and Enhances Treg, Reducing the Severity of EAE
Authors: Farias Alessandro S. , Spagnol Gabriela S. , Bordeaux‐Rego Pedro , Oliveira Camila O.F. , Fontana Ana Gabriela M. , de Paula Rosemeire F.O. , Santos Mariana P.A. , Pradella Fernando , Moraes Adriel S. , Oliveira Elaine C. , Longhini Ana Leda F. , Rezende Alexandre C.S. , Vaisberg Mauro W. , Santos Leonilda M.B.
Published: March 2013

Background

A growing body of evidence supports the hypothesis that vitamin D is an important environmental factor in the etiology of T‐cell‐mediated autoimmune diseases such as multiple sclerosis (MS).

Aim

The purpose of this study was exploring the mechanisms underlying the beneficial effect of vitamin D3 in encephalomyelitis (EAE).

Methods

We treated monophasic experimental autoimmune EAE, induced in Lewis rat, with vitamin D3 and adoptively transfer tolerogenic bone marrow‐derived DCs generated in the presence of vitamin D3.

Results

This study provides evidence that the in vivo administration of vitamin D3, as well as the adoptive transfer of vitamin D3‐induced IDO+ immature/tolerogenic dendritic cells, leads to a significant increase in the percentage of CD4+CD25+Foxp3+ regulatory T cells in the lymph nodes in a rat model of MS, experimental autoimmune EAE. Concomitant with the increase in this cell population, there is a significant decrease in the number of autoreactive T cells in the central nervous system. Bone marrow‐derived DCs cultivated in the presence of vitamin D3 present a tolerogenic profile with high IL‐10, TNFα, and IDO expression and decreased MHC‐II and CD80 expression. The adoptive transfer of IDO + DCs induces a significant increase in the percentage of CD4+CD25+Foxp3+ T cells in the lymph nodes, comparable with vitamin D3 treatment.

Conclusion

These mechanisms contribute actively to the generation of a microenvironment in the lymph nodes that suppresses the activation of encephalitogenic T cells, resulting in the downregulation of the inflammatory response in the central nervous system.
Ketamine: Use in Anesthesia
Authors: Marland Susan , Ellerton John , Andolfatto Gary , Strapazzon Giacomo , Thomassen Oyvind , Brandner Brigitta , Weatherall Andrew , Paal Peter
Published: March 2013

The role of ketamine anesthesia in the prehospital, emergency department and operating theater settings is not well defined. A nonsystematic review of ketamine was performed by authors from Australia, Europe, and North America. Results were discussed among authors and the final manuscript accepted. Ketamine is a useful agent for induction of anesthesia, procedural sedation, and analgesia. Its properties are appealing in many awkward clinical scenarios. Practitioners need to be cognizant of its side effects and limitations.
Eye‐Mediated Induction of Specific Immune Tolerance to Encephalitogenic Antigens
Authors: Farooq Shukkur M. , Ashour Hossam M.
Published: March 2013

Aims

Administration of antigens into the anterior chamber (AC) of the eye induces a form of antigen‐specific immune tolerance termed anterior chamber‐associated immune deviation (ACAID). This immune tolerance effectively impairs host delayed‐type hypersensitivity (DTH) responses. We hypothesized that ACAID could be generated in BALB/c mice following AC inoculation of the encephalitogenic antigens myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP).

Methods

We used DTH assays and local adoptive transfer (LAT) assays to test whether MOG/MBP‐induced ACAID following their administration into the AC, whether they elicited this immune tolerance via CD8+ T cells, and whether their AC coadministration (MOG/MBP) induced specific immune tolerance to one or both antigens.

Results

We showed that MOG/MBP‐induced AC‐mediated specific immune tolerance, as evident from impaired DTH responses. This antigen‐driven DTH suppression was solely mediated via splenic CD8+ T cells as confirmed by LAT assays. Finally, a single AC injection with both antigens was sufficient to induce specific immune tolerance to these antigens, as evident from DTH and LAT assays.

Conclusion

ACAID T‐cell regulation could be used as a therapeutic tool in the treatment of complicated autoimmune diseases that involve multiple antigens such as multiple sclerosis.
Outcome of salvage surgery for anal squamous cell carcinoma
Authors: Harris D. A. , Williamson J. , Davies M. , Evans M. D. , Drew P. , Beynon J. ,   the Swansea Pelvic Oncology Group
Published: March 2013

Aim

The purpose of this study was to examine factors related to treatment failure following chemoradiotherapy for squamous cancer and to compare the outcome of salvage surgery in one unit with national audit standards published by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) (ACPGBI position statement for management of anal cancer. Colorectal Disease 2011; 13(Suppl. 1): 1–52).

Method

Patients with squamous cell carcinoma of the anus treated with radical intent between 1997 and 2010 in a single tertiary referral oncology institute were prospectively identified. Multivariate analysis was used to establish factors associated with treatment failure. Cancer‐specific end‐points after salvage surgery were determined by Kaplan–Meier survival analysis.

Results

Ninety‐five patients received chemoradiotherapy with radical intent with a 5‐year overall survival of 83% (all stages) at a median follow up of 35 months. Of these, 11 (12%) required salvage surgery, five of whom were Stage T4 at presentation. Six patients had failed to respond to chemoradiotherapy and five presented with recurrence at a median of 10 (10–36) months. Only Stage T4 disease at presentation was predictive of the need for salvage surgery (OR 5.6, CI 4.9–6.3, P = 0.015). There was no surgical mortality and no delayed perineal healing where a myocutaneous flap was used. The resection margin was involved in one (9%) patient. The 5‐year survival rate was 64%. Audit standards for case selection, local control, survival and perineal complications were achieved.

Conclusion

Long‐term survival was achieved in two‐ thirds of patients following salvage surgery after failed primary chemoradiotherapy for anal cancer in a multidisciplinary oncological unit. Stage T4 disease at presentation strongly predicted the need for subsequent salvage intervention.
Linking Public Participation in Scientific Research to the Indicators and Needs of International Environmental Agreements
Authors: Danielsen Finn , Pirhofer‐Walzl Karin , Adrian Teis P. , Kapijimpanga Daniel R. , Burgess Neil D. , Jensen Per M. , Bonney Rick , Funder Mikkel , Landa Arild , Levermann Nette , Madsen Jesper
Published: March 2013

Different monitoring approaches collect data that can measure progress toward achieving global environmental indicators. These indicators can: (1) Audit management actions; (2) Inform policy choices; and (3) Raise awareness among the public and policy makers. We present a generic, empirically based, framework of different environmental monitoring approaches, ranging from scientist‐driven to those undertaken by local people. This framework is used to assess monitoring possibilities for the Convention on Biological Diversity “2020” indicators, and those of 11 other international environmental agreements. Of the 186 indicators in these 12 environmental agreements, 69 (37%) require monitoring by professional scientists, whereas 117 (63%) can involve community members as “citizen scientists.” Promoting “community‐based” and “citizen science” approaches could significantly enrich monitoring progress within global environmental conventions. It would also link environmental monitoring to awareness raising and enhanced decision‐making at all levels of resource management.
‘She's My Sister‐In‐Law, My Visitor, My Friend’ – Challenges of Staff Identity in Home Follow‐Up in an HIV Trial in Western Kenya
Authors: Madiega Philister Adhiambo , Jones Gemma , Prince Ruth Jane , Geissler Paul Wenzel
Published: March 2013

Identities ascribed to research staff in face‐to‐face encounters with participants have been raised as key ethical challenge in transnational health research. ‘Misattributed’ identities that do not just deviate from researchers' self‐image, but obscure unequivocal aspects of researcher identity – e.g. that they are researchers – are a case of such ethical problem. Yet, the reasonable expectation of unconcealed identity can conflict with another ethical premise: confidentiality; this poses challenges to staff visiting participants at home. We explore these around a case study of ‘follow‐up’ staff, observed during an ethnographic study of a Kenyan HIV ‘trial community’, which included participant observation, conversations, and interviews with staff (n = 79) and participants (n = 89). We found that because of the need to maintain confidentiality and because of some suspicions towards researchers, research staff drew upon alternative identities – presenting themselves to non‐participants as relatives or friends, rather than as researchers. Several staff experienced this as necessary but uncomfortable. Simultaneously, staff and participants forged close relations in line with their fictional identities, which however also posed challenges because they entailed personal responsibilities that were difficult to live up to, due to limited resources, and the trial's limited duration. Similar challenges may arise in transnational HIV treatment programmes and should be explored further in that context.
Ethical Challenges that Arise at the Community Interface of Health Research: Village Reporters’ Experiences in Western Kenya
Authors: Chantler Tracey , Otewa Faith , Onyango Peter , Okoth Ben , Odhiambo Frank , Parker Michael , Geissler Paul Wenzel
Published: March 2013

Community Engagement (CE) has been presented by bio‐ethicists and scientists as a straightforward and unequivocal good which can minimize the risks of exploitation and ensure a fair distribution of research benefits in developing countries. By means of ethnographic fieldwork undertaken in Kenya between 2007 and 2009 we explored how CE is understood and enacted in paediatric vaccine trials conducted by the Kenyan Medical Research Institute and the US Centers for Disease Control (KEMRI/CDC). In this paper we focus on the role of paid volunteers who act as an interface between villagers KEMRI/CDC. Village Reporters’ (VRs) position of being both with the community and with KEMRI/CDC is advantageous for the conduct of trials. However it is also problematic in terms of exercising trust, balancing allegiances and representing community views. VRs role is shaped by ambiguities related to their employment status and their dual accountability to researchers and their villages. VRs are understandably careful to stress their commitment to self‐less community service since it augments their respectability at community level and opens up opportunities for financial gain and self‐development. Simultaneously VRs association with KEMRI/CDC and proximity to trial participants requires them to negotiate implicit and explicit expectations for material and medical assistance in a cultural setting in which much importance is placed on sharing and mutuality. To ensure continuity of productive interactions between VRs, and similar community intermediaries, and researchers, open discussion is needed about the problematic aspects of relational ethics, issues concerning undue influence, power relations and negotiating expectations.
Dose‐ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus
Authors: Kiyosue A. , Hayashi N. , Komori H. , Leonsson‐Zachrisson M. , Johnsson E.
Published: March 2013

Aim

To assess the glucose‐lowering effects of monotherapy with the glucokinase activator AZD1656 in Japanese patients with type 2 diabetes mellitus.

Methods

This was a randomized, double‐blind, placebo‐controlled study performed in Japan (NCT01152385). Patients (n = 224) were randomized to AZD1656 (40–200, 20–140 or 10–80 mg titrated doses) or placebo. The primary variable was the placebo‐corrected change from baseline to 4 months in glycated haemoglobin (HbA1c). Effects on fasting plasma glucose (FPG) and safety were also assessed.

Results

HbA1c was reduced numerically from baseline by 0.3–0.8% with AZD1656 and by 0.1% with placebo over the first 2 months of treatment, after which effects of AZD1656 started to decline. The changes from baseline to 4 months in HbA1c were not significant for the AZD1656 40–200 mg group versus placebo [mean (95% CI) placebo‐corrected change: −0.22 (−0.65, 0.20)%; p = 0.30]. Formal significance testing was not carried out for the other two AZD1656 dose groups. A higher percentage of patients on AZD1656 achieved HbA1c ≤ 7% after 4 months versus placebo, but responder rates were low. Results for FPG reflected those for HbA1c. Cases of hypoglycaemia were rare with AZD1656 (one patient) and no safety concerns were raised.

Conclusions

Although initially favourable plasma glucose reductions were observed, there was a loss of effect over time with sustained AZD1656 treatment. The study design did not allow an evaluation of the reasons for this lack of long‐term efficacy.
WHY DO PEOPLE USE DEBIT CARDS: EVIDENCE FROM CHECKING ACCOUNTS
Authors: FUSARO MARC ANTHONY
Published: March 2013

Debit cards are the fastest growing consumer payment method despite being more expensive and less versatile than credit cards. In this paper, we investigate some of the oft cited explanations for debit card use. Checking account data shows that debit card use is correlated with age, pay frequency, overdrafting, and ATM use, but not income, gender, crime, or expenditure. The data contain some signs that debit cards might be used as a method of spending restraint. (JEL D14, G21, L14)
SPENDING WISELY? HOW RESOURCES AFFECT KNOWLEDGE PRODUCTION IN UNIVERSITIES
Authors: WHALLEY ALEXANDER , HICKS JUSTIN
Published: March 2013

Every year billions of dollars are spent on research grants to produce new knowledge in universities. However, as grants may also affect other research funding, the effects of financial resources on knowledge production remain unclear. To uncover how financial resources affect knowledge production, we study the effects of research spending itself. Utilizing the legal constraints on university spending from an endowment we develop an instrumental variables approach. Our approach instruments for university research spending with time‐series variation in stock prices interacted with cross‐sectional variation in initial endowment market values for research universities in the United States. Our analysis reveals that research spending has a substantial positive effect on the number of papers produced, but not their impact. We also demonstrate that research spending effects are quite similar at private and public universities. (JEL H5, I2, O3)
YOUR RIGHT ARM FOR A PUBLICATION IN AER?
Authors: ATTEMA ARTHUR E. , BROUWER WERNER B.F. , VAN EXEL JOB
Published: March 2013

The time tradeoff (TTO) method is popular in medical decision making for valuing health states. We use it to elicit economists' preferences for publishing in top economic journals and for living without limbs. The economists value journal publications highly and have a clear preference among them, with the American Economic Review (AER) the most preferred. Their responses imply they would sacrifice more than half a thumb for an AER publication. These TTO results are consistent with ranking and willingness to pay results, and indicate that journal preferences are not entirely determined by impact factors or by expectations of a salary increase following a publication in a prestigious journal. (JEL A10, B41, I10)
IDENTIFYING CHANGES IN THE SPATIAL DISTRIBUTION OF CRIME: EVIDENCE FROM A REFEREE EXPERIMENT IN THE NATIONAL FOOTBALL LEAGUE
Authors: KITCHENS CARL
Published: March 2013

Between the 2009–2010 and 2010–2011 seasons, the National Football League (NFL) repositioned one of its officials in order to prevent injuries among officials. This creates a quasi‐experiment for studying how a change in the extent of policing affects detection of offenses. Using play‐by‐play data from the 2009–2010 and 2010–2011 NFL season, I estimate how the detection of offensive holding changes when the positioning of an official changes. I find that there is approximately a 20 increase in the number of offensive holding penalties called after the NFL repositioned the official. Penalties called on defensive linemen fell as a result of the repositioning. Overall, there was no change in the total number of penalties called. Using the estimated change in the probability of a penalty, I estimate the probability of an official calling a penalty. I infer that NFL officials detect approximately 60% of crimes committed on the field. (JEL K4, Z0, D0)