bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐frequency drug purity and price series as tools for explaining drug trends and harms in Victoria, Australia
Authors: Scott Nick , Caulkins Jonathan P , Ritter Alison , Quinn Catherine , Dietze Paul
Published: September 2014

Aims

Methamphetamine‐related harms in Victoria have increased recently in the context of stable or declining use prevalence. We determine how changes in price and purity of methamphetamine compared to other drugs such as heroin may, in part, explain these divergent patterns.

Methods

Detailed methamphetamine and heroin purchase price data from 2152 participant interviews from the Melbourne Injecting Drug User cohort study were used to generate drug price series for the period January 2009–June 2013. Data on drug purity from 8818 seizures made within Victoria were used to generate drug purity series during the same period. Purity‐adjusted price data for methamphetamine and heroin were obtained for the period 2009–13 by combining the two data sets.

Results

While the average purity of heroin seizures remained consistent and low, the average purity of powder and of crystal methamphetamine seizures increased from 12% [95% confidence interval (CI) = 10–14%] to 37% (95% CI = 20–54%) and 21% (95% CI = 18–23%) to 64% (95% CI = 60–68%), respectively. Crystal methamphetamine purity was bimodal, with observations generally less than 20% or greater than 70%. The average unadjusted price per gram for heroin decreased from $374 (95% CI = $367–381) to $294 (95% CI = $280–308), powder methamphetamine did not change significantly from $252 (95% CI = $233–271), and crystal methamphetamine increased substantially from $464 (95% CI = $416–511) in 2009 to $795 (95% CI = $737–853) in 2011. This increase was offset by an even greater increase in purity, meaning the average purity‐adjusted price per gram declined. Furthermore, pure prices of both methamphetamine forms were similar, whereas their unadjusted prices were not. The pure price of heroin fluctuated with no ongoing trends.

Conclusions

Decreases in methamphetamine purity‐adjusted price along with the bimodality of crystal methamphetamine purity may account for some of the recent increase in methamphetamine‐related harm. For a given amount spent, methamphetamine purchase power has increased and the presence of extreme purity variations may challenge individuals' control of consumption.
The association between family affluence and smoking among 15‐year‐old adolescents in 33 European countries, Israel and Canada: the role of national wealth
Authors: Pförtner Timo‐Kolja , Moor Irene , Rathmann Katharina , Hublet Anne , Molcho Michal , Kunst Anton E. , Richter Matthias
Published: September 2014

Aims

To examine the role of national wealth in the association between family affluence and adolescent weekly smoking, early smoking behaviour and weekly smoking among former experimenters.

Design and Participants

Data were used from the Health Behaviour in School‐aged Children (HBSC) study conducted in 2005/2006 in 35 countries from Europe and North America that comprises 60 490 students aged 15 years. Multi‐level logistic regression was conducted using Markov chain Monte Carlo methods (MCMC) to explore whether associations between family affluence and smoking outcomes were dependent upon national wealth.

Measurement

Family Affluence Scale (FAS) as an indicator for the socio‐economic position of students. Current weekly smoking behaviour is defined as at least weekly smoking (dichotomous). Early smoking behaviour is measured by smoking more than a first puff before age 13 years (dichotomous). Weekly smoking among former experimenters is restricted to those who had tried a first puff in the past.

Findings

The logistic multi‐level models indicated an association of family affluence with current weekly smoking [odds ratio (OR) = 1.088; 95% credible interval (CrI) = 1.055–1.121, P < 0.001], early smoking behaviour (OR = 1.066; CrI = 1.028–1.104, P < 0.001) and smoking among former experimenters (OR = 1.100; CrI = 1.071–1.130; P < 0.001). Gross domestic product (GDP) per capita was associated positively and significantly with the relationship between family affluence and current weekly smoking (OR = 1.005; CrI = 1.003–1.007; P < 0.001), early smoking behaviour (OR = 1.003; CrI = 1.000–1.005; P = 0.012) and smoking among former experimenters (OR = 1.004; CrI = 1.002–1.006; P < 0.001). The association of family affluence and smoking outcomes was significantly stronger for girls.

Conclusions

The difference in smoking prevalence between rich and poor is greater in more affluent countries.
Long Non‐coding RNAs: The Epigenetic Regulators Involved in the Pathogenesis of Reproductive Disorder
Authors: Shen Chen , Zhong Nanbert
Published: September 2014

Long non‐coding RNAs (lncRNAs) are long single‐stranded RNAs without translation potential. LncRNAs function in regulating epigenetic and cellular processes through various mechanisms. Nowadays, rapidly growing evidence has shown that abnormally expressed lncRNAs were involved in various inflammation‐related states or diseases. Abnormal inflammation responses contribute to reproductive pathology and play vital roles in developing most disorders of the female reproductive system. In this review, we discussed the history of ncRNAs including lncRNAs, methodologies for lncRNA identification, mechanisms of lncRNA expression and regulation and mainly discussed the expression and function of lncRNAs in the female reproductive system with special focus on the inflammation and infection pathway. By analyzing the present available studies of lncRNA transcripts within the reproductive system and the current understanding of the biology of lncRNAs, we have suggested the important diagnostic and therapeutic roles of lncRNAs in the etiology of reproductive disorders.
Increased Circulating Th1/Th2 Ratios But Not Other Lymphocyte Subsets During Controlled Ovarian Stimulation are Linked to Subsequent Implantation Failure after Transfer of In Vitro Fertilized Embryos
Authors: Liang Pei‐Yan , Yin Biao , Cai Jing , Hu Xiao‐Dong , Song Cheng , Wu Tong‐Hua , Zhao Jing , Li Guan‐Gui , Zeng Yong
Published: September 2014

Problem

To investigate alterations of circulating lymphocyte subsets in women undergoing controlled ovarian stimulation (COS) and survey their relations with pregnancy outcome.

Method of Study

Fifty‐one women were included in this study, of which 24 women were successfully pregnant in the index IVF cycle (the successful pregnancy group, sPG) and 27 women failed to get pregnant (the non‐pregnancy group, nPG). Peripheral blood was collected at three time points during COS: on the day before the first GnRHa administration (GnRHa day), on the day before the first Gn administration (Gn day), and on the day before HCG administration (HCG day). The intracellular Th1(IFN‐γ and TNF‐α)/Th2(IL‐10) ratios in circulating Th cells after in vitro phorbol‐12‐myristate‐13‐acetate stimulation, the NK cytotoxicity, and the percentage of T, B and NK cell subsets were assessed by flow cytometer. A third group consisting of patients with recurrent implantation failure (RIF group, n = 18) was also enrolled, and the intracellular Th1/Th2 ratios were assessed at HCG day.

Results

Intergroup comparison: The ratios of IFN‐γ/IL‐10 and TNF‐α/IL‐10 at HCG day were significantly higher (P < 0.05) in nPG than those in sPG, while no change at GnRHa day or Gn day. Higher (P < 0.05) ratios of IFN‐γ/IL‐10 and TNF‐α/IL‐10 at HCG day were also observed in RIF group compared to those in sPG. No significant change (P > 0.05) was found in other assessed lymphocyte subsets or in the concentrations of progesterone, estradiol, luteinizing hormone, or follicle‐stimulating hormone between the sPG and nPG at the three time points. Intragroup comparison: The ratios of IFN‐γ/IL‐10 and TNF‐α/IL‐10 at HCG day were significantly (P < 0.05) lower than those at GnRHa day in sPG, but not in nPG. No significant (P > 0.05) difference was found in other assessed parameters or at other time points.

Conclusions

The ratios of Th1/Th2 were fluctuated during COS, and they might affect the pregnancy outcome of IVF. The circulating NK cytotoxicity and percentage of lymphocyte subsets were relatively stable during the COS.
Social Worker Manpower, Community Economic Disadvantage, and Family Violence: Initial Evidence from Taiwan
Authors: Lee Shou‐Lu
Published: September 2014

This study is the first to explore the effect of social worker manpower on family violence incidents. In addition, it is the first study to investigate the geography of family violence in Taiwan. Using data from the County‐Level Important Indicator Query System, this study performs panel regressions to analyze the determinants of county‐level family violence incidents between 2005 and 2011. The empirical results clearly indicate that family violence incidents tend to be higher in counties that suffer economic disadvantage and in which there is an inadequate deployment of social worker manpower. The findings have important implications for combating family violence.
The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder
Authors: Benedetti Francesco , Riccaboni Roberta , Poletti Sara , Radaelli Daniele , Locatelli Clara , Lorenzi Cristina , Pirovano Adele , Smeraldi Enrico , Colombo Cristina
Published: September 2014

Objective

Bipolar disorder (BD) is associated with a higher risk of suicide and with worse early life stress. A serotonin (5‐hydroxytryptamine; 5‐HT) transporter‐linked polymorphic region (5‐HTTLPR) has been shown to influence the relationship between stress and the risk of attempting suicide in the general population, but has not been investigated in BD.

Methods

We studied 136 inpatients (93 females, 43 males) with a major depressive episode in the course of BD. Early and recent stressful life events were scored on the Social Readjustment Rating Scale (SRRS). Regional gray matter (GM) volumes were analyzed, acquiring T1‐weighted images on a 3.0 Tesla scanner.

Results

Homozygote l/l patients attempted suicide in a higher proportion than *s carriers. A separate‐slopes logistic regression showed a significant effect of 5‐HTTLPR on the relationship between stress, depression, and suicide among *s carriers, but not among l/l homozygotes, early stress associated with worse probability of attempting suicide and with earlier age at onset of BD. Exposure to early stress correlated with GM volumes in the right prefrontal cortex (Brodmann area 46) – again, in *s carriers only.

Conclusions

5‐HTTLPR modulated the relationship between early life stress and the core features of bipolar illness. 5‐HTTLPR*s carriers showed a higher sensitivity to the effects of stress; when exposed to low levels of early stress, they were protected against suicide in respect to l/l, but higher levels of stress progressively increased their risk of suicide and reduced the age at onset of illness.
Electrophysiological (EEG) evidence for reduced performance monitoring in euthymic bipolar disorder
Authors: Morsel Anne M , Morrens Manuel , Temmerman Anke , Sabbe Bernard , de Bruijn Ellen RA
Published: September 2014

Objectives

Apart from mood episodes, many cognitive deficits are present in bipolar disorder (BD). Performance monitoring is an important aspect of executive functioning and involves continuous monitoring of behavior and making subsequent changes when an error is made. On a neurophysiological level, the error‐related negativity (ERN), an event‐related brain potential (ERP) generated in the anterior cingulate cortex (ACC), reflects this process of performance monitoring. Abnormal ERN amplitudes have been observed in many major psychiatric disorders. However, despite conflicting evidence regarding the role of the ACC in BD, no studies to date have investigated performance monitoring as reflected in the ERN in BD.

Methods

Sixteen patients with BD in a euthymic state and 14 matched healthy controls performed a speeded two‐choice reaction‐time paradigm (Flankers Task) while electroencephalogram (EEG) measures were obtained. Behavioral and ERP measurements were analyzed for the two groups.

Results

The patients with BD, although euthymic, scored higher on depressive symptoms than healthy controls. While no behavioral group differences were found, patients with BD displayed lower ERN amplitudes than healthy controls when controlling for effects of residual mood.

Conclusions

The lower ERN amplitudes in the BD group reflect reduced performance monitoring and extend current knowledge of executive functioning in BD. Importantly, these findings go a long way to resolving the contradictory results regarding ACC involvement in BD by showing that taking into account residual mood may greatly influence error‐related ACC activations and is critically important in understanding cognitive deficits in BD.
Simultaneous Variable Selection for Joint Models of Longitudinal and Survival Outcomes
Authors: He Zangdong , Tu Wanzhu , Wang Sijian , Fu Haoda , Yu Zhangsheng
Published: September 2014

Joint models of longitudinal and survival outcomes have been used with increasing frequency in clinical investigations. Correct specification of fixed and random effects is essential for practical data analysis. Simultaneous selection of variables in both longitudinal and survival components functions as a necessary safeguard against model misspecification. However, variable selection in such models has not been studied. No existing computational tools, to the best of our knowledge, have been made available to practitioners. In this article, we describe a penalized likelihood method with adaptive least absolute shrinkage and selection operator (ALASSO) penalty functions for simultaneous selection of fixed and random effects in joint models. To perform selection in variance components of random effects, we reparameterize the variance components using a Cholesky decomposition; in doing so, a penalty function of group shrinkage is introduced. To reduce the estimation bias resulted from penalization, we propose a two-stage selection procedure in which the magnitude of the bias is ameliorated in the second stage. The penalized likelihood is approximated by Gaussian quadrature and optimized by an EM algorithm. Simulation study showed excellent selection results in the first stage and small estimation biases in the second stage. To illustrate, we analyzed a longitudinally observed clinical marker and patient survival in a cohort of patients with heart failure.
Remote conditioning the heart overview: translatability and mechanism
Authors: Schmidt Michael Rahbek , Redington Andrew , Bøtker Hans Erik
Published: September 2014

Conditioning the heart to resist predictable and unpredictable ischaemia–reperfusion (IR) injury is one of the fastest growing areas of bench to bedside research within cardiology. Basic science has provided important insights into signalling pathways and protective mechanisms in the heart, and a growing number of clinical studies have, with important exceptions, shown the potential applicability and beneficial effect of various mechanical conditioning strategies achieved by intermittent short‐lasting‐induced ischaemia of the heart itself or a remote tissue. Remote ischaemic conditioning (RIC) in particular has been utilized in a number of clinical settings with promising results. However, while many novel ‘downstream’ mechanisms of RIC have been discovered, translation to pharmacological conditioning has not yet been convincingly demonstrated in clinical studies. One explanation for this apparent failure may be that most pharmacological approaches mimic a single instrument in a complex orchestra activated by mechanical conditioning. Recent studies, however, provide important insights into upstream events occurring in RIC, which may allow for development of drugs activating more complex systems of biological organ protection. With this review, we will systematically examine the first generation of pharmacological cardioprotection studies and then provide a summary of the recent discoveries in basic science that could illuminate the path towards more advanced approaches in the next generation of pharmacological agents that may work by reproducing the diverse effects of RIC, thereby providing protection against IR injury.

Linked Articles

This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐8
Hydrogen peroxide stimulation of CFTR reveals an Epac‐mediated, soluble AC‐dependent cAMP amplification pathway common to GPCR signalling
Authors: Ivonnet P , Salathe M , Conner G E
Published: September 2014

Background and Purpose

H2O2 is widely understood to regulate intracellular signalling. In airway epithelia, H2O2 stimulates anion secretion primarily by activating an autocrine PGE2 signalling pathway via EP4 and EP1 receptors to initiate cytic fibrosis transmembrane regulator (CFTR)‐mediated Cl− secretion. This study investigated signalling downstream of the receptors activated by H2O2.

Experimental Approach

Anion secretion by differentiated bronchial epithelial cells was measured in Ussing chambers during stimulation with H2O2, an EP4 receptor agonist or β2‐adrenoceptor agonist in the presence and absence of inhibitors of ACs and downstream effectors. Intracellular calcium ([Ca2+]I) changes were followed by microscopy using fura–2‐loaded cells and PKA activation followed by FRET microscopy.

Key Results

Transmembrane adenylyl cyclase (tmAC) and soluble AC (sAC) were both necessary for H2O2 and EP4 receptor‐mediated CFTR activation in bronchial epithelia. H2O2 and EP4 receptor agonist stimulated tmAC to increase exchange protein activated by cAMP (Epac) activity that drives PLC activation to raise [Ca2+]i via Ca2+ store release (and not entry). Increased [Ca2+]i led to sAC activation and further increases in CFTR activity. Stimulation of sAC did not depend on changes in [HCO3−]. Ca2+‐activated apical KCa1.1 channels and cAMP‐activated basolateral KV7.1 channels contributed to H2O2‐stimulated anion currents. A similar Epac‐mediated pathway was seen following β2‐adrenoceptor or forskolin stimulation.

Conclusions and Implications

H2O2 initiated a complex signalling cascade that used direct stimulation of tmACs by Gαs followed by Epac‐mediated Ca2+ crosstalk to activate sAC. The Epac‐mediated Ca2+ signal constituted a positive feedback loop that amplified CFTR anion secretion following stimulation of tmAC by a variety of stimuli.
Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart
Authors: Kojima Akiko , Ito Yuki , Kitagawa Hirotoshi , Matsuura Hiroshi
Published: September 2014

Background and Purpose

Propofol is a widely used intravenous anaesthetic agent, but has undesirable cardiac side effects, including bradyarrhythmia and its severe form asystole. This study examined the ionic and cellular mechanisms underlying propofol‐induced bradycardia.

Experimental Approach

Sinoatrial node cells, isolated from guinea pig hearts, were current‐ and voltage‐clamped to record action potentials and major ionic currents involved in their spontaneous activity, such as the hyperpolarization‐activated cation current (If), T‐type and L‐type Ca2+ currents (ICa,T and ICa,L, respectively) and the rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs, respectively). ECGs were recorded from Langendorff‐perfused, isolated guinea pig hearts.

Key Results

Propofol (≥5 μM) reversibly decreased the firing rate of spontaneous action potentials and their diastolic depolarization rate. Propofol impaired If activation by shifting the voltage‐dependent activation to more hyperpolarized potentials (≥1 μM), slowing the activation kinetics (≥3 μM) and decreasing the maximal conductance (≥10 μM). Propofol decreased ICa,T (≥3 μM) and ICa,L (≥1 μM). Propofol suppressed IKs (≥3 μM), but had a minimal effect on IKr. Furthermore, propofol (≥5 μM) decreased heart rates in Langendorff‐perfused hearts. The sinoatrial node cell model reasonably well reproduced the negative chronotropic action of propofol.

Conclusions and Implications

Micromolar concentrations of propofol suppressed the slow diastolic depolarization and firing rate of sinoatrial node action potentials by impairing If activation and reducing ICa,T, ICa,L and IKs. These observations suggest that the direct inhibitory effect of propofol on sinoatrial node automaticity, mediated via multiple channel inhibition, underlies the propofol‐induced bradycardia observed in clinical settings.
The sphingosine 1‐phosphate receptor agonist FTY720 is neuroprotective after cuprizone‐induced CNS demyelination
Authors: Slowik A , Schmidt T , Beyer C , Amor S , Clarner T , Kipp M
Published: September 2014

Background and Purpose

Modulation of the sphingosine 1‐phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti‐inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection.

Experimental Approach

In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin‐induced experimental demyelination. We used histological, immunohistochemical and gene expression methods.

Key Results

The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone‐induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein‐positive spheroids in axons was less distinct in FTY720‐treated animals, indicating that this compound alleviated ongoing axonal damage.

Conclusions and Implications

We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.
Protective role of olesoxime against wild‐type α‐synuclein‐induced toxicity in human neuronally differentiated SHSY‐5Y cells
Authors: Gouarné C , Tracz J , Paoli M Giraudon , Deluca V , Seimandi M , Tardif G , Xilouri M , Stefanis L , Bordet T , Pruss R M
Published: September 2014

Background and Purpose

Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α‐Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the SNCA gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether olesoxime, a promising neuroprotective drug can prevent ASYN‐mediated neurotoxicity.

Experimental Approach

We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild‐type ASYN in neuronally differentiated human neuroblastoma (SHSY‐5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane‐bound ASYN oligomers and cell death combining both apoptotic and non‐apoptotic pathways.

Key Results

Olesoxime fully protected differentiated SHSY‐5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase‐9 activation suggesting that olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, olesoxime displayed neurotrophic effects on neuronally differentiated SHSY‐5Y cells, independent of ASYN expression, by promoting their differentiation.

Conclusions and Implications

Because ASYN is a common underlying factor in many cases of PD, olesoxime could be a promising therapy to slow neurodegeneration in PD.
Beery‐Buktenica Developmental Test of Visual‐Motor Integration (Beery‐VMI): lessons from exploration of cultural variations in visual‐motor integration performance of preschoolers
Authors: Lim C. Y. , Tan P. C. , Koh C. , Koh E. , Guo H. , Yusoff N. D. , See C. Q. , Tan T.
Published: September 2014

Background

Visual‐motor integration (VMI) is important in children's development because it is associated with the performance of many functional skills. Deficits in VMI have been linked to difficulties in academic performance and functional tasks. Clinical assessment experience of occupational therapists in Singapore suggested that there is a potential difference between the VMI performance of Singaporean and American children. Cross‐cultural studies also implied that culture has an influence on a child's VMI performance, as it shapes the activities that a child participates in. The purpose of this study was to (1) explore if there was a difference between the VMI performance of Singaporean and American preschoolers, and (2) determine if there were ethnic differences in the VMI performance of Singaporean preschoolers.

Methods

The Beery‐VMI, which was standardized in America, is commonly used by occupational therapists in Singapore to assess the VMI ability of children. We administered the Beery‐VMI (fifth edition) full form test (excluding the supplemental tests) to 385 preschoolers (mean age = 63.3 months) from randomly selected schools in Singapore. We compared the scores of Singaporean preschoolers with those of the American standardization norms using the one‐sample t‐test. Scores of different ethnic groups among the Singapore population were also compared using a one‐way anova, followed by the Bonferroni post‐hoc test.

Results

Singaporean preschoolers and the standardization sample of American children performed significantly differently in all age groups (P < 0.05). Among the Singapore population, the scores were also significantly different (P < 0.05) between the (i) Chinese and Malay and (ii) Chinese and Indians ethnic groups.

Conclusion

Preschoolers from different cultural and ethnic groups had different VMI performance. Certain cultural beliefs and practices may affect VMI performance. Clinicians should exercise caution when using an assessment in communities and cultures outside the ones on which it was standardized.
Atopy and cause‐specific mortality
Authors: Skaaby T. , Husemoen L. L. N. , Thuesen B. H. , Hammer‐Helmich L. , Linneberg A.
Published: September 2014

Background

Atopy is the familial or personal propensity to develop immunoglobulin E (IgE) antibodies against common environmental allergens and is associated with high risk of allergic disease. It has been proposed that atopy may have effects on risk of cardiovascular disease and cancer.

Objectives

We investigated the association of atopy with all‐cause and cause‐specific mortality.

Methods

We included a total of 14 849 individuals from five Danish population‐based cohorts with measurements of atopy defined as serum‐specific IgE positivity against inhalant allergens. Participants were followed by linkage to the Danish Registry of Causes of Death to obtain information on mortality status and cause of death (median follow‐up time 11.3 years). The relative mortality risk was estimated by Cox regression and expressed as hazard ratios, HRs (95% confidence intervals, CIs).

Results

A total of 1776 person died during follow‐up. The mortality risk for atopics vs. non‐atopics was: for all‐cause mortality (HR = 1.03, 95% CI: 0.90, 1.17); neoplasms (HR = 0.86, 95% CI: 0.69, 1.06); endocrine, nutritional and metabolic disorders (HR = 1.48, 95% CI: 0.71, 3.08); mental and behavioural disorders (HR = 2.26, 95% CI: 1.18, 4.30); diseases of the nervous system (HR = 1.36, 95% CI: 0.65, 2.87); diseases of the circulatory system (HR = 1.00, 95% CI: 0.78, 1.29); diseases of the respiratory system (HR = 0.94, 95% CI: 0.55, 1.60); and diseases of the digestive system (HR = 1.75, 95% CI: 1.03, 2.98).

Conclusions & Clinical Relevance

We found no statistically significant association between atopy and all‐cause mortality. However, atopy was associated with a significantly higher risk of dying from mental and behavioural disorders and gastrointestinal diseases, particularly liver diseases, and a lower risk of dying from breast cancer, but these associations were not statistically significant when applying the Bonferroni adjusted significance level. Further studies are needed to confirm our findings.
The association between paracetamol use and asthma: causation or coincidence?
Authors: Weatherall M. , Ioannides S. , Braithwaite I. , Beasley R.
Published: September 2014

A better understanding of the causation of asthma and allergic disorders could potentially lead to intervention strategies that reduce their prevalence and severity. One potential causative factor is the use of paracetamol. Most of the evidence for the link with asthma is from non‐experimental studies of paracetamol exposure in utero, infancy, childhood and adult life; however, it has been difficult to rule out confounding and bias in the associations observed. The two randomized clinical trials of the effect of paracetamol in patients with asthma have been difficult to interpret, due to methodological issues. There have been no randomized controlled trials of paracetamol use and the development of asthma. Both asthma and paracetamol use are common, and so even if there is a relatively small effect of paracetamol exposure on the development of asthma or its severity, then such an effect would be of major public health significance. It is proposed that randomized controlled trials of the effect of paracetamol on the development of asthma and its severity are a high research priority.
Long‐term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma
Authors: Trzil J. E. , Masseau I. , Webb T. L. , Chang C.‐H. , Dodam J. R. , Cohn L. A. , Liu H. , Quimby J. M. , Dow S. W. , Reinero C. R.
Published: September 2014

Background

Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodelling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model.

Objective

To document effects of allogeneic, adipose‐derived MSCs on airway inflammation, AHR, and remodelling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma.

Methods

Cats with chronic, experimentally induced asthma received six intravenous infusions of MSCs (0.36–2.5 × 10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for 1 year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia, pulmonary mechanics and clinical scoring to assess AHR, and thoracic computed tomographic (CT) scans to assess structural changes (airway remodelling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen‐specific IgE, cellular IL‐10 production, and allergen‐specific lymphocyte proliferation were performed.

Results

There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC‐treated animals compared to placebo‐treated cats at month 8 of the study (LA P = 0.0311; BWT P = 0.0489). No differences were noted between groups in the immunologic assays.

Conclusions and Clinical Relevance

When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodelling by month 8, although the effect was not sustained at month 12. Further study of MSC therapy including repeated MSC administration is warranted to assess impact on remodelling in chronic asthma.
A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma
Authors: Wadt K.A.W. , Aoude L.G. , Johansson P. , Solinas A. , Pritchard A. , Crainic O. , Andersen M.T. , Kiilgaard J.F. , Heegaard S. , Sunde L. , Federspiel B. , Madore J. , Thompson J.F. , McCarthy S.W. , Goodwin A. , Tsao H. , Jönsson G. , Busam K. , Gupta R. , Trent J.M. , Gerdes A.‐M. , Brown K.M. , Scolyer R.A. , Hayward N.K.
Published: September 2014

We report four previously undescribed families with germline BRCA1‐associated protein‐1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.
A randomized clinical trial evaluating the efficacy of the sandwich bone augmentation technique in increasing buccal bone thickness during implant placement. II. Tomographic, histologic, immunohistochemical, and RNA analyses
Authors: Fu Jia‐Hui , Rios Hector , Al‐Hezaimi Khalid , Oh Tae‐Ju , Benavides Erika , Wang Hom‐Lay
Published: September 2014

Objectives

This study aimed to evaluate the biologic and structural phenotypes of the bone regenerated via the sandwich bone augmentation (SBA) technique, on buccal implant dehiscence defects.

Material and Methods

Twenty‐six patients with one buccal implant dehiscence defect each were randomly assigned to two groups. Both groups received a standardized amount of mineralized cancellous and cortical allogenic bone graft. In the test group, a bovine pericardium membrane was placed over the graft, while no membrane was placed in the control group. After 6 months of healing, a bone core biopsy of the regenerated bone was harvested and processed for histologic, immunohistochemical, mRNA, and micro‐computed tomography (μCT) analyses. Of the 26 bone core biopsies, only six cores from the test group and six cores from the control group were suitable for the analysis.

Results

Bone volume (BV) in the test group was maintained, but tissue maturation appeared to be delayed. In contrast, tissue maturation appeared to be completed in the control group, but BV was compromised. Micro‐CT analysis showed that specimens from the control group were more structured and mineralized compared with those from the test group. Histologic analysis showed more residual graft particles scattered in a loose fibrous connective tissue matrix with sparse bone formation in the test group, while the control group showed obvious vital bone formation surrounding the residual graft particles. Positive periostin (POSTN), sclerostin, and runt‐related transcription factor‐2 (RUNX2) immunoreactivities were detected in both the control and test groups. However, tartrate‐resistant acid phosphatase (TRAP) positive was mostly noted in the control group. There were significant differences in POSTN, RUNX2 and VEGF expressions between the test and control groups.

Conclusion

These findings indicated that the SBA technique was an effective method in preserving adequate structural volume while promoting new vital bone formation. Use of the collagen barrier membrane has successfully maintained the volumetric dimensions of the ridge but might have slowed down the complete maturation of the outermost layer of the grafted site.
Randomized trial showing efficacy and safety of twice‐daily remogliflozin etabonate for the treatment of type 2 diabetes
Authors: Sykes A. P. , O'Connor‐Semmes R. , Dobbins R. , Dorey D. J. , Lorimer J. D. , Walker S. , Wilkison W. O. , Kler L.
Published: September 2014

We compared the efficacy of twice‐daily doses of remogliflozin etabonate (RE) and once‐daily pioglitazone with placebo for reduction in glycated haemoglobin (HbA1c) concentration. In this 12‐week, double‐blind, randomized, active‐ and placebo‐controlled trial, 336 treatment‐naïve subjects with type 2 diabetes and an HbA1c of 7.0–9.5% (53–80 mmol/mol) were randomized to RE (50, 100, 250, 500 or 1000 mg twice daily), matching placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c from baseline. Other endpoints included changes in body weight, lipid levels, safety and tolerability. RE produced a decreasing dose response in HbA1c at week 12 (p < 0.001), with reductions in HbA1c versus placebo ranging from 0.64 to 1.07% (p < 0.001). Statistically significant reductions in body weight for RE compared with placebo were also observed. Twice‐daily RE resulted in a dose‐ordered improvement in glycaemic control and was generally well tolerated.
Predator responses to novel haemolymph defences of western corn rootworm (Diabrotica virgifera) larvae
Authors: Welch Kelton D. , Lundgren Jonathan G.
Published: September 2014

Many herbivorous arthropods use defensive chemistry to discourage predators from attacking. This chemistry relies on the ability of predators to rapidly learn to recognize and avoid offensive stimuli. Western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), employs multifaceted chemical defences in its haemolymph, which may contribute significantly to its success as a major economic pest. Here, we test the hypothesis that agrobiont predators can rapidly learn to recognize and avoid WCR larvae, and will thereby reduce their contribution to WCR suppression. In controlled feeding assays, the effectiveness of WCR haemolymph defences varied across three predator taxa (crickets, centipedes, and ants). Centipedes (Chilopoda: Lithobiidae) were minimally affected by WCR defences, but crickets [Gryllus pennsylvanicus Burmeister (Orthoptera: Gryllidae)] spent less time feeding on WCR than on an undefended control prey, house fly maggots. However, we uncovered no evidence indicating that experienced crickets rapidly learn to avoid WCR larvae, indicating that haemolymph defences offer few, if any, survival benefits for WCR. Colonies of ants [Lasius neoniger Emery (Hymenoptera: Formicidae)] switched from low worker participation in initial attacks on WCR to higher worker participation in subsequent attacks, indicating an attempt to overcome, rather than avoid, WCR haemolymph defences. These results suggest that a diverse assemblage of natural enemies will show a diverse array of behavioural responses to toxic pest prey, and highlight the importance of behavioural diversity in driving the function of natural enemy assemblages.
Central pontine and extrapontine myelinolysis: a systematic review
Authors: Singh T. D. , Fugate J. E. , Rabinstein A. A.
Published: September 2014

The purpose was to perform a systematic review of studies on central pontine and extrapontine myelinolysis [forms of osmotic demyelination syndrome (ODS)] and define the spectrum of causes, risk factors, clinical and radiological presentations, and functional outcomes of this disorder. A thorough search of the literature was conducted using multiple databases (PubMed, Ovid Medline and Google) and bibliographies of key articles to identify all case series of adult patients withODSpublished from 1959 to January 2013. Only series with five or more cases published in English were considered. Of the 2602 articles identified, 38 case series were included comprising a total of 541 patients who fulfilled our inclusion criteria. The most common predisposing factor was hyponatremia (78%) and the most common presentation was encephalopathy (39%). Favorable recovery occurred in 51.9% of patients and death in 24.8%. Liver transplant patients withODShad a combined rate of death and disability of 77.4%, compared with 44.7% in those without liver transplantation (P < 0.001).ODSis found to have a good recovery in more than half of cases and its mortality has decreased with each passing decade. Favorable prognosis is possible in patients ofODS, even with severe neurological presentation. Further research is required to confirm the differences found in liver transplant recipients.
Investigating inhibitory control in children with epilepsy: An fMRI study
Authors: Triplett Regina L. , Velanova Katerina , Luna Beatriz , Padmanabhan Aarthi , Gaillard William D. , Asato Miya R.
Published: September 2014

Objective

Deficits in executive function are noted increasingly in children with epilepsy and have been associated with poor academic and psychosocial outcomes. Impaired inhibitory control contributes to executive dysfunction in children with epilepsy; however, its neuroanatomic basis has not yet been investigated. We used functional magnetic resonance imaging (fMRI) to probe the integrity of activation in brain regions underlying inhibitory control in children with epilepsy.

Methods

This cross‐sectional study consisted of 34 children aged 8–17 years: 17 with well‐controlled epilepsy and 17 age‐ and sex‐matched controls. Participants performed the antisaccade (AS) task, representative of inhibitory control, during fMRI scanning. We compared AS performance during neutral and reward task conditions and evaluated task‐related blood oxygen level–dependent (BOLD) activation.

Results

Children with epilepsy demonstrated impaired AS performance compared to controls during both neutral (nonreward) and reward trials, but exhibited significant task improvement during reward trials. Post hoc analysis revealed that younger patients made more errors than older patients and all controls. fMRI results showed preserved activation in task‐relevant regions in patients and controls, with the exception of increased activation in the left posterior cingulate gyrus in patients specifically with generalized epilepsy across neutral and reward trials.

Significance

Despite impaired inhibitory control, children with epilepsy accessed typical neural pathways as did their peers without epilepsy. Children with epilepsy showed improved behavioral performance in response to the reward condition, suggesting potential benefits of the use of incentives in cognitive remediation.
Glutaryl‐coenzyme A dehydrogenase from Geobacter metallireducens – interaction with electron transferring flavoprotein and kinetic basis of unidirectional catalysis
Authors: Estelmann Sebastian , Boll Matthias
Published: September 2014

Glutaryl‐CoA dehydrogenases (GDHs) are FAD containing acyl‐CoA dehydrogenases that usually catalyze the dehydrogenation and decarboxylation of glutaryl‐CoA to crotonyl‐CoA with an electron transferring flavoprotein (ETF) acting as natural electron acceptor. In anaerobic bacteria, GDHs play an important role in the benzoyl‐CoA degradation pathway of monocyclic aromatic compounds. In the present study, we identified, purified and characterized the benzoate‐induced BamOP as the electron accepting ETF of GDH (BamM) from the Fe(III)‐respiring Geobacter metallireducens. The BamOP heterodimer contained FAD and AMP as cofactors. In the absence of an artificial electron acceptor, at pH values above 8, the BamMOP‐components catalyzed the expected glutaryl‐CoA oxidation to crotonyl‐CoA and CO2; however, at pH values below 7, the redox‐neutral glutaryl‐CoA conversion to butyryl‐CoA and CO2 became the dominant reaction. This previously unknown, strictly ETF‐dependent coupled glutaryl‐CoA oxidation/crotonyl‐CoA reduction activity was facilitated by an unexpected two‐electron transfer between FAD(BamM) and FAD(BamOP), as well as by the similar redox potentials of the two FAD cofactors in the substrate‐bound state. The strict order of electron/proton transfer and C‐C‐cleavage events including transient charge‐transfer complexes did not allow an energetic coupling of electron transfer and decarboxylation. This explains why it was difficult to release the glutaconyl‐CoA intermediate from reduced GDH. Moreover, it provides a kinetic rational for the apparent inability of BamM to catalyze the reverse reductive crotonyl‐CoA carboxylation, even under thermodynamically favourable conditions. For this reason reductive crotonyl‐CoA carboxylation, a key reaction in C2‐assimilation via the ethylmalonyl‐CoA pathway, is accomplished by a different crotonyl‐CoA carboxylase/reductase via a covalent NADPH/ene‐adduct.
Important ecological traits for selecting Biserrula pelecinus L. (biserrula) genotypes for their potential introduction into agricultural systems
Authors: Loi A. , Franca A. , Nutt B. J. , Yates R. J. , D'Antuono M. F. , Howieson J. G.
Published: September 2014

An investigation of eleven genotypes and two cultivars of Biserrula pelecinus L. (biserrula) was conducted in Western Australia to study their ecological and agronomic traits. All biserrula genotypes were productive in the 2 years of testing, with dry‐matter production ranging from 3·5 to 4·9 t ha−1 and seed yield ranging from 314 to 1381 kg ha−1. Biserrula has high initial levels of hard seededness (95–100%) and a more gradual hard seed breakdown (68–92%) in summer. The high levels of hard seed decreased the seedling densities of biserrula in the second year, while were at highest levels in the third year after the plots were cropped to wheat. A further experiment was conducted to study the interaction between spray‐topping and seed set. This study showed subterranean clover seed yields were more tolerant to herbicides than a number of biserrula genotypes. There were significant responses to the herbicides within the biserrula genotypes, and 95GCN59 was less affected. The rhizobium experiment showed a strong host strain/interaction and has emphasized the importance of simultaneous breeding and selection of plant germplasm run in parallel with the selection of elite strains of rhizobia such as WSM1497 to optimize nitrogen fixation.