bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of adiponectin polymorphisms with the risk of diabetic nephropathy in type 2 diabetes: A meta‐analysis 脂联素基因多态性与2型糖尿病肾病的相关性：一项meta分析
Authors: Cai Yuli , Zeng Tianshu , Chen Lulu
Published: May 2014

Objective

Adiponectin gene polymorphisms have been reported to be associated with the risk of diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) patients. However, the results are inconsistent.

Methods

Electronic literature databases and reference lists of relevant articles published until December 2013 were searched as part of a systematic review and meta‐analysis to clarify the association between adiponectin gene polymorphisms and DN susceptibility in T2DM. Fixed‐ or random‐effects models were used to calculate the effect sizes of odds ratio (OR) and 95% confidence intervals (95%CI).

Results

Eleven case control studies were included. Overall, a significant association was observed for rs2241766T/G polymorphisms under the recessive model (GG vs TT+TG: OR 1.75; 95% CI 1.09–2.80; P = 0.02). For rs17300539G/A, a significant association was observed under the GA vs GG model (OR 1.74; 95% CI 1.13–2.68; P = 0.01) and A vs G allele model OR 1.65; 95% CI 1.13–2.41; P = 0.009). After stratification by ethnicity, we found that the rs2241766 T/G dominant model (GG+TG vs TT: OR 1.52; 95% CI 1.12–2.07; P = 0.007), heterozygous model (TG vs TT: OR 1.52; 95% CI 1.01–2.27; P = 0.04) and G vs T allele (OR 1.50; 95% CI 1.07–2.10; P = 0.02) may be associated with DN risk in the Caucasian population. For rs17300593G/A, the dominant model (GA+AA vs GG: OR 1.75; 95% CI 1.15–2.67; P = 0.009) may be associated with DN risk in the Caucasian population.

Conclusion

Adiponectin rs2241766T/G and rs17300593G/A rather than rs1501299G/T and rs266729C/G polymorphisms were associated with the risk of DN in T2DM, especially in the Caucasian population.
Postoperative radiation boost does not improve local recurrence rates in extremity soft tissue sarcomas
Authors: Alamanda Vignesh K , Song Yanna , Shinohara Eric , Schwartz Herbert S , Holt Ginger E
Published: May 2014

Introduction

The standard of care for extremity soft tissue sarcomas continues to be negative‐margin limb salvage surgery. Radiotherapy is frequently used as an adjunct to decrease local recurrence. No differences in survival have been found between preoperative and postoperative radiotherapy regimens. However, it is uncertain if the use of a postoperative boost in addition to preoperative radiotherapy reduces local recurrence rates.

Methods

This retrospective review evaluated patients who received preoperative radiotherapy (n = 49) and patients who received preoperative radiotherapy with a postoperative boost (n = 45). The primary endpoint analysed was local recurrence, with distant metastasis and death due to sarcoma analysed as secondary endpoints. Wilcoxon rank‐sum test and either χ2 or Fisher's exact test were used to compare variables. Multivariable regression analyses were used to take into account potential confounders and identify variables that affected outcomes.

Results

No differences in the proportion or rate of local recurrence, distant metastasis or death due to sarcoma were observed between the two groups (P > 0.05). The two groups were similarly matched with respect to demographics such as age, race and sex and tumour characteristics including excision status, tumour site, size, depth, grade, American Joint Committee on Cancer stage, chemotherapy receipt and histological subtype (P > 0.05). The postoperative boost group had a larger proportion of patients with positive microscopic margins (62% vs 10%; P < 0.001).

Conclusion

No differences in rates of local recurrence, distant metastasis or death due to sarcoma were found in patients who received both pre‐ and postoperative radiotherapy when compared with those who received only preoperative radiotherapy.
Reference absolute and indexed values for left and right ventricular volume, function and mass from cardiac computed tomography
Authors: Stojanovska Jadranka , Prasitdumrong Hutsaya , Patel Smita , Sundaram Baskaran , Gross Barry H , Yilmaz Zeynep N , Kazerooni Ella A
Published: May 2014

Introduction

Left ventricular (LV) and right ventricular (RV) volumetric and functional parameters are important biomarkers for morbidity and mortality in patients with heart failure.

Purpose

To retrospectively determine reference mean values of LV and RV volume, function and mass normalised by age, gender and body surface area (BSA) from retrospectively electrocardiographically gated 64‐slice cardiac computed tomography (CCT) by using automated analysis software in healthy adults.

Materials and Methods

The study was approved by the institutional review board with a waiver of informed consent. Seventy‐four healthy subjects (49% female, mean age 49.6 ± 11) free of hypertension and hypercholesterolaemia with a normal CCT formed the study population. Analyses of LV and RV volume (end‐diastolic, end‐systolic and stroke volumes), function (ejection fraction), LV mass and inter‐rater reproducibility were performed with commercially available analysis software capable of automated contour detection. General linear model analysis was performed to assess statistical significance by age group after adjustment for gender and BSA. Bland–Altman analysis assessed the inter‐rater agreement.

Results

The reference range for LV and RV volume, function, and LV mass was normalised to age, gender and BSA. Statistically significant differences were noted between genders in both LV mass and RV volume (P‐value < 0.0001). Age, in concert with gender, was associated with significant differences in RV end‐diastolic volume and LV ejection fraction (P‐values 0.027 and 0.03). Bland–Altman analysis showed acceptable limits of agreement (±1.5% for ejection fraction) without systematic error.

Conclusion

LV and RV volume, function and mass normalised to age, gender and BSA can be reported from CCT datasets, providing additional information important for patient management.
Distribution of the verrucomicrobial clade Spartobacteria along a salinity gradient in the Baltic Sea
Authors: Bergen Benjamin , Herlemann Daniel P. R. , Labrenz Matthias , Jürgens Klaus
Published: May 2014

A recent pyrosequencing study along the whole Baltic Sea salinity transect identified members of the Verrucomicrobia class Spartobacteria as an important component of Baltic Sea bacterioplankton. In this study, catalysed reporter deposition‐fluorescence in situ hybridization was used for cellular quantification. The published probes VER47 and SPA714 were optimized for samples from the Baltic Sea and a new, specific probe (SPA476) was used to quantify the dominant spartobacterial lineage ‘LD29’. The results confirmed that in the brackish surface waters of the Baltic Sea Spartobacteria comprise an important component, constituting up to 12% of all bacteria. The positive correlation and physical association of Spartobacteria with phytoplankton suggest their involvement in the utilization of phytoplankton‐derived organic matter in the Baltic Sea.
A calibration study of SAPS II with Norwegian intensive care registry data
Authors: HAALAND Ø. A. , LINDEMARK F. , FLAATTEN H. , KVÅLE R. , JOHANSSON K. A.
Published: May 2014

Background

Mortality prediction is important in intensive care. The Simplified Acute Physiology Score (SAPS) II is a tool for predicting such mortality. However, the original SAPS II is poorly calibrated to current intensive care unit (ICU) populations because it draws on data, which is more than 20 years old. We aimed to improve the calibration of SAPS II using data from the Norwegian Intensive Care Registry (NIR). This is the first recalibration of SAPS II for Nordic data.

Methods

A first‐level customization was applied to improve calibration of the original SAPS II model (Model A). NIR data used covered more than 90% of adult patients admitted to ICUs in Norway from 2008 to 2010 (n = 30712).

Results

The modified SAPS II, Model B, outperformed the original Model A with respect to calibration. Model B gave more accurate predictions of mortality than Model A (Hosmer–Lemeshow's C: 22.01 vs. 689.07; Brier score: 0.120 vs. 0.131; Cox's calibration regression: α = −0.093 vs. −0.747, β = 0.921 vs. 0.735, (α|β = 1) = −0.009 vs. −0.630). The standardized mortality ratio was 0.73 [95% confidence interval (CI) of 0.70–0.76] for Model A and 0.99 (95% CI of 0.95–1.04) for Model B. Discrimination was good for both models (area under receiver operating characteristic curve = 0.83 for both models).

Conclusions

As expected, Model B is better calibrated than Model A, and both models have similar uniformity of fit and equal discrimination. Introducing Model B into Norwegian ICUs may improve precision in decision‐making. Units will have a more realistic benchmark for the assessment of ICU performance. Mortality risk estimates from Model B are better than previous SAPS II estimates have been.
Pentax Airway Scope® vs Macintosh laryngoscope for tracheal intubation in adult patients: a systematic review and meta‐analysis
Authors: Hoshijima H. , Kuratani N. , Hirabayashi Y. , Takeuchi R. , Shiga T. , Masaki E.
Published: May 2014

The Pentax Airway Scope® is a single‐use optical videolaryngoscope designed to assist with difficult tracheal intubation. We systematically reviewed the efficacy of the Pentax Airway Scope with that of a conventional laryngoscope for tracheal intubation in adults with ‘normal’ and ‘difficult’ airways. We included 17 randomised controlled trials with a total of 1801 participants. We used the DerSimonian and Laird random‐effects model to calculate pooled relative risk or weighted mean differences. The relative risk (95% CI) of a Cormack–Lehane grade‐1 laryngeal view was 2.40 (1.76–2.49) with the Pentax Airway Scope compared with the Macintosh laryngoscope, p < 0.00001. We found no other differences between the two laryngoscopes. Despite a superior laryngeal view, the Pentax Airway Scope provides little clinical benefit over the conventional laryngoscope.
L‐type calcium channels in sympathetic α3β2‐nAChR‐mediated cerebral nitrergic neurogenic vasodilation
Authors: Wu C. Y.‐C. , Lee R. H.‐C. , Chen P.‐Y. , Tsai A. P.‐Y. , Chen M.‐F. , Kuo J.‐S. , Lee T. J.‐F.
Published: May 2014

Aim

Nicotine stimulation of α3β2‐nicotinic acetylcholine receptors (α3β2‐nAChRs) located on sympathetic nerves innervating basilar arteries causes calcium‐dependent noradrenaline release, leading to activation of parasympathetic nitrergic nerves and dilation of basilar arteries. This study aimed to investigate the major subtype of calcium channels located on cerebral peri‐vascular sympathetic nerves, which is involved in nicotine‐induced α3β2‐nAChR‐mediated nitrergic vasodilation in basilar arteries.

Methods

Nicotine‐ and transmural nerve stimulation (TNS)‐induced dilation of isolated porcine basilar arteries was examined using in vitro tissue bath. Nicotine‐induced calcium influx, nicotine‐induced noradrenaline release and nicotine‐induced inward currents were evaluated in rat superior cervical ganglion (SCG) neurones, peri‐vascular sympathetic nerves of porcine basilar arteries and α3β2‐nAChRs‐expressing oocytes respectively. mRNA and protein expression of Cav1.2 and Cav1.3 channels were detected by RT‐PCR, Western blotting and immunohistochemistry.

Results

Nicotine‐induced vasodilation was not affected by ω‐agatoxin TK (selective P/Q‐type calcium channel blocker) or ω‐conotoxin GVIA (N‐type calcium channel blocker). The vasodilation, however, was inhibited by nicardipine (L‐type calcium channel blocker) in concentrations which did not affect TNS‐induced vasodilation, suggesting the specific blockade. Nicardipine concentration‐dependently inhibited nicotine‐induced calcium influx in rat SCG neurones and reduced nicotine‐induced noradrenaline release from peri‐vascular sympathetic nerves of porcine basilar arteries. Nicardipine (10 μm), which significantly blocked nicotine‐induced vasorelaxation by 70%, did not appreciably affect nicotine‐induced inward currents in α3β2‐nAChRs‐expressing oocytes. Furthermore, the mRNAs and proteins of Cav1.2 and Cav1.3 channels were expressed in porcine SCG and peri‐vascular nerve terminals.

Conclusion

The sympathetic neuronal calcium influx through L‐type calcium channels is modulated by α3β2‐nAChRs. This calcium influx causes noradrenaline release, initiating sympathetic–parasympathetic (axo‐axonal) interaction‐induced nitrergic dilation of porcine basilar arteries.
Single housing during early adolescence causes time‐, area‐ and peptide‐specific alterations in endogenous opioids of rat brain
Authors: Granholm L , Roman E , Nylander I
Published: May 2014

Background and Purpose

A number of experimental procedures require single housing to assess individual behaviour and physiological responses to pharmacological treatments. The endogenous opioids are closely linked to social interaction, especially early in life, and disturbance in the social environment may affect opioid peptides and thereby confound experimental outcome. The aim of the present study was to examine time‐dependent effects of single housing on opioid peptides in rats.

Experimental Approach

Early adolescent Sprague Dawley rats (post‐natal day 22) were subjected to either prolonged (7 days) or short (30 min) single housing. Several brain regions were dissected and immunoreactive levels of Met‐enkephalin‐Arg6Phe7 (MEAP), dynorphin B and nociception/orphanin FQ, as well as serum corticosterone were measured using RIA.

Key Results

Prolonged single housing reduced immunoreactive MEAP in hypothalamus, cortical regions, amygdala, substantia nigra and periaqueductal grey. Short single housing resulted in an acute stress response as indicated by high levels of corticosterone, accompanied by elevated immunoreactive nociceptin/orphanin FQ in medial prefrontal cortex, nucleus accumbens and amygdala. Neither short nor prolonged single housing affected dynorphin B.

Conclusions and Implications

Disruption in social environmental conditions of rats, through single housing during early adolescence, resulted in time‐, area‐ and peptide‐specific alterations in endogenous opioids in the brain. These results provide further evidence for an association between early life social environment and opioids. Furthermore, the results have implications for experimental design; in any pharmacological study involving opioid peptides, it is important to distinguish between effects induced by housing and treatment.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Novel TAZ modulators enhance myogenic differentiation and muscle regeneration
Authors: Park Gun Hwa , Jeong Hana , Jeong Mi‐Gyeong , Jang Eun Jung , Bae Myung Ae , Lee Ye‐Lim , Kim Nak Jung , Hong Jeong‐Ho , Hwang Eun Sook
Published: May 2014

Background and Purpose

The transcriptional co‐activator with PDZ‐binding motif (TAZ) is a key controller of mesenchymal stem cell differentiation through its nuclear localization and subsequent interaction with master transcription factors. In particular, TAZ directly associates with myoblast determining protein D (MyoD) and activates MyoD‐induced myogenic gene expression, thereby enhancing myogenic differentiation. Here, we have synthesized and characterized low MW compounds modulating myogenic differentiation via induction of TAZ nuclear localization.

Experimental Approach

COS7 cells stably transfected with GFP‐TAZ were used in a high content imaging screen for compounds specifically enhancing nuclear localization of TAZ. We then studied the effects of such TAZ modulators on myocyte differentiation of C2C12 cells and myogenic transdifferentiation of mouse embryonic fibroblast cells in vitro and muscle regeneration in vivo.

Key Results

We identified two TAZ modulators, TM‐53, and its structural isomer, TM‐54. Each compound strongly enhanced nuclear localization of TAZ by reducing S89‐phosphorylation and dose‐dependently augmented myogenic differentiation and MyoD‐mediated myogenic transdifferentiation through an activation of MyoD–TAZ interaction. The myogenic stimulatory effects of TM‐53 and TM‐54 were impaired in the absence of TAZ, but retrieved by the restoration of TAZ. In addition, administration of TM‐53 and TM‐54 enhanced injury‐induced muscle regeneration in vivo and attenuated myofiber injury in vitro.

Conclusions and Implications

The novel TAZ modulators TM‐53 and TM‐54 accelerated myogenic differentiation and improved muscle regeneration and function after injury, demonstrating that low MW compounds targeting the nuclear localization of TAZ have beneficial effects in skeletal muscle regeneration and in recovery from muscle degenerative diseases.
Modulation of transglutaminase 2 activity in H9c2 cells by PKC and PKA signalling: a role for transglutaminase 2 in cytoprotection
Authors: Almami Ibtesam , Dickenson John M , Hargreaves Alan J , Bonner Philip L R
Published: May 2014

Background and Purpose

Tissue transglutaminase (TG2) has been shown to mediate cell survival in many cell types. In this study, we investigated whether the role of TG2 in cytoprotection was mediated by the activation of PKA and PKC in cardiomyocyte‐like H9c2 cells.

Experimental Approach

H9c2 cells were extracted following stimulation with phorbol‐12‐myristate‐13‐acetate (PMA) and forskolin. Transglutaminase activity was determined using an amine incorporating and a protein crosslinking assay. The presence of TG isoforms (TG1, 2, 3) was determined using Western blot analysis. The role of TG2 in PMA‐ and forskolin‐induced cytoprotection was investigated by monitoring H2O2‐induced oxidative stress in H9c2 cells.

Key Results

Western blotting showed TG2 >> TG1 protein expression but no detectable TG3. The amine incorporating activity of TG2 in H9c2 cells increased in a time and concentration‐dependent manner following stimulation with PMA and forskolin. PMA and forskolin‐induced TG2 activity was blocked by PKC (Ro 31‐8220) and PKA (KT 5720 and Rp‐8‐Cl‐cAMPS) inhibitors respectively. The PMA‐ and forskolin‐induced increases in TG2 activity were attenuated by the TG2 inhibitors Z‐DON and R283. Immunocytochemistry revealed TG2‐mediated biotin‐X‐cadaverine incorporation into proteins and proteomic analysis identified known (β‐tubulin) and novel (α‐actinin) protein substrates for TG2. Pretreatment with PMA and forskolin reversed H2O2‐induced decrease in MTT reduction and release of LDH. TG2 inhibitors R283 and Z‐DON blocked PMA‐ and forskolin‐induced cytoprotection.

Conclusions and Implications

TG2 activity was stimulated via PKA‐ and PKC‐dependent signalling pathways in H9c2 cells These results suggest a role for TG2 in cytoprotection induced by these kinases.
Pathway‐selective antagonism of proteinase activated receptor 2
Authors: Suen J Y , Cotterell A , Lohman R J , Lim J , Han A , Yau M K , Liu L , Cooper M A , Vesey D A , Fairlie D P
Published: May 2014

Background and Purpose

Proteinase activated receptor 2 (PAR2) is a GPCR associated with inflammation, metabolism and disease. Clues to understanding how to block PAR2 signalling associated with disease without inhibiting PAR2 activation in normal physiology could be provided by studies of biased signalling.

Experimental Approach

PAR2 ligand GB88 was profiled for PAR2 agonist and antagonist properties by several functional assays associated with intracellular G‐protein‐coupled signalling in vitro in three cell types and with PAR2‐induced rat paw oedema in vivo.

Key Results

In HT29 cells, GB88 was a PAR2 antagonist in terms of Ca2+ mobilization and PKC phosphorylation, but a PAR2 agonist in attenuating forskolin‐induced cAMP accumulation, increasing ERK1/2 phosphorylation, RhoA activation, myosin phosphatase phosphorylation and actin filament rearrangement. In CHO‐hPAR2 cells, GB88 inhibited Ca2+ release, but activated Gi/o and increased ERK1/2 phosphorylation. In human kidney tubule cells, GB88 inhibited cytokine secretion (IL6, IL8, GM‐CSF, TNF‐α) mediated by PAR2. A rat paw oedema induced by PAR2 agonists was also inhibited by orally administered GB88 and compared with effects of locally administered inhibitors of G‐protein coupled pathways.

Conclusions and Implications

GB88 is a biased antagonist of PAR2 that selectively inhibits PAR2/Gq/11/Ca2+/PKC signalling, leading to anti‐inflammatory activity in vivo, while being an agonist in activating three other PAR2‐activated pathways (cAMP, ERK, Rho) in human cells. These findings highlight opportunities to design drugs to block specific PAR2‐linked signalling pathways in disease, without blocking beneficial PAR2 signalling in normal physiology, and to dissect PAR2‐associated mechanisms of disease in vivo.
Palmitoylethanolamide normalizes intestinal motility in a model of post‐inflammatory accelerated transit: involvement of CB1 receptors and TRPV1 channels
Authors: Capasso Raffaele , Orlando Pierangelo , Pagano Ester , Aveta Teresa , Buono Lorena , Borrelli Francesca , Di Marzo Vincenzo , Izzo Angelo A
Published: May 2014

Background and Purpose

Palmitoylethanolamide (PEA), a naturally occurring acylethanolamide chemically related to the endocannabinoid anandamide, interacts with targets that have been identified in peripheral nerves controlling gastrointestinal motility, such as cannabinoid CB1 and CB2 receptors, TRPV1 channels and PPARα. Here, we investigated the effect of PEA in a mouse model of functional accelerated transit which persists after the resolution of colonic inflammation (post‐inflammatory irritable bowel syndrome).

Experimental Approach

Intestinal inflammation was induced by intracolonic administration of oil of mustard (OM). Mice were tested for motility and biochemical and molecular biology changes 4 weeks later. PEA, oleoylethanolamide and endocannabinoid levels were measured by liquid chromatography‐mass spectrometry and receptor and enzyme mRNA expression by qRT‐PCR.

Key Results

OM induced transient colitis and a functional post‐inflammatory increase in upper gastrointestinal transit, associated with increased intestinal anandamide (but not 2‐arachidonoylglycerol, PEA or oleoylethanolamide) levels and down‐regulation of mRNA for TRPV1 channels. Exogenous PEA inhibited the OM‐induced increase in transit and tended to increase anandamide levels. Palmitic acid had a weaker effect on transit. Inhibition of transit by PEA was blocked by rimonabant (CB1 receptor antagonist), further increased by 5′‐iodoresiniferatoxin (TRPV1 antagonist) and not significantly modified by the PPARα antagonist GW6471.

Conclusions and Implications

Intestinal endocannabinoids and TRPV1 channel were dysregulated in a functional model of accelerated transit exhibiting aspects of post‐inflammatory irritable bowel syndrome. PEA counteracted the accelerated transit, the effect being mediated by CB1 receptors (possibly via increased anandamide levels) and modulated by TRPV1 channels.
Prolonged morphine treatment alters δ opioid receptor post‐internalization trafficking
Authors: Ong E W , Xue L , Olmstead M C , Cahill C M
Published: May 2014

Background and Purpose

The δ opioid receptor (DOP receptor) undergoes internalization both constitutively and in response to agonists. Previous work has shown that DOP receptors traffic from intracellular compartments to neuronal cell membranes following prolonged morphine treatment. Here, we examined the effects of prolonged morphine treatment on the post‐internalization trafficking of DOP receptors.

Experimental Approach

Using primary cultures of dorsal root ganglia neurons, we measured the co‐localization of endogenous DOP receptors with post‐endocytic compartments following both prolonged and acute agonist treatments.

Key Results

A departure from the constitutive trafficking pathway was observed following acute DOP receptor agonist‐induced internalization by deltorphin II. That is, the DOP receptor underwent distinct agonist‐induced post‐endocytic sorting. Following prolonged morphine treatment, constitutive DOP receptor trafficking was augmented. SNC80 following prolonged morphine treatment also caused non‐constitutive DOP receptor agonist‐induced post‐endocytic sorting. The μ opioid receptor (MOP receptor) agonist DAMGO induced DOP receptor internalization and trafficking following prolonged morphine treatment. Finally, all of the alterations to DOP receptor trafficking induced by both DOP and MOP receptor agonists were inhibited or absent when those agonists were co‐administered with a DOP receptor antagonist, SDM‐25N.

Conclusions and Implications

The results support the hypothesis that prolonged morphine treatment induces the formation of MOP–DOP receptor interactions and subsequent augmentation of the available cell surface DOP receptors, at least some of which are in the form of a MOP/DOP receptor species. The pharmacology and trafficking of this species appear to be unique compared to those of its individual constituents.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Therapeutic use of botulinum toxin in migraine: mechanisms of action
Authors: Ramachandran Roshni , Yaksh Tony L
Published: May 2014

Migraine pain represents sensations arising from the activation of trigeminal afferents, which innervate the meningeal vasculature and project to the trigeminal nucleus caudalis (TNC). Pain secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the TNC. Such viscerosomatic convergence accounts for referral of migraine pain arising from meningeal afferents to particular extracranial dermatomes. Botulinum toxins (BoNTs) delivered into extracranial dermatomes are effective in and approved for treating chronic migraine pain. Aside from their well‐described effect upon motor endplates, BoNTs are also taken up in local afferent nerve terminals where they cleave soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) proteins, and prevent local terminal release. However, a local extracranial effect of BoNT cannot account for allthe effects of BoNT upon migraine. We now know that peripherally delivered BoNTs are taken up in sensory afferents and transported to cleave SNARE proteins in the ganglion and TNC, prevent evoked afferent release and downstream activation. Such effects upon somatic input (as from the face) likewise would not alone account for block of input from converging meningeal afferents. This current work suggests that BoNTs may undergo transcytosis to cleave SNAREs in second‐order neurons or in adjacent afferent terminals. Finally, while SNAREs mediate exocytotic release, they are also involved in transport of channels and receptors involved in facilitated pain states. The role of such post‐synaptic effects of BoNT action in migraine remains to be determined.
Comments on ‘A quantitative model of amphetamine action on the serotonin transporter’, by Sandtner et al., Br J Pharmacol 171: 1007–1018
Authors: De Felice Louis J , Cameron Krasnodara N
Published: May 2014

Linked Articles

This article is a Commentary on Sandtner W, Schmid D, Schicker K, Gerstbrein K, Koenig X, Mayer FP, Boehm S, Freissmuth M and Sitte HH (2014). A quantitative model of amphetamine action on the 5‐HT transporter. Br J Pharmacol 171: 1007–1018. doi: 10.1111/bph.12520. The authors reply in Schmid et al., (2015). Br J Pharmacol 172: this issue. doi: 10.1111/bph.12766
A formyl peptide receptor agonist suppresses inflammation and bone damage in arthritis
Authors: Kao W , Gu R , Jia Y , Wei Xuemin , Fan H , Harris J , Zhang Zhiyi , Quinn J , Morand E F , Yang Y H
Published: May 2014

Background and Purpose

Annexin A1 (AnxA1) is an endogenous anti‐inflammatory protein and agonist of the formyl peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune‐mediated disease has been little explored. We investigated the effects of a synthetic FPR agonist on joint disease in the K/BxN model of rheumatoid arthritis (RA) and RA fibroblast‐like synoviocytes (FLS).

Experimental Approach

Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild‐type (WT) or AnxA1−/− mice and clinical and histopathological manifestations measured 8–11 days later. WT mice were given the FPR agonist compound 43 (Cpd43) (6 or 30 mg·kg−1 i.p.) for 4 days. Effects of AnxA1 and Cpd43 on RANKL‐induced osteoclastogenesis were assessed in RAW 264.7 cells and human RA FLS and macrophages.

Key Results

Treatment with Cpd43 before or after the onset of arthritis reduced clinical disease severity and attenuated synovial TNF‐α and osteoclast‐associated gene expression. Deletion of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL‐6 secretion by mouse macrophages. In human RA joint‐derived FLS and monocyte‐derived macrophages, Cpd43 treatment inhibited IL‐6 release, while blocking FPR2 or silencing AnxA1 increased this release.

Conclusions and Implications

The FPR agonist Cpd43 reduced osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti‐inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents capable of ameliorating inflammation and bone damage in RA.
Late, never or non‐existent: the inaccessibility of preclinical evidence for new drugs
Authors: Federico C A , Carlisle B , Kimmelman J , Fergusson D A
Published: May 2014

Background and Purpose

Animal studies establish much of the evidence used to support clinical development of new drugs. Recent studies suggest that many preclinical investigations are withheld from publication, leading to exaggerated estimates of clinical utility. We sought to estimate the volume and properties of all published animal efficacy studies for a cohort of novel drugs.

Experimental Approach

We searched biomedical databases to identify 47 novel drugs whose first trials were reported between 2000 and 2003, inclusive. Next, we searched for all published animal studies testing the same drug, regardless of publication date. We then extracted items from titles and abstracts of eligible studies.

Key Results

We identified 2462 efficacy studies, representing an average of 52 studies per drug. No published efficacy studies were available for three drugs in our sample. The volume of efficacy studies was related to how far the drug had progressed in clinical development (Spearman's correlation coefficient = 0.66, P < 0.0001). Most (87%) accessible animal efficacy studies were reported after publication of the first trial, and for 17% of the drugs in our sample, no efficacy studies were published before the first trial report. Disease indications used in trials often did not match those modelled in efficacy studies; for 35% of indications tested in trials, we were unable to identify any published efficacy studies in models of the same indication.

Conclusions and Implications

The volume of published efficacy studies is large, although numerous gaps reflect non‐publication, publication delay or non‐performance of efficacy studies supporting trials.
The impact of the Hologic vs the ICMR database in diagnosis of osteoporosis among South Indian subjects
Authors: Shetty Sahana , Kapoor Nitin , Naik Dukhabandhu , Asha Hesarghatta S , Thomas Nihal , Paul Thomas V
Published: May 2014

Background and Objectives

Recently, the Indian Council of Medical Research (ICMR) has published normative data for bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry (DXA) scanning. However, the impact this has had on the diagnosis of osteoporosis when compared to currently used Caucasian databases has not been analysed. Hence, this study was undertaken to look at agreement between the Hologic Database (HD) based on BMD normative data in Caucasians and the ICMR database (ICMRD) in defining osteoporosis in subjects with or without hip fracture.

Materials and Methods

It is a cross ‐sectional study of 2976 subjects (men 341, women 2757) (mean age ± SD = 62·2 ± 7·2 years), including 316 subjects with low impact hip fracture: 2199 were from the hospital database, and 461 were healthy postmenopausal women from the community who underwent (DXA) scanning between January 2010 and March 2013. Recalculated T scores from ICMRD were used for the diagnosis of osteoporosis and compared with HD.

Results

An almost perfect agreement existed between the two databases for the diagnosis of osteoporosis at the hip (κ −0·82, P < 0·0001) in all subjects, and a moderate relationship existed in those with hip fracture (κ −0·65, P < 0·0001). Seventy‐three of 316 hip fracture subjects (23·5%) defined as osteoporosis according to HD were classified as osteopenia according to ICMRD.

Conclusion

The threshold of hip BMDT score for treating osteoporosis may have to be redefined if the ICMR reference database is used. Initiation of treatment in these subjects must be based on multiple fracture risk factor assessment in addition to looking at BMD. Further studies with a larger sample size of subjects with fracture are needed to validate our findings.
Chronic kidney disease score for predicting postoperative masked renal insufficiency in patients with primary aldosteronism
Authors: Tanase‐Nakao Kanako , Naruse Mitsuhide , Nanba Kazutaka , Tsuiki Mika , Tagami Tetsuya , Usui Takeshi , Okuno Hiroshi , Shimatsu Akira , Hashimoto Shigeatsu , Katabami Takuyuki , Ogo Atsushi , Okumura Ataru , Umakoshi Hironobu , Suzuki Tomoko
Published: May 2014

Context

Chronic kidney disease (CKD) is sometimes unmasked after unilateral adrenalectomy in patients with primary aldosteronism (PA) without expectation.

Objective

Our study aim was to elucidate factors responsible for developing postoperative CKD and to provide a simple scoring system to predict postoperative CKD in PA.

Design and Patients

Forty‐five patients with PA treated with unilateral adrenalectomy and followed for at least 1 month postsurgery were studied. Thirty‐one patients with non‐PA adrenal disease who underwent unilateral adrenalectomy were also studied as control. Patients with pre‐operative estimated glomerular filtration rate (eGFR) < 60 ml/min/1·73 m2 were excluded from both groups.

Results

A statistically significant (P < 0·001) decrease in eGFR was observed in PA group within 1 month of surgery, then stabilized. Of the 45 patients with PA, 17 (37·8%) developed CKD after surgery. None of the non‐PA group developed CKD after surgery. Of the pre‐operative variables, logistic regression analysis showed that lower eGFR and higher aldosterone‐to‐renin ratios (ARR) were the independent predictors for postoperative CKD in PA. Optimal cut‐off values of the two variables analysed with ROC curves were as follows: eGFR ≤ 76·9 ml/min/1·73 m2 and ARR ≥ 305. Using these data, we created a CKD score as a tool for predicting postoperative CKD, with an AUC for the score of 0·8866.

Conclusion

The pre‐operative eGFR and ARR were the significant contributing factors for postoperative CKD in PA. By combining these independent factors, we created a CKD score which provides useful information before surgery about the risk for development of postoperative CKD.
Interplay of cell proliferation and cell death in Drosophila tissue regeneration
Authors: Kashio Soshiro , Obata Fumiaki , Miura Masayuki
Published: May 2014

Regeneration is a fascinating process that allows some organisms to reconstruct damaged tissues. In addition to the classical regeneration model of the Drosophila larval imaginal discs, the genetically induced tissue ablation model has promoted the understanding of molecular mechanisms underlying cell death, proliferation, and remodeling for tissue regeneration. Recent studies have also revealed that tissue injury responses occur not only locally but also systemically, even in the uninjured region. Genetic studies in Drosophila have demonstrated the dynamic role of the cell death‐induced tissue response in the reconstruction of damaged tissues.
Alcohol health literacy in young adults with Type 1 diabetes and its impact on diabetes management
Authors: Barnard K. D. , Dyson P. , Sinclair J. M. A. , Lawton J. , Anthony D. , Cranston M. , Holt R. I. G.
Published: May 2014

Aims

To investigate the knowledge of alcohol and carbohydrate content of commonly consumed alcoholic drinks among young adults with Type 1 diabetes and to explore alcohol consumption while identifying diabetes self‐management strategies used to minimize alcohol‐associated risk.

Method

We conducted an open‐access, multiple‐choice web survey to investigate knowledge of alcohol and carbohydrate content of typical alcoholic drinks using images. Respondents to the survey also recorded their current alcohol consumption and diabetes self‐management strategies when drinking.

Results

A total of 547 people aged 18–30 years responded to the survey (341 women; 192 men; mean (sd) age 24.5 (3.7) years), of whom 365 (66.7%) drank alcohol. In all, 84 (32.9%) women and 31 (22.6%) men scored higher than the cut‐off score for increased‐risk drinking. Knowledge accuracy of alcohol units was poor: only 7.3% (n = 40) correctly identified the alcohol content of six or more out of 10 drinks. Knowledge of carbohydrate content was also poor: no respondent correctly identified the carbohydrate content of six or more out of 10 drinks. Various and inconsistent strategies to minimize alcohol‐associated risk were reported.

Conclusions

Alcohol consumption was common among the survey respondents, but knowledge of alcohol and carbohydrate content was poor. Greater alcohol‐related health literacy is required to minimize alcohol‐associated risk. Further research should help develop effective strategies to improve health literacy and support safe drinking for young adults with Type 1 diabetes.
Diabetes in people with an intellectual disability: a systematic review of prevalence, incidence and impact
Authors: McVilly K. , McGillivray J. , Curtis A. , Lehmann J. , Morrish L. , Speight J.
Published: May 2014

Aims

To establish the prevalence and incidence of Type 1 and Type 2 diabetes in people with an intellectual and developmental disability and determine their impact on health and well‐being and to appraise the evidence available to inform good practice in diabetes management for people with intellectual and developmental disabilities.

Methods

We conducted separate searches of multiple databases (EMBASE, CINAHL, MEDLINE, PsycINFO, SCOPUS, Web of Science, PUBMED and Cochrane Library) to find relevant articles.

Results

A total of 13 studies were identified: 13 addressed the prevalence of diabetes in people with intellectual and developmental disability, three addressed the impact of diabetes on their health and well‐being and three addressed the management of diabetes. The prevalence of diabetes in people with intellectual and developmental disability remains uncertain, and the incidence of diabetes in this group of people is unknown. There is some evidence to support the assertion that people with intellectual and developmental disability might be at greater risk of diabetes than the general population. Overall, the quality of the evidence on which to base prevention and management strategies is variable.

Conclusions

There is a paucity of research focusing on the prevalence, incidence and impact of diabetes among people with intellectual and developmental disability. Further research is needed to inform policy and practice in this area and, in particular, work is needed to develop methodologies, evaluation tools, educational resources and diabetes care support services appropriate to the needs of people with intellectual and developmental disability.
Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with Type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24‐week randomized, double‐blind study
Authors: Bajaj M. , Gilman R. , Patel S. , Kempthorne‐Rawson J. , Lewis‐D'Agostino D. , Woerle H.‐J.
Published: May 2014

Aims

To investigate the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor linagliptin in patients with Type 2 diabetes mellitus inadequately controlled by a combination of metformin and pioglitazone.

Methods

This was a multi‐centre, phase 3, randomized, double‐blind, placebo‐controlled study comparing linagliptin 5 mg once daily (n = 183) and placebo (n = 89) as add‐on to metformin and pioglitazone. The primary endpoint was the change from baseline in glycated haemoglobin (HbA1c) after 24 weeks.

Results

The placebo‐corrected adjusted mean (se) change in HbA1c from baseline to 24 weeks was –6 (1) mmol/mol [–0.57 (0.13)%] (P < 0.0001). In patients with baseline HbA1c ≥ 53 mmol/mol (7.0%), 32.4% of patients in the linagliptin group and 13.8% in the placebo group achieved HbA1c < 53 mmol/mol (7.0%) (odds ratio 2.94; P = 0.0033). The placebo‐corrected adjusted mean (se) change from baseline in fasting plasma glucose at week 24 was –0.57 (0.26) mmol/l [–10.4 (4.7) mg/dl] (P = 0.0280). The incidence of serious adverse events was 2.2% with linagliptin and 3.4% with placebo. Investigator‐defined hypoglycaemia occurred in 5.5% of the linagliptin group and 5.6% of the placebo group. No meaningful changes in mean body weight were noted for either group.

Conclusions

Linagliptin as add‐on therapy to metformin and pioglitazone produced significant and clinically meaningful improvements in glycaemic control, without an additional risk of hypoglycaemia or weight gain (Clinical Trials Registry No: NCT 00996658).
Cardiovascular risk profiles in relation to newly diagnosed Type 2 diabetes diagnosed by either glucose or HbA1c criteria in Chinese adults in Qingdao, China
Authors: Qie L. Y. , Sun J. P. , Ning F. , Pang Z. C. , Gao W. G. , Ren J. , Nan H. R. , Zhang L. , Qiao Q. ,   the Qingdao Diabetes Survey Group in 2006 and 2009
Published: May 2014

Aims

To study the cardiovascular disease risk profiles in newly diagnosed diabetes diagnosed by either glucose or/and HbA1c criteria in Chinese adults.

Methods

Two population‐based cross‐sectional studies were conducted in 2006 and 2009, respectively. Data from 1987 men and 2815 women aged 35–74 years were analysed. Newly diagnosed diabetes was defined according to either glucose (fasting and/or 2‐h glucose), HbA1c or both criteria.

Results

Ageing, positive family history of diabetes, elevated levels of waist circumference, systolic blood pressure, total cholesterol, triglycerides and γ‐glutamyl transferase were independently associated with newly diagnosed diabetes defined by glucose criterion alone, but not for diabetes defined by HbA1c criterion alone. Only waist circumference, total cholesterol and smoking were significantly associated with the presence of diabetes defined by HbA1c criterion alone.

Conclusions

Cardiovascular disease risk profiles were different in patients with newly diagnosed diabetes defined by the two diagnostic criteria for diabetes. This may have certain clinical implications on diabetes management and research.
Retracted: Comparison of vildagliptin and glimepiride: effects on glycaemic control, fat tolerance and inflammatory markers in people with Type 2 diabetes
Authors: Derosa G. , Bonaventura A. , Bianchi L. , Romano D. , Fogari E. , D'Angelo A. , Maffioli P.
Published: May 2014

Aims

To compare the effects of vildagliptin with those of glimepiride on glycaemic control, fat tolerance and inflammatory markers in people with Type 2 diabetes mellitus receiving metformin treatment.

Methods

A total of 167 participants were randomized to vildagliptin 50 mg twice a day or glimepiride 2 mg three times a day, for 6 months. We evaluated the following variables: BMI; glycaemic control; fasting plasma insulin; homeostatic model assessment of insulin resistance index; fasting plasma proinsulin; glucagon; lipid profile; adiponectin; high‐sensitivity C‐reactive protein; interleukin‐6; and tumour necrosis factor‐α. A euglycaemic‐hyperinsulinaemic clamp procedure and an oral fat load test were also performed.

Results

Despite a similar decrease in HbA1c levels (P = 0.009, and P = 0.008, respectively), body weight increased with glimepiride (P = 0.048 vs baseline) and decreased with vildagliptin (P = 0.041 vs baseline and vs glimepiride). Fasting plasma insulin and homeostatic model assessment of insulin resistance index were significantly lower with vildagliptin compared with glimepiride (P = 0.035 and 0.047). M value, an index of insulin sensitivity, increased with vildagliptin, both compared with baseline and with glimepiride (P = 0.028 and 0.039, respectively). Vildagliptin improved all post‐oral fat load peaks of lipid profile compared with glimepiride. Adiponectin levels were higher (P = 0.035) and high‐sensitivity C‐reactive protein levels were lower (P = 0.038) with vildagliptin vs glimepiride. During the oral fat load test, interleukin‐6, high‐sensitivity C‐reactive protein and tumour necrosis factor‐α peaks were lower and adiponectin peak was higher in the vildagliptin group than in the glimepiride group. There was a higher dropout rate as a result of hypoglycaemia in the glimepiride group than in the vildagliptin group.

Conclusions

Vildagliptin was more effective than glimepiride in reducing post‐oral fat load peaks of lipid‐trafficking adipocytokines and inflammatory markers.
Long‐term changes in dietary and food intake behaviour in the Diabetes Prevention Program Outcomes Study
Authors: Jaacks L. M. , Ma Y. , Davis N. , Delahanty L. M. , Mayer‐Davis E. J. , Franks P. W. , Brown‐Friday J. , Isonaga M. , Kriska A. M. , Venditti E. M. , Wylie‐Rosett J. ,   the Diabetes Prevention Program Research Group
Published: May 2014

Aims

To compare change in dietary intake, with an emphasis on food groups and food intake behaviour, over time across treatment arms in a diabetes prevention trial and to assess the differences in dietary intake among demographic groups within treatment arms.

Methods

Data are from the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Participants were randomized to a lifestyle intervention (n = 1079), metformin (n = 1073) or placebo (n = 1082) for an average of 3 years, after which the initial results regarding the benefits of the lifestyle intervention were released and all participants were offered a modified lifestyle intervention. Dietary intake was assessed using a food frequency questionnaire at baseline and at 1, 5, 6 and 9 years after randomization.

Results

Compared with the metformin and placebo arms, participants in the lifestyle arm maintained a lower total fat and saturated fat and a higher fibre intake up to 9 years after randomization and lower intakes of red meat and sweets were maintained for up to 5 years. Younger participants had higher intakes of poultry and lower intakes of fruits compared with their older counterparts, particularly in the lifestyle arm. Black participants tended to have lower dairy and higher poultry intakes compared with white and Hispanic participants. In the lifestyle arm, men tended to have higher grain, fruit and fish intakes than women.

Conclusions

Changes in nutrient intake among participants in the lifestyle intervention were maintained for up to 9 years. Younger participants reported more unhealthy diets over time and thus may benefit from additional support to achieve and maintain dietary goals.