bluuebunny/crossref_metadata_2025 huggingface dataset:
Upregulated expression of monocyte chemoattractant protein‐1 in human periodontal ligament cells induced by interleukin‐1β
Authors: Jin J , Cao J
Published: October 2014

Background

Root resorption during orthodontic treatment is a complex and sterile inflammatory process, characterized by the recruitment of mononuclear cells in the local periodontal ligament. This study aimed to investigate whether interleukin (IL)‐1β could induce the migration of monocytes through upregulating monocyte chemoattractant protein (MCP)‐1 expression in human periodontal ligament cells.

Methods

Human periodontal ligament cells were cultured in medium containing various IL‐1β concentrations. After 24 hours of incubation, the messenger RNA (mRNA) and MCP‐1 protein in periodontal ligament cells were detected by reverse transcriptase–polymerase chain reaction and Western blot analysis, respectively. The effect of supernatants of periodontal ligament cells on THP‐1 cells was analysed via migration assay.

Results

IL‐1β (10 ng/mL and 25 ng/mL) increased the expression of MCP‐1 mRNA and protein in periodontal ligament cells (p < 0.05). In addition, the supernatants from the IL‐1β‐treated periodontal ligament cells increased the migratory response of THP‐1 cells (p < 0.05), which could be blocked by the anti‐MCP‐1 antibody.

Conclusions

IL‐1β had the potential to induce the migratory response of monocytes via upregulation of the expression of MCP‐1 in human periodontal ligament cells and could contribute to orthodontic root resorption.
Artemether‐lumefantrine co‐administration with antiretrovirals: population pharmacokinetics and dosing implications
Authors: Hoglund Richard M. , Byakika‐Kibwika Pauline , Lamorde Mohammed , Merry Concepta , Ashton Michael , Hanpithakpong Warunee , Day Nicholas P. J. , White Nicholas J. , Äbelö Angela , Tarning Joel
Published: October 2014

Aim

Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl‐lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

Method

Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non‐linear mixed effects modelling approach.

Results

Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether‐lumefantrine dose is required to achieve equivalent exposures when co‐administered with efavirenz (250% increase) and nevirapine (75% increase). When co‐administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

Conclusion

There are substantial drug interactions between artemether‐lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria‐HIV co‐infected patients.
The cGMP/PKG pathway as a common mediator of cardioprotection: translatability and mechanism
Authors: Inserte Javier , Garcia‐Dorado David
Published: October 2014

Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of reperfusion injury have been identified, including alterations in cytosolic Ca2+ handling, sarcoplasmic reticulum‐mediated Ca2+ oscillations and hypercontracture, proteolysis secondary to calpain activation and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca2+ oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischaemia/reperfusion and preserved by ischaemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischaemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction.

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 sulphide protects against NSAID‐enteropathy through modulation of bile and the microbiota
Authors: Blackler Rory W , Motta Jean‐Paul , Manko Anna , Workentine Matthew , Bercik Premysl , Surette Michael G , Wallace John L
Published: October 2014

Background and Purpose

Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID‐induced intestinal damage and bleeding. We evaluated the ability of a hydrogen sulphide donor to protect against NSAID‐induced enteropathy.

Experimental Approach

Intestinal ulceration and bleeding were induced in Wistar rats by oral administration of naproxen. The effects of suppression of endogenous hydrogen sulphide synthesis or administration of a hydrogen sulphide donor (diallyl disulphide) on naproxen‐induced enteropathy was examined. Effects of diallyl disulphide on small intestinal inflammation and intestinal microbiota were also assessed. Bile collected after in vivo naproxen and diallyl disulphide administration was evaluated for cytotoxicity in vitro using cultured intestinal epithelial cells.

Key Results

Suppression of endogenous hydrogen sulphide synthesis by β‐cyano‐L‐alanine exacerbated naproxen‐induced enteropathy. Diallyl disulphide co‐administration dose‐dependently reduced the severity of naproxen‐induced small intestinal damage, inflammation and bleeding. Diallyl disulphide administration attenuated naproxen‐induced increases in the cytotoxicity of bile on cultured enterocytes, and prevented or reversed naproxen‐induced changes in the intestinal microbiota.

Conclusions and Implications

Hydrogen sulphide protects against NSAID‐enteropathy in rats, in part reducing the cytotoxicity of bile and preventing NSAID‐induced dysbiosis.
Biphasic modulation by mGlu5 receptors of TRPV1‐mediated intracellular calcium elevation in sensory neurons contributes to heat sensitivity
Authors: Masuoka T , Nakamura T , Kudo M , Yoshida J , Takaoka Y , Kato N , Ishibashi T , Imaizumi N , Nishio M
Published: October 2014

Background and Purpose

Elevation of glutamate, an excitatory amino acid, during inflammation and injury plays a crucial role in the reception and transmission of sensory information via ionotropic and metabotropic receptors. This study aimed to investigate the mechanisms underlying the biphasic effects of metabotropic glutamate mGlu5 receptor activation on responses to noxious heat.

Experimental Approach

We assessed the effects of intraplantar quisqualate, a non‐selective glutamate receptor agonist, on heat and mechanical pain behaviours in mice. In addition, the effects of quisqualate on the intracellular calcium response and on membrane currents mediated by TRPV1 channels, were examined in cultured dorsal root ganglion neurons from mice.

Key Results

Activation of mGlu5 receptors in hind paw transiently increased, then decreased, the response to noxious heat. In sensory neurons, activation of mGlu5 receptors potentiated TRPV1‐mediated intracellular calcium elevation, while terminating activation of mGlu5 receptors depressed it. TRPV1‐induced currents were potentiated by activation of mGlu5 receptors under voltage clamp conditions and these disappeared after washout. However, voltage‐gated calcium currents were inhibited by the mGlu5 receptor agonist, even after washout.

Conclusions and Implications

These results suggest that, in sensory neurons, mGlu5 receptors biphasically modulate TRPV1‐mediated intracellular calcium response via transient potentiation of TRPV1 channel‐induced currents and persistent inhibition of voltage‐gated calcium currents, contributing to heat hyper‐ and hypoalgesia.
The endocannabinoid system regulates synaptic transmission in nucleus accumbens by increasing DAGL‐α expression following short‐term morphine withdrawal
Authors: Wang Xing‐Qin , Ma Jie , Cui Wei , Yuan Wei‐Xin , Zhu Gang , Yang Qian , Heng Li‐Jun , Gao Guo‐Dong
Published: October 2014

Background and Purpose

The endocannabinoid (eCB) system is involved in pathways that regulate drug addiction and eCB‐mediated synaptic plasticity has been linked with addictive behaviours. Here, we investigated the molecular mechanisms underlying the changes in eCB‐dependent synaptic plasticity in the nucleus accumbens core (NAcc) following short‐term withdrawal from repeated morphine treatment.

Experimental Approach

Conditioned place preference (CPP) was used to evaluate the rewarding effects of morphine in rats. Evoked inhibitory postsynaptic currents of medium spiny neurons in NAcc were measured using whole‐cell patch‐clamp recordings. Changes in depolarization‐induced suppression of inhibition (DSI) in the NAcc were assessed to determine the effect of short‐term morphine withdrawal on the eCB system. To identify the potential modulation mechanism of short‐term morphine withdrawal on the eCB system, the expression of diacylglycerol lipase α (DGL‐α) and monoacylglycerol lipase was detected by Western blot analysis.

Key Results

Repeated morphine administration for 7 days induced stable CPP. Compared with the saline group, the level of DSI in the NAcc was significantly increased in rats after short‐term morphine withdrawal. Furthermore, this increase in DSI coincided with a significant increase in the expression of DGL‐α.

Conclusions and Implications

Short‐term morphine withdrawal potentiates eCB modulation of inhibitory synaptic transmission in the NAcc. We also found that DGL‐α expression was elevated after short‐term morphine withdrawal, suggesting that the eCB 2‐arachidonyl‐glycerol but not anandamide mediates the increase in DSI. These findings provide useful insights into the mechanisms underlying eCB‐mediated plasticity in the NAcc during drug addiction.

Linked Articles

This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc
Presynaptic adenosine A2A receptors dampen cannabinoid CB1 receptor‐mediated inhibition of corticostriatal glutamatergic transmission
Authors: Ferreira S G , Gonçalves F Q , Marques J M , Tomé Â R , Rodrigues R J , Nunes‐Correia I , Ledent C , Harkany T , Venance L , Cunha R A , Köfalvi A
Published: October 2014

Background and Purpose

Both cannabinoid CB1 and adenosine A2A receptors (CB1 receptors and A2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB1−A2A receptor interaction has already been elucidated, but the presynaptic A2A receptor‐mediated control of presynaptic neuromodulation by CB1 receptors remains to be defined. Because the corticostriatal terminals provide the major input to the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions.

Experimental Approach

Pharmacological manipulation of CB1 and A2A receptors was carried out in brain nerve terminals isolated from rats and mice, using flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement. Whole‐cell patch‐clamp recordings were made in horizontal corticostriatal slices.

Key Results

Flow synaptometry showed that A2A receptors were extensively co‐localized with CB1 receptor‐immunopositive corticostriatal terminals and A2A receptors co‐immunoprecipitated CB1 receptors in these purified terminals. A2A receptor activation decreased CB1 receptor radioligand binding and decreased the CB1 receptor‐mediated inhibition of high‐K+‐evoked glutamate release in corticostriatal terminals. Accordingly, A2A receptor activation prevented CB1 receptor‐mediated paired‐pulse facilitation and attenuated the CB1 receptor‐mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices.

Conclusions and Implications

Activation of presynaptic A2A receptors dampened CB1 receptor‐mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB1 receptor‐mediated presynaptic inhibition, allowing frequency‐dependent enhancement of synaptic efficacy at corticostriatal synapses.
Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat
Authors: Lilius T O , Jokinen V , Neuvonen M S , Niemi M , Kalso E A , Rauhala P V
Published: October 2014

Background and Purpose

The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal.

Experimental Approach

Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine‐3‐glucuronide, ketamine and norketamine were measured using HPLC‐tandem mass spectrometry.

Key Results

In morphine‐naïve rats, ketamine caused no antinociception whereas in morphine‐tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine‐tolerant ketamine‐treated rats, the morphine, ketamine and norketamine concentrations were 2.1‐, 1.4‐ and 3.4‐fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine‐tolerant ketamine‐treated rats, ketamine concentration was sixfold compared with morphine‐naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed.

Conclusions and Implications

The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans.
Validity, internal consistency reliability and one‐year stability of the Slovene translation of the Measure of Processes of Care (20‐item version)
Authors: Groleger Sršen K. , Vidmar G. , Zupan A.
Published: October 2014

Background

The Measure of Processes of Care (MPOC) was developed as a self‐administered questionnaire for parents to report on behaviours of healthcare providers. The original (MPOC‐56) and the 20‐item version (MPOC‐20) have established reliability and validity, but the instrument must be rechecked whenever translated and applied in a different social and cultural setting. The aim of our study was to evaluate validity, internal consistency reliability and 1‐year stability of the Slovene translation of MPOC‐20.

Methods

Parents of children who were admitted as inpatients or outpatients of several hospitals and health centres were invited to participate. MPOC‐20, the Client Satisfaction Questionnaire (CSQ‐8) and a separate question on stress and worries were sent by mail. Descriptive item analysis was performed. Cronbach's alpha coefficient and corrected item‐total correlations were used to assess internal consistency for each of the five MPOC‐20 subscales. To evaluate validity, we correlated the MPOC‐20 subscale scores with CSQ‐8 scores and a stress alleviation rating. Assessment with MPOC‐20 was performed again 1 year later and we used paired‐samples tests to compare mean scores of both assessments.

Results

Parents of 235 children participated in the study (80% mothers). They reported high general satisfaction as 15 out of the 20 MPOC‐20 mean item scores were above 5 (out of 7) and none was below 4. The mean MPOC‐20 mean subscale scores were 5.83 (SD 1.10) for Coordinated and Comprehensive Care for Child and Family, 5.62 (SD 1.12) for Respectful and Supportive Care, 5.45 (SD 1.23) for Enabling and Partnership, 5.33 (SD 1.61) for Providing Specific Information about the Child and 4.59 (SD 1.65) for Providing General Information. The ranking order of the mean rating of the MPOC‐20 subscales was similar to previous studies. The parents reported that they felt their stress and worries had been notably or slightly reduced through the process of care in the last year in more than two‐thirds of the cases. All the MPOC‐20 subscales (as well as the CSQ‐8 scale) showed high internal consistency: the corrected item‐total correlations were far above the lower limit for item's acceptance of 0.3. After 1 year (66 returned questionnaires) none of the mean subscale scores changed statistically significantly (P‐values 0.159–0.910).

Conclusion

The Slovene translation of the MPOC‐20 can be considered as a valid and reliable instrument that shows good stability over a period of 1 year, and as such it can be adopted in clinical practice.
Higher body mass index and larger waist circumference may be predictors of thyroid carcinoma in patients with Hürthle‐cell lesion/neoplasm fine‐needle aspiration diagnosis
Authors: Arduc Ayse , Dogan Bercem Aycicek , Tuna Mazhar Muslum , Tutuncu Yasemin , Isik Serhat , Berker Dilek , Guler Serdar
Published: October 2014

Objective

High body mass index (BMI) has been found to be associated with raised thyroid cancer risk, particularly in women. We examined the associations for BMI and waist circumference (WC) with thyroid cancer risk among women with Hürthle‐cell lesion/neoplasm (HLN) on fine‐needle aspiration biopsy (FNAB) with the hypothesis that BMI and WC could guide the management of these challenging indeterminate lesions.

Methods

This cross‐sectional study included 224 women with HLN who underwent thyroidectomy. In all patients, TSH and thyroid auto‐antibodies were evaluated, and thyroid nodule features were recorded. Patients were grouped according to BMI (<30 or ≥30 kg/m2) and WC (<88 or ≥88 cm). Relationships of thyroid cancer with BMI and WC were assessed using logistic regression analysis.

Results

Mean weight, BMI (31·26 ± 5·1 vs 26·47 ± 5·9, P < 0·001), WC (98·23 ± 7·6 vs 86·18 ± 11, P = 0·001), and proportion of patients with high BMI (≥30 kg/m2) (65·9 vs 33·8%, P < 0·001) or large WC (≥88 cm) (84·1 vs 47·9%, P < 0·001) were significantly higher in malignant group compared to benign group. In regression analysis, BMI and WC significantly associated with existence of malignancy. Malignancy risk was 3·819‐fold higher (95% CI: 2·068–7·054) in BMI≥30 kg/m2 group compared to BMI<30 kg/m2, which was independent of TSH and age. Large WC was also associated with increased risk (OR = 5·593, 95% CI: 2·736–11·434). Baseline tumour characteristics were similar according to BMI and WC groups.

Conclusions

A great BMI and large WC were associated with higher thyroid cancer risk in patients with FNAB diagnosis of HLN. Further studies are needed to use BMI or WC in the management of patients with HLN.
Analysing empowerment‐oriented email consultation for parents: development of the Guiding the Empowerment Process model
Authors: Nieuwboer Christa C. , Fukkink Ruben G. , Hermanns Jo M. A.
Published: October 2014

Online consultation is increasingly offered by parenting practitioners, but it is not clear if it is feasible to provide empowerment‐oriented support in a single session email consultation. Based on the empowerment theory, we developed the Guiding the Empowerment Process model (GEP model) to evaluate text‐based consultation. By content analysis of the email advice (n = 129; 5997 sentences in total), we investigated the feasibility of the newly developed model (inter‐observer agreement, internal consistency and factor structure) and its validity. Concurrent validity was evaluated by comparing coding results using the GEP model and a Social Support model that partially intersects with empowerment. Results showed good inter‐observer reliability and internal consistency of the GEP model. The results provided evidence for its concurrent validity by a significant correlation of the coding results from the GEP model with the Social Support model, although it was also distinctive. All described techniques which practitioners may employ to guide the parental process towards empowerment were observed in the sample. Also, guidance was provided in all components of the empowerment process. Feasibility of the GEP model for content analysis of email consultation in parental support from a theoretical empowerment perspective has been demonstrated.
Long‐term psychosocial and behavioral adjustment in individuals receiving genetic test results in Lynch syndrome
Authors: Esplen M.J. , Wong J. , Aronson M. , Butler K. , Rothenmund H. , Semotiuk K. , Madlensky L. , Way C. , Dicks E. , Green J. , Gallinger S.
Published: October 2014

A cross‐sectional study of 155 participants who underwent genetic testing for Lynch syndrome (LS) examined long‐term psychosocial and behavioral outcomes. Participants completed standardized measures of perceived risk, psychosocial functioning, knowledge, and a questionnaire of screening activities. Participants were on average 47.3 years and had undergone testing a mean of 5.5 years prior. Eighty four (54%) tested positive for a LS mutation and 71 (46%) negative. For unaffected carriers, perceived lifetime risk of colorectal cancer was 68%, and surprisingly, 40% among those testing negative. Most individuals demonstrated normative levels of psychosocial functioning. However, 25% of those testing negative had moderate depressive symptoms, as measured by the Center for Epidemiologic Studies for Depression Scale, and 31% elevated state anxiety on the State‐Trait Anxiety Inventory. Being female and a stronger escape – avoidant coping style were predictive of depressive symptoms. For state anxiety, similar patterns were observed. Quality of life and social support were significantly associated with lower anxiety. Carriers maintained higher knowledge compared to those testing negative, and were more engaged in screening. In summary, most individuals adapt to genetic test results over the long term and continue to engage in screening. A subgroup, including some non‐carriers, may require added psychosocial support.
Multicenter comparison of laboratory performance in cytomegalovirus and Epstein–Barr virus viral load testing using international standards
Authors: Rychert Jenna , Danziger‐Isakov Lara , Yen‐Lieberman Belinda , Storch Gregory , Buller Richard , Sweet Stewart C. , Mehta Aneesh K. , Cheeseman Jennifer A. , Heeger Peter , Rosenberg Eric S. , Fishman Jay A.
Published: October 2014

Background

Infections with cytomegalovirus (CMV) and Epstein–Barr virus (EBV) remain important in solid organ transplantation. Quantitative viral nucleic acid testing is a major advance to patient management. These assays are limited by a lack of standardization, resulting in viral load measurements that differ among clinical laboratories. The variability in viral load measurements makes interpretation of multicenter clinical trials data difficult. This study compares the current practices in CMV and EBV viral load testing at four large transplant centers participating in multicenter Clinical Trials in Organ Transplantation and the Clinical Trials in Organ Transplantation in Children (CTOT and CTOTC).

Methods

Viral load testing was performed on well‐defined viral preparations according to standard operating procedures at each site.

Results

Among centers, CMV viral load testing was accurate compared to WHO International Standards and within acceptable variation for this testing method. Epstein–Barr virus viral load data were more variable and less accurate despite the use of international standards.

Conclusions

These data suggest that comparison of CMV, but not EBV, viral load measurements at these sites is possible using current assays and control standards. Standardization of these assays is facilitated using the WHO International Standards and will allow comparison of viral load results among transplant centers. Assay standardization must be performed prior to initiation of multicenter trials.
Initial combination of linagliptin and metformin compared with linagliptin monotherapy in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia: a randomized, double‐blind, active‐controlled, parallel group, multinational clinical trial
Authors: Ross S. A. , Caballero A. E. , Del Prato S. , Gallwitz B. , Lewis‐D'Agostino D. , Bailes Z. , Thiemann S. , Patel S. , Woerle H.‐J. , von Eynatten M.
Published: October 2014

Aims

To evaluate glucose‐lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted.

Methods

A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5–12.0%, were randomized 1:1 to double‐blind, free‐combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per‐protocol completers' cohort: n = 245).

Results

The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by –2.8 ± 0.1% with linagliptin/metformin and –2.0 ± 0.1% with linagliptin; a treatment difference of –0.8% (95% confidence interval –1.1 to –0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent‐to‐treat principles: adjusted mean ± s.e. changes in HbA1c of –2.7 ± 0.1% and –1.8 ± 0.1%, respectively; treatment difference of –0.9% (95% CI –1.3 to –0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug‐related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (–1.3 kg between‐group difference; p =0.0033).

Conclusions

Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non‐insulin therapy.
ANALYZING COMOVEMENTS IN HOUSING PRICES USING VINE COPULAS
Authors: Zimmer David M.
Published: October 2014

Prior to the housing crisis, the Gaussian copula provided the basis for estimates of the degree of diversification of structured mortgage‐based securities. The Gaussian copula's popularity stemmed not only from its link to the familiar normal distribution, but also from the fact that, unlike other copula‐based models, it readily extends to higher dimensions. But the Gaussian copula has asymptotic independence, such that events, regardless of the strength of their correlation, become independent if one pushes far enough into the tails. Instead, this article forms multivariate models of housing price comovements using vine copulas. These more flexible models not only fit the data better, but they also uncover far stronger correlations between housing price movements, especially during extreme market swings. (JEL G21, C32, C51)
Urban working‐class food consumption and nutrition in Britain in 1904
Authors: Gazeley Ian , Newell Andrew
Published: October 2014

This article re‐examines the food consumption of working‐class households in 1904 and compares the nutritional content of these diets with modern measures of adequacy. We find a fairly steep gradient of nutritional attainment relative to economic class, with high levels of vitamin and mineral deficiency among the very poorest working households. However, we conclude that the average unskilled‐headed working household was better fed and nourished than previously thought. When proper allowance is made for the likely consumption of alcohol, household energy intakes were significantly higher still. We investigate the likely impact of contemporary cultural food distribution norms and conclude on the basis of the very limited evidence available that women may have received, on average, about 80 per cent of a man's share of the available food. We adjust energy requirements for likely higher physical activity rates and smaller stature and find that except among the poorest households, early twentieth‐century diets were sufficient to provide energy for reasonably physically demanding work. These results are consistent with recent attempts to relate the available anthropometric evidence to long‐run trends in food consumption. We also find that the lower tail of the household nutrition distribution drops away very rapidly, so that few households are estimated to have suffered severe food shortages.
Urban growth and change in 1940s Southeast Asia
Authors: Huff Gregg , Huff Gillian
Published: October 2014

This article analyses demographic change in Southeast Asia's main cities during and soon after the Second World War Japanese occupation. We argue that two main patterns of population movements are evident. In food‐deficit areas, a search for food security typically led to large net inflows to main urban centres. By contrast, an urban exodus dominated in food surplus regions because the chief risk was to personal safety, especially from Japanese and Allied bombing. Black markets were ubiquitous, and essential to sustaining livelihoods in cities with food‐deficit hinterlands. In Rangoon and Manila, wartime population fluctuations were enormous. Famines in Java and northern Indochina severely impacted Jakarta and Hanoi through inflows of people from rural areas. In most countries, the war's aftermath of refugees, revolution, and political disruption generated major rural–urban population relocations. Turmoil in the 1940s had the permanent consequences of augmenting the primacy of Southeast Asia's main cities and promoting squatter settlement.
Seeking help for first‐episode psychosis: a family narrative
Authors: Connor Charlotte , Greenfield Sheila , Lester Helen , Channa Sunita , Palmer Colin , Barker Clare , Lavis Anna , Birchwood Max
Published: October 2014

Aim

Delayed help‐seeking can have serious consequences for young people with first‐episode psychosis (FEP), in terms of treatment response and outcome. Young people's narratives about help‐seeking are important to understand why delays occur; however, as the majority of help‐seeking is initiated by family members, through a general practitioner (GP), family narratives are also of interest. The aim of this study was to explore help‐seeking for FEP, including first contact with a GP.

Method

A semistructured interview was developed using a topic guide. Framework analysis was used to analyse data and a deductive qualitative method for applied research. The study was set in Birmingham, UK. Participants were interviewed separately by researchers. Joint coding and identification of 14 complete family dyads was then explored for emerging patterns within the family context.

Results

Family responses to FEP that had an impact on help‐seeking behaviour included withdrawal, normalization, stigma, fear and guilt; poor knowledge of availability, and means of access to mental health services was also important. Help‐seeking was usually instigated by a family member through a GP, although this was not the case for two of our families, and while contact with GP was generally described as a positive experience for several families, it was hindered by poor communication and lack of engagement.

Conclusion

Families play a key role in facilitating help‐seeking for FEP, but attempts are often derailed by complex family responses to illness. Public mental health interventions should focus on increasing community awareness of psychosis and improving access and alternative routes to mental health services. However, improvements will have little impact unless primary care and other help‐seeking sources engage in open and easy dialogue with the families and young people trying to access their specialist services.
Lungeing on hard and soft surfaces: Movement symmetry of trotting horses considered sound by their owners
Authors: Pfau T. , Jennings C. , Mitchell H. , Olsen E. , Walker A. , Egenvall A. , Tröster S. , Weller R. , Rhodin M.
Published: October 2014

Reasons for performing study

Lungeing is often part of the clinical lameness examination. The difference in movement symmetry, which is a commonly employed lameness measure, has not been quantified between surfaces.

Objectives

To compare head and pelvic movement symmetry between surfaces and reins during lungeing.

Study design

Quantitative gait analysis in 23 horses considered sound by their owners.

Methods

Twenty‐three horses were assessed in‐hand and on the lunge on both reins on hard and soft surfaces with inertial sensors. Seven movement symmetry parameters were quantified and used to establish 2 groups, namely symmetrical (n = 9) and forelimb‐lame horses (n = 14), based on values from straight‐line assessment. Movement symmetry values for left rein measurements were side corrected to allow comparison of the amount of movement symmetry between reins. A mixed model (P<0.05) was used to study effects on movement symmetry of surface (hard/soft) and rein (inside/outside with respect to movement symmetry on the straight).

Results

In forelimb‐lame horses, surface and rein were identified as significantly affecting all head movement symmetry measures (rein, all P<0.0001; surface, all P<0.042). In the symmetrical group, no significant influence of surface or rein was identified for head movement symmetry (rein, all P>0.245; surface, all P>0.073). No significant influence of surface or rein was identified for any of the pelvic movement symmetry measures in either group.

Conclusions

While more symmetrical horses showed a consistent amount of movement symmetry across surfaces/reins, horses objectively quantified as lame on the straight showed decreased movement symmetry during lungeing, in particular with the lame limb on the inside of a hard circle. The variation within group questions straight‐line movement symmetry as a sole measure of lameness without quantification of movement symmetry on the lunge, ideally on hard and soft surfaces to evaluate differences between reins and surfaces. In future, thresholds for lungeing need to be determined using simultaneous visual and objective assessment.
Incidence of palmar process fractures of the distal phalanx and association with front hoof conformation in foals
Authors: Faramarzi B. , McMicking H. , Halland S. , Kaneps A. , Dobson H.
Published: October 2014

Reasons for performing study

Recent studies indicate a high prevalence of fractures of the palmar processes (PP) of the distal phalanx in foals. However, information on the prevalence of such fractures in different breeds and the effect of predisposing factors, such as hoof conformation, is limited.

Objectives

To examine the prevalence of distal phalanxPPfractures in foals and report the relationship of distal limb and hoof conformation with the prevalence of fracture.

Study design

Longitudinal study.

Methods

Front hooves of 19 Thoroughbred, Quarter Horse and Arabian foals were examined. Digital radiographic and photographic images of the distal aspect of the forelimbs were taken at ∼2.5 month intervals. Five radiographic projections of each limb were as follows: lateromedial; horizontal beam dorsopalmar; dorso60°proximal‐palmarodistal oblique; dorso60°proximo45°lateral‐palmarodistomedial oblique; and dorso60°proximo45°medial‐palmarodistolateral oblique. The relationship between measurements and the prevalence of fractures was assessed by 3‐wayANOVA.

Results

Fractures were found in 74% (n = 14) of the foals during the study period. The prevalences of lateralPPand medialPPfractures were not significantly different. Several hoof measurements were associated withPPfractures. Longer dorsal length of the distal phalanx was associated with medialPPfractures, while smaller lateral angle and shorter lateral palmar length were associated with a higher prevalence of lateralPPfractures.

Conclusions

This study revealed a high prevalence ofPPfractures in young foals, particularly in Thoroughbred foals. The hoof conformation may be one of the contributory factors toPPfractures in foals.
Binding to Cep164, but not EB1, is essential for centriolar localization of TTBK2 and its function in ciliogenesis
Authors: Oda Toshiaki , Chiba Shuhei , Nagai Tomoaki , Mizuno Kensaku
Published: October 2014

Primary cilia are formed by extending the microtubule‐based axoneme from the mother centriole‐derived basal body. Recruitment of Tau tubulin kinase‐2 (TTBK2) to the mother centriole and subsequent removal of CP110 and its interactor Cep97 are crucial for the initiation of ciliogenesis. We analyzed the roles of two TTBK2‐binding proteins, EB1 and Cep164, in centriolar localization of TTBK2. TTBK2 bound EB1 and Cep164 through its SxIP motifs and a proline‐rich motif, respectively. Using TTBK2 variants that contained mutations in the SxIP or proline‐rich motifs, we obtained evidence that Cep164, but not EB1, is essential for centriolar localization of TTBK2. Depletion of TTBK2 inhibited CP110 removal and ciliogenesis, whereas expression of wild‐type TTBK2, but not non‐Cep164‐binding mutants, rescued CP110 removal and ciliogenesis in TTBK2‐depleted cells. Therefore, Cep164 binding is essential for the function of TTBK2 in promoting CP110 removal and ciliogenesis. We also provide evidence that TTBK2 has the potential to effectively phosphorylate Cep164 and Cep97 and inhibits the interaction between Cep164 and its binding partner Dishevelled‐3 (an important regulator of ciliogenesis) in a kinase activity‐dependent manner.
Treatment decision‐making among Canadian youth with severe haemophilia: a qualitative approach
Authors: Lane S. J. , Walker I. , Chan A. K. , Heddle N. M. , Poon M.‐C. , Minuk L. , Jardine L. , Arnold E. , Sholapur N. , Webert K. E.
Published: October 2014

The first generation of young men using primary prophylaxis is coming of age. Important questions regarding the management of severe haemophilia with prophylaxis persist: Can prophylaxis be stopped? At what age? To what effect? Can the regimen be individualized? The reasons why some individuals discontinue or poorly comply with prophylaxis are not well understood. These issues have been explored using predominantly quantitative rese‐arch approaches, yielding little insight into treatment decision‐making from the perspectives of persons with haemophilia (PWH). Positioning the PWH as a source of expertise about their condition and its management, we undertook a qualitative study: (i) to explore and understand the lived experience of young men with severe haemophilia A or B and (ii) to identify the factors and inter‐relationships between factors that affect young men's treatment decision‐making. This manuscript reports primarily on the second objective. A modified Straussian, grounded theory methodology was used for data collection (interviews) and preliminary analysis. The study sample, youth aged 15–29, with severe haemophilia A or B, was chosen selectively and recruited through three Canadian Haemophilia Treatment Centres. We found treatment decision‐making to be multi‐factorial and used the Framework method to analyze the inter‐relationships between factors. A typology of four distinct approaches to treatment was identified: lifestyle routine prophylaxis, situational prophylaxis, strict routine prophylaxis and no prophylaxis. Standardized treatment definitions (i.e.: ‘primary’ and ‘secondary’, ‘prophylaxis’) do not adequately describe the ways participants treat. Naming the variation of approaches documented in this study can improve PWH/provider communication, treatment planning and education.
Clues in the Differential Diagnosis of Primary vs Secondary Cough, Exercise, and Sexual Headaches
Authors: Alvarez Rocío , Ramón César , Pascual Julio
Published: October 2014

Activity‐related headaches can be provoked by Valsalva maneuvers (“cough headache”), prolonged exercise (“exertional headache”) and sexual excitation (“sexual headache”). These entities are a challenging diagnostic problem as can be primary or secondary and the etiologies for secondary cases differ depending on the headache type. In this paper we review the clinical clues which help us in the differential diagnosis of patients consulting due to activity‐related headaches. Cough headache is the most common in terms of consultation. Primary cough headache should be suspected in patients older than 50 years, if pain does not predominate in the occipital area, if pain lasts seconds, when there are no other symptoms/signs and if indomethacin relieves the headache attacks. Almost half of cough headaches are secondary, usually to a Chiari type I malformation. Secondary cough headache should be suspected in young people, when pain is occipital and lasts longer than one minute, and especially if there are other symptoms/signs and if there is no response to indomethacin. Every patient with cough headache needs cranio‐cervical MRI. Primary exercise/sexual headaches are more common than secondary, which should be suspected in women especially with one episode, when there are other symptoms/signs, in people older than 40 and if the headache lasts longer than 24 hours. These patients must have quickly a CT and then brain MRI with MRA or an angioCT to exclude space‐occupying lesions or subarachnoid hemorrhage.
A comparison of the quality of care in accident and emergency departments in England and the Netherlands as experienced by patients
Authors: Bos Nanne , Seccombe Ian J. , Sturms Leontien M. , Stellato Rebecca , Schrijvers Augustinus J.P. , van Stel Henk F.
Published: October 2014

Background

Measuring patients’ experiences to determine health‐care performance and quality of care from their perspective can provide valuable evidence for international improvements in the quality of care. We compare patients’ experiences in Accident & Emergency departments (A&E) in England and the Netherlands and discuss the usefulness of this comparison.

Methods

A cross‐sectional survey was conducted among patients attending A&Es aged 18 years and older. In England, 134 A&Es were surveyed. In the Netherlands, nine hospitals participated in the study. Main outcome measures were patients’ experiences represented by six domain scores aggregated on the country level or on the A&E level.

Results

In England, 43 892 completed questionnaires were received (40%). In the Netherlands, 1865 completed questionnaires were received (42%). Three of six domain scores were significantly higher for patients in the Netherlands: ‘waiting time’ [mean scores of 73.8 (NL) versus 67.2 (ENG)], ‘doctors and nurses’ [mean scores of 85.7 (NL) versus 80.6 (ENG)] and ‘your care and treatment’ [mean scores of 82.6 (NL) and 80.2 (ENG)]. The variance among the English A&Es was large. The best and worst practices on five domains were English.

Conclusions

The mean quality of care in the A&E appeared to be better in the Netherlands on three domains, but the best practices were English A&Es. The within‐country differences between A&Es were much larger than differences between countries. Healthcare performance in the A&E can be compared between countries by surveying patients’ experiences, and there seems much to learn across A&Es both within and among countries.
‘I Blame the Parents’: Analysing Popular Support for the Deficient Household Social Capital Transmission Thesis
Authors: Collins Alan , Cox Joe , Leonard Alan
Published: October 2014

This article explores belief in parental deficiency as a causal factor of youth anti‐social behaviour and crime. Empirical interrogation of household interview data from a UK city considers whether there is widespread support for blaming parents. Somewhat surprisingly, lower‐income households and those containing young people, are found to be more likely to consider parental responsibility a problem. Most notably, a tendency to blame the parents strongly associates with a perception that people in the area do not treat each other with respect.
Current management of relapsing‐remitting multiple sclerosis
Authors: Sedal L. , Wilson I. B. , McDonald E. A.
Published: October 2014

Multiple sclerosis was without effective disease‐modifying therapy for many years. The introduction of the injectable therapies (interferon and glatiramer acetate) some 20 years ago was considered a major advance. Recent years have heralded a revolution in treatment options with the introduction of intravenous natalizumab and, even more recently, three oral agents. We are currently in a period of determining the best use of these therapies to ensure prevention of disease progression while maintaining patient safety. Despite these new treatments, there are still many patients living with disability as a result of multiple sclerosis and significant attention must be given to symptomatic management.