bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular pharmacogenetics: a promise for genomically‐guided therapy and personalized medicine
Authors: Zaiou M. , El Amri H.
Published: October 2016

Cardiovascular disease (CVD) is the leading cause of death worldwide. The basic causes of CVD are not fully understood yet. Substantial evidence suggests that genetic predisposition plays a vital role in the physiopathology of this complex disease. Hence, identification of genetic contributors to CVD will likely add diagnostic accuracy and better prediction of an individual's risk. With high‐throughput genetics and genomics technology and newer genome‐wide study approaches, a number of genetic variations across the human genome were uncovered. Evidence suggests that genetic defects could influence CVD development and inter‐individual responses to widely used cardiovascular drugs like clopidogrel, aspirin, warfarin, and statins, and therefore, they may be integrated into clinical practice. If clinically validated, better understanding of these genetic variations may provide new opportunities for personalized diagnostic, pharmacogenetic‐based drug selection and best treatment in personalized medicine. However, numerous gaps remain unsolved due to the lack of underlying pathological mechanisms for how genetic predisposition could contribute to CVD. This review provides an overview of the extraordinary scientific progress in our understanding of genetic and genomic basis of CVD as well as the development of relevant genetic biomarkers for this disease. Some of the actual limitations to the promise of these markers and their translation for the benefit of patients will be discussed.
Loss of the arginine methyltranserase PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly
Authors: Kernohan K.D. , McBride A. , Xi Y. , Martin N. , Schwartzentruber J. , Dyment D.A. , Majewski J. , Blaser S. ,   Care4Rare Canada Consortium, Boycott K.M. , Chitayat D.
Published: October 2016

Post‐translational protein modifications exponentially expand the functional complement of proteins encoded by the human genome. One such modification is the covalent addition of a methyl group to arginine or lysine residues, which is used to regulate a substantial proportion of the proteome. Arginine and lysine methylation are catalyzed by protein arginine methyltransferase (PRMTs) and protein lysine methyltransferase proteins (PKMTs), respectively; each methyltransferase has a specific set of target substrates. Here, we report a male with severe intellectual disability, facial dysmorphism, microcephaly, short stature, brachydactyly, cryptorchidism and seizures who was found to have a homozygous 15,309 bp deletion encompassing the transcription start site of PRMT7, which we confirmed is functionally a null allele. We show that the patient's cells have decreased levels of protein arginine methylation, and that affected proteins include the essential histones, H2B and H4. Finally, we demonstrate that patient cells have altered Wnt signaling, which may have contributed to the skeletal abnormalities. Our findings confirm the recent disease association of PRMT7, expand the phenotypic manifestations of this disorder and provide insight into the molecular pathogenesis of this new condition.
Localized bone regeneration around dental implants using recombinant bone morphogenetic protein‐2 and platelet‐derived growth factor‐BB in the canine
Authors: Thoma Daniel S. , Cha Jae‐Kook , Sapata Vitor M. , Jung Ronald E. , Hüsler Juerg , Jung Ui‐Won
Published: October 2016

Objectives

To test whether or not one of two biological mediators (recombinant human bone morphogenetic protein‐2 (rhBMP‐2) and recombinant human platelet‐derived growth factor (rhPDGF‐BB)) is superior to the other and compared with control groups for bone regeneration around implants based on histomorphometrical outcome measures.

Materials and methods

Box‐type defects (10 × 5 × 5 mm) were prepared on the buccal sides of the left and right edentulous ridge in ten mongrel dogs. Implants were placed at each site, the defects either received (i) bovine‐derived particulated bone mineral (DBBM) mixed with rhBMP‐2 and a collagen membrane (CM) (DBBM/BMP‐2), (ii) DBBM mixed with rhPDGF‐BB and CM (DBBM/PDGF), (iii) DBBM and CM (DBBM) and (iv) empty control (control). Animals were euthanized post‐surgery at 8 weeks and 16 weeks. Histomorphometrical analyses were performed.

Results

The mean percentages of regenerated area within total defect area amounted to 56.95% for DBBM/BMP‐2, 48.86% for DBBM/PDFG, 33.44% for DBBM and 1.59% for control at 8 weeks, and 26.79% for DBBM/BMP‐2, 23.78% for DBBM/PDFG, 30.21% for DBBM and 5.07% for control at 16 weeks with no statistically significant differences between the groups (P > 0.05). The mean amount of regenerated bone was 26.97% for DBBM/BMP‐2, 22.02% for DBBM/PDFG, 5.03% for DBBM and 1.25% for control at 8 weeks, and at 16 weeks, these values were lower in the two groups with biological mediators (DBBM/BMP‐2 = 13.35%; DBBM/PDGF = 6.96%) and only slightly increased in group DBBM (10.68%) and the control group (4.95%) compared with 8 weeks. The first bone‐to‐implant contact values on the buccal side were minimal for DBBM/BMP‐2 (0.57 mm) and maximal for control (3.72 mm) at 8 weeks.

Conclusions

The use of biological mediators (rhBMP‐2 and rhPDGF‐BB) can increase the amount of bone regeneration at dehiscence‐type defects compared with controls at 8 weeks, but not at 16 weeks due to enhanced hard tissue remodeling processes.
The importance of combined 24‐hour multichannel intraluminal impedance–pH monitoring in the evaluation of children with suspected laryngopharyngeal reflux
Authors: Pavić I. , Babić I. , Čepin Bogović J. , Hojsak I.
Published: October 2016

Objective

The aim of this study was to investigate the diagnostic usefulness of combined multichannel intraluminal impedance–pH (MII‐pH) monitoring in children with suspected laryngopharyngeal reflux (LPR).

Design, setting and participants

A prospective study including children in whom, due to LPR suggestive symptoms, MII‐pH monitoring was performed at tertiary medical centre from February 2012 to July 2015.

Interventions

All included children underwent same diagnostic protocol which included examination by single pulmonologist and ENT specialist and underwent 24‐hour MII‐pH monitoring.

Main outcomes

Primary outcome was to determine MII‐pH characteristics of the children in whom LPR was suspected based on symptoms and ENT examination.

Results

One hundred and four patients (mean age 8.9 years; range 0.4–17.9 years; male/female 57/47) participated in the study. In children with signs and symptoms suggestive of LPR, MII‐pH monitoring found the median incidence of proximal gastro‐oesophageal reflux (GER) of 15 (range 0–129), proximal acidic GER of 6.5 (range 0–66) and weakly acidic GER of 5 (range 0–102). There were significant positive correlations between the number of GER (proximal total, acidic and weakly acid) with Reflux Finding Score, Reflux Symptom Index and presence of eosinophils in nasal swabs. The only endoscopy ENT finding which significantly correlated with total proximal GER, acid proximal GER and weakly acidic proximal GER was arytenoid hyperaemia.

Conclusion

Both acid and non‐acid reflux seem to have a significant role in the pathogenesis of LPR.
Rank aggregation of local expert knowledge for conservation planning of the critically endangered saola
Authors: Wilkinson Nicholas M. , Van Duc Luong
Published: October 2016

There has been much recent interest in using local knowledge and expert opinion for conservation planning, particularly for hard‐to‐detect species. Although it is possible to ask for direct estimation of quantities such as population size, relative abundance is easier to estimate. However, an expert's knowledge is often geographically restricted relative to the area of interest. Combining (or aggregating) experts’ assessments of relative abundance is difficult when each expert only knows a part of the area of interest. We used Google's PageRank algorithm to aggregate ranked abundance scores elicited from local experts through a rapid rural‐appraisal method. We applied this technique to conservation planning for the saola(Pseudoryx nghetinhensis), a poorly known bovid. Near a priority landscape for the species, composed of 3 contiguous protected areas, we asked groups of local people to indicate relative abundances of saola and other species by placing beans on community maps. For each village, we used this information to rank areas within the knowledge area of that village for saola abundance. We used simulations to compare alternative methods to aggregate the rankings from the different villages. The best‐performing method was then used to produce a single map of relative abundance across the entire landscape, an area larger than that known to any one village. This map has informed prioritization of surveys and conservation action in the continued absence of direct information about the saola.
Fabric defect detection based on golden image subtraction
Authors: Jing Jun‐Feng , Chen Shan , Li Peng‐Fei
Published: October 2016

To realise the universality and practicality of fabric defect detection in the textile industry, this paper proposes two approaches based on the Gabor filter and the golden image subtraction method. A method known as Gabor preprocessed golden image subtraction is first introduced, which filters a test fabric image by the real component of the Gabor filter with a 1 Hz centre frequency and a 90° angle. Golden image subtraction performs subtractions between the golden template and the filtered image to obtain a resultant image, and the segmentation threshold is determined by the direct threshold. The second method is Gabor preprocessed golden image subtraction based on a genetic algorithm, which can automatically select the parameter groups of the Gabor filter via the genetic algorithm. In addition, the paper also presents an extensive comparison between the proposed methods and wavelet preprocessed golden image subtraction. Meanwhile, the performances of the aforementioned three methods are tested in a real machine vision detection system to meet the actual demands of the textile industry. It can be concluded that Gabor preprocessed golden image subtraction provides the best detection results. The overall detection success rate is 95.62%, with 80 defect‐free images and 80 defective images for fabric textures of common types.
Low concentrations of TNF‐α promote osteogenic differentiation via activation of the ephrinB2‐EphB4 signalling pathway
Authors: Wang Limei , Zhang Jin , Wang Cunwei , Qi Yuping , Du Mi , Liu Wenhua , Yang Chengzhe , Yang Pishan
Published: October 2016

Objectives

Low concentrations of tumour necrosis factor‐alpha (TNF‐α) have been reported to promote osteogenic differentiation. In this study, a series of in vitro experiments was performed to investigate underlying molecular mechanisms involved.

Materials and methods

MC3T3‐E1 murine preosteoblasts were treated with TNF‐α at doses of 0, 0.1 or 1 ng/mL. The ephrinB2‐EphB4 signalling pathway was activated using ephrinB2‐fc, or inhibited using lentiviruses encoding siRNAs specifically targeting EphB4. Cell proliferation/survival was evaluated using the Cell Counting Kit‐8 (CCK‐8) assay, and expression levels of Runx2, BSP, ephrinB2 and EphB4 were determined using RT‐PCR and Western blotting. ALP activity in these cells was also determined, and mineral nodule formation was evaluated with alizarin red S staining.

Results

Low concentrations of TNF‐α had no influence on cell proliferation/survival. However, expression levels of Runx2, BSP, ephrinB2 and EphB4, as well as ALP activity and mineral nodule formation, were significantly enhanced in MC3T3‐E1 cells treated with low concentrations of TNF‐α. Moreover, activation of the ephrinB2‐EphB4 signalling pathway by ephrinB2‐fc enhanced TNF‐α‐induced osteogenic differentiation, while down‐regulation of EphB4 level reversed the positive effect of TNF‐α.

Conclusions

Low concentrations of TNF‐α promoted osteogenic differentiation via activation of the ephrinB2‐EphB4 signalling pathway.
Clinical features in patients of cough variant asthma with normal and high level of exhaled fractional nitric oxide
Authors: Tang Wei , Zhou Jun , Miao Lili , Shi GuoCao
Published: October 2016

Objective

Cough variant asthma (CVA) is a subtype of asthma that is characterized by a chronic cough. The clinical characteristics and pulmonary function in patients with CVA who had normal and high exhaled fractional nitric oxide (FeNO) levels were compared.

Methods

The clinical history and pulmonary function data from 99 patients with newly diagnosed CVA were collected.

Result

Newly diagnosed subjects with CVA were divided into a high FeNO group (FeNO value over or equal to 25 ppb, n = 52) and a normal FeNO group (FeNO lower than 25 ppb, n = 47). There were more patients with coexistent allergic rhinitis or with family histories of allergic diseases in the high FeNO group. More patients in the high FeNO group reported that their chronic cough was triggered by allergen exposure. In the high FeNO group, the patients were younger than in the normal FeNO group. It was shown that baseline lung function tests were normal in all subjects, apart from a reduced midexpiratory flow rate (FEF25‐75). There was a significant decrease in FEF25‐75 in the high FeNO group compared with the normal FeNO group. No difference was found in the PD20 or the maximal FEV1 drop between the two groups. The multi‐factor logistic regression analysis showed that concomitant with allergic rhinitis was the high risk factor of a high FeNO in these subjects with CVA (OR = 5.03, 95% CI, 1.88‐13.49).

Conclusion

CVA patients showed heterogeneity according to FeNO level. Patients with high FeNO level are more likely to experience symptoms associated with allergies.
Mutation analysis of the EGFR gene and its downstream signaling pathway in thymic carcinoma patients from a Chinese Han population
Authors: Zhan Ping , Chen Xiao , Wu Xiao‐Yuan , Hou Zhi‐Bo , Qian Qian , Zhang Yu , Zou Jue , Zhang Yuan‐Qing , Wan Ming‐Yue , Wang Jian‐Dong , Yu Li‐Ke , Xie Hai‐yan
Published: October 2016

Introduction

For thymic carcinoma (TC), which is a rare epithelial neoplasm of the thymus gland, median survival with current treatments is only 2 years.

Objectives

Mutations in the epidermal growth factor receptor (EGFR) gene or its downstream effectors may cause constitutive activation that leads to cell proliferation and metastases. Thus, molecular profiling is essential for selecting TC patients who may respond to anti‐EGFR therapies.

Methods

Genomic DNA was extracted from 61 histological samples of TCs. Real‐time polymerase chain reaction (PCR) and direct sequencing were used to assess the mutations in the EGFR downstream pathway.

Results

Gene mutations were identified in seven patients (11.5%). In particular, the identified mutations included four mutations in the KRAS gene, one mutation in the BRAF gene, one mutation in the PIK3CA gene, and only one mutation in the EGFR gene itself. Gene mutations in the EGFR downstream pathway were associated with shorter survival time and were observed to be an independent prognostic factor for TC patients.

Conclusion

Mutations in the EGFR downstream pathway are not rare in TCs. These data offer interesting possibilities for the future management of TCs, particularly in the era of new targeted therapies.
Prevalence of asthma and rhinitis in a Tunisian population
Authors: Sonia Toujani , Meriem Mjid , Yacine Ouahchi , Nozha Ben Salah , Nadia Mhiri , Bechir Louzir , Jalloul Daghfous , Jouda Chérif , Majed Béji
Published: October 2016

Background

Asthma and rhinitis are a major public health problem because of their frequency, their impact on quality of life and economic burden. In Tunisia, epidemiological data are scarce. The aim of the present study was to estimate the prevalence of asthma and rhinitis in a representative Tunisian population and to analyze the association between them.

Methods

It was a cross‐sectional population‐based study, involving individuals aged between 2 and 52 years, living in Tunis. A sample of the general population was generated using a random stratified sampling method. A detailed face‐to‐face questionnaire based on ISAAC and the ECRHS survey was used. Classification of rhinitis was evaluated according to ARIA.

Results

Data were obtained from 4470 responders (40.2% male and 59.8% female). The response rate was 96.5%. The prevalence of current asthma was 6.5% (CI 5.9%‐7.8%). A slight female predominance was observed in children and adolescents but in adulthood gender‐specific prevalence estimates were similar. The prevalence of rhinitis in the general population was 11.7% (CI 10.1%‐13.5%) in children and 13.4% (CI 11.1%‐14.6%) in 15 years and older. No statistically significant differences were found according to gender and age. Almost half of asthmatics’ had current rhinitis or rhinoconjunctivitis versus 13.4% in the population sample (P < 0.001). Current asthma was reported in 22.5% subjects with current rhinitis or with rhinoconjunctivitis.

Conclusions

Asthma and rhinitis represent a considerable public health problem in children and adults up to age 52 in Tunisian population. Our results confirm also the strong association between them. These findings highlight the need for a clinical global assessment of asthma together with rhinitis.
Thyroid hormone use during cardiac transplant organ procurement
Authors: Cooper Lauren B. , Milano Carmelo A. , Williams Melissa , Swafford Wendy , Croezen Donna , Van Bakel Adrian B. , Rogers Joseph G. , Patel Chetan B.
Published: October 2016

Background

Acute hypothyroidism after brain death results in hemodynamic impairments that limit availability of donor hearts. Thyroid hormone infusions can halt that process and lead to increased utilization of donor organs, but prolonged use of thyroid replacement has not been well studied.

Methods

We developed a 15‐question survey regarding policies, procedures, and reporting of thyroid hormone use by organ procurement organizations (OPOs). The survey was posted for 5 weeks on the Association of OPOs Portal.

Results

We received 29 responses, representing 24 OPOs. Seventy‐two percent reported their OPOs use thyroid hormone for all potential donors and 90% have a protocol for thyroid hormone use. There is a large variation in the maximum dose of thyroid hormone used, and many OPOs have no weaning protocol. Most OPOs do not collect data on total thyroid hormone administered during procurement and would favor more detailed report of thyroid hormone use.

Conclusions

Thyroid hormone use can have important implications for organ selection and cardiac function before and after transplantation. Protocols vary widely with respect to why and how to use and wean thyroid hormone. We believe there should be more detailed reporting of thyroid hormone use for future studies to ensure appropriate donor management.
Blepharochalasis: something to cry about
Authors: Browning Richard J. , Sanchez April T. , Mullins Stephen , Sheehan Daniel J. , Davis Loretta S.
Published: October 2016

Blepharochalasis is a rare disorder of unknown etiology defined by loose, atrophic periorbital skin following recurrent episodes of eyelid edema. Characteristic histopathology shows complete absence of elastic fibers. The current case progressed after multiple episodes of crying, which may be related to matrix metalloproteinase dysregulation. This case offers further insights into the possible pathogenesis of blepharochalasis, paving the way for more targeted, disease‐modifying therapies.
Cutaneous carcinosarcoma: a series of six cases and a review of the literature
Authors: Clark Joshua J. , Bowen Anneli R. , Bowen Glen M. , Hyngstrom John R. , Hadley Michael L. , Duffy Keith , Florell Scott R. , Wada David A.
Published: October 2016

Background

Cutaneous carcinosarcoma is a rare tumor with distinct malignant epithelial and mesenchymal cell populations. The histologic subtypes of epithelial and mesenchymal components in cutaneous carcinosarcoma are variable, as an assortment of carcinomatous and sarcomatous patterns have been described in the literature.

Methods

Clinical information was obtained from patient charts and archival slides were retrieved and reviewed.

Results

We present a novel series of six distinct cases of cutaneous carcinosarcoma and review the literature. Our cases consisted of basal cell, pilomatrical, squamous cell, and trichoblastic variants. These cases occurred in elderly men on sun exposed skin with treatment and follow up was available for 4 of 6 cases. The four cases were treated with Mohs micrographic surgery with mean follow up of nine months.

Conclusion

We report six cases of cutaneous carcinosarcoma with distinctive clinical and histologic characterization not previously described in a single series.
Atypical retiform hemangioendothelioma arising in a patient with Milroy disease: a case report and review of the literature
Authors: Arriola Aileen Grace P. , Taylor Laura A. , Asemota Eseosa , Boos Markus D. , Elder David E. , Weber Kristy L. , Micheletti Robert G. , Zhang Paul J.
Published: October 2016

Retiform hemangioendothelioma (RH) is a rare vascular neoplasm with a high rate of local recurrence and low metastatic potential. We describe an unusual case of RH in a 45‐year‐old patient with Milroy disease, with a prominent solid component diffusely involving a chronic lymphedematous leg. This case is consistent with the postulated relationship between lymphedema and vascular neoplasms developing as a result of local immune dysfunction, and highlights the need to closely monitor patients with Milroy disease for pathologic changes. Our case highlights a unique example of RH with atypical features. There are several noteworthy unusual clinical and histologic findings including diffuse involvement of an entire limb, solid component with cytologic atypia, D2‐40 expression, and first‐time‐reported association with Milroy disease. Given the atypical histologic presentation of cytologic atypia, solid areas and atypical immunohistochemical profile with D2‐40 positivity, this case could cause diagnostic difficulty, especially in the setting of such a broad clinical differential.
The political economy of targeting – a critical review
Authors: Schüring Esther , Gassmann Franziska
Published: October 2016

The political economy models of targeting postulate that going universal is a win‐win situation, for the poor and the middle class, as well as those who are in power. This article critically discusses the assumptions behind the political economy arguments of targeting and tests whether a universal mechanism is bound to politically excel in a low‐income country context. On the basis of attitudinal surveys with the urban, rural and student population in Zambia, we do not find any support for the predictions of the political economy models. We discuss the assumptions of the political economy models in the light of these findings and consider potentially decisive parameters that the models currently do not incorporate.
Platelets Toll‐like receptor‐4 in Crohns disease
Authors: Schmid Werner , Novacek Gottfried , Vogelsang Harald , Papay Pavol , Primas Christian , Eser Alexander , Panzer Simon
Published: October 2016

Background

Platelets are activated in Crohn's disease (CD) and interplay with leukocytes. Engagement of Toll‐like receptor‐4 (TLR‐4), which is expressed in human platelets, may be involved in crosstalks between platelets and leukocytes leading to their mutual activation for host defense.

Materials and methods

Human neutrophil peptides (HNPs), lipoprotein binding peptides, and sCD14 were determined by enzyme‐linked immunosorbent assays in 42 patients with active CD, in 43 patients with CD in remission, and in 30 healthy individuals. Neutrophil‐platelet aggregates and binding of the TLR‐4 monoclonal antibody to platelets were determined by flow cytometry.

Results

Levels of HNPs were higher in patients with CD than in controls (P = 0.0003 vs. active CD and P = 0.01 vs. CD in remission). Likewise, neutrophils with adhering platelets were higher in patients with active CD than in controls (P = 0.004). Binding of the TLR‐4 antibody in patients with active CD was similar to that in controls, while patients in remission had significantly higher binding capacities (P = 0.59 and P = 0.003). Incubation of plasma from patients with active disease or patients in remission with platelets from healthy controls confirmed lower binding of the TLR‐4 antibody in the presence of plasma from active diseased patients compared to controls (P = 0.039), possibly due to high levels of lipopolysaccharides, as suggested by high levels of sCD14 and lipoprotein binding protein.

Conclusion

Our study indicates involvement of platelet TLR‐4 in enhancing the secretion of antimicrobial peptides from neutrophils. While platelet aggregation can be due to a variety of mechanisms in inflammatory disease, the mutual activation of platelets and neutrophils may augment host defense.
Prediction of renal function upon reperfusion by ex situ controlled oxygenated rewarming
Authors: Minor Thomas , Sutschet Katja , Witzke Oliver , Paul Andreas , Gallinat Anja
Published: October 2016

Background

Post‐transplant function of suboptimal kidney grafts can be improved but not accurately predicted by hypothermic machine perfusion. Therefore, a new concept of ex situ pre‐implantation machine perfusion with controlled rewarming up to subnormothermic temperatures was developed and evaluated.

Materials and methods

Porcine kidneys (n = 6/group) were retrieved before or 30 min after cardiac arrest of the donor and subjected to 18 h of static cold storage. In some cases, 90 min of machine‐controlled oxygenated rewarming (COR) was added thereafter. Functional integrity was evaluated in all kidneys by subsequent normothermic reperfusion in vitro. After supplementation of the preservation solution (Custodiol‐N solution + 5 g/L dextran 40) with 10 mg/dL creatinine, ex situ renal function was assessed by monitoring urine output, urinary creatinine and creatinine clearance at 20 °C. Functional integrity was evaluated in all kidneys by normothermic reperfusion.

Results

COR resulted in a more than twofold improvement of postreperfusion creatinine clearance, oxygen consumption and enzyme release upon reperfusion, when compared with static cold storage. Predictive discrimination between kidneys with good or impaired function upon reperfusion based on parameters during perfusion at 4 °C was only moderate. This improved significantly at 20 °C. Correlation with renal clearance upon reperfusion was weak for vascular resistance at 8° (r2 = 0·2) and 20 °C (r2 = 0·41). Best correlation was found for clearance measurements at 20° (r2 = 0·81).

Conclusions

Reconditioning by controlled oxygenated rewarming up to 20 °C improves renal function after reperfusion and can be utilized to assess graft integrity of predamaged donor kidneys.
Sex‐specific vitamin D effects on blood coagulation among overweight adults
Authors: Al‐Daghri Nasser M. , Alokail Majed S. , Manousopoulou Antigoni , Heinson Ashley , Al‐Attas Omar , Al‐Saleh Yousef , Sabico Shaun , Yakout Sobhy , Woelk Christopher H. , Chrousos George P. , Garbis Spiros D.
Published: October 2016

Background

Overweight adults are at increased risk for cardiovascular disease and vitamin D deficiency, whereas an important feature to vitamin D physiology is its sex dependence. The aim of this study was to examine whether vitamin D status improvement exerts a sexually dimorphic effect on serum proteins associated with cardiovascular risk among overweight adults.

Materials and methods

Unprocessed serum from age‐ and BMI‐matched men (n = 26) and premenopausal women (n = 24) with vitamin D deficiency and after they achieved sufficiency through a 12‐month nutritional intervention was analysed using our previously published depletion‐free quantitative proteomics method. Key findings were verified with ELISA. Differentially expressed proteins were subjected to in silico bioinformatics assessment using principal component analysis, hierarchical clustering and Metacore™ pathway analysis. All mass spectrometry proteomic data are available via ProteomeXchange (identifier: PXD003663).

Results

A total of 282 proteins were differentially expressed after the intervention between men and women (P‐value ≤ 0·05), in which the blood coagulation pathway was significantly enriched. In agreement with the proteomics findings, ELISA measurements showed vitamin K‐dependent protein C, von Willebrand factor, fibrinogen gamma chain and multimerin‐1 proteins, of relevance to blood coagulation, to be differentially affected (P‐value ≤ 0·05) between sexes after vitamin D status correction.

Conclusions

This study identified novel protein‐level molecular indicators on the sexually dimorphic effect of vitamin D status correction associated with blood coagulation among overweight adults. These sex‐mediated vitamin D effects should be factored in the design and interpretation of vitamin D observational and interventional studies testing cardiometabolic outcomes.
High rates of extra‐pair paternity in a socially monogamous beetle with biparental care
Authors: DILLARD JACQUELINE R.
Published: October 2016

1. Nest construction and paternity assurance are predicted to favour biparental care in insects. The horned passalus (Odontotaenius disjunctus) is a socially monogamous beetle with biparental care that breeds in decaying logs. The genetic mating system of the horned passalus was investigated to determine if paternity assurance is likely to drive the evolution or maintenance of paternal care in this system. Parental time budgets were also examined to better understand the types and frequencies of behaviours performed by parents.

2. Genotyping‐by‐sequencing revealed high levels of extra‐pair paternity, with 54.8% of offspring sired by extra‐pair males and 70% of nests containing extra‐pair young.

3. More heterozygous social males were cuckolded less than more homozygous social males. Extra‐pair mating, however, seems unlikely to increase offspring genetic diversity as extra‐pair offspring were not more heterozygous than within‐pair offspring, and average brood heterozygosity did not increase with higher rates of extra‐pair paternity.

4. Behavioural observations demonstrated that parents spent on average 46.5% of their time processing the decaying wood resource for larval offspring. Because resource processing is a by‐product of feeding and provides shareable benefits for all larvae in the brood, this form of paternal care could be favoured despite low paternity.
The relapse rate and predictors of relapse in patients with first‐episode psychosis following discontinuation of antipsychotic medication
Authors: Di Capite Suzanne , Upthegrove Rachel , Mallikarjun Pavan
Published: October 2016

Background

To determine the “real world” relapse rate in patients with first‐episode psychosis (FEP) who had discontinued antipsychotic medication and identify socio‐demographic and clinical factors associated with the risk of relapse.

Methods

Quantitative data were obtained via case‐note review on 63 patients with FEP who had discontinued antipsychotic medication from Birmingham Early Intervention Service between 2012 and 2015. The follow‐up period was until either: an occurrence of a relapse; end of 12‐month study period; end of patient's case‐note record. Relapse was defined as a return of symptoms requiring one of the following: home treatment, hospital admission or was based on clinical teams’ decision as having a relapse. A pro‐forma targeted pre‐defined socio‐demographic and clinical factors. Survival analysis was undertaken to estimate the 12‐month relapse rate following discontinuation of antipsychotics and Cox regression performed to identify relapse predictors.

Results

The Kaplan‐Meier 12‐month relapse estimate was 67% (95% confidence interval, 54%, 80%). Significant factors (P < .05) independently associated with an increased risk of relapse following discontinuation of antipsychotic medication were: male gender, not being in education, employment or training (NEET) and number of previous psychiatric hospital admissions.

Conclusions

Relapse is common after discontinuation of antipsychotic medication following recovery from a FEP. It is important that patients who wish to discontinue their medication are informed of the high relapse rates and the associated risks. Furthermore, male patients, patients with NEET status and those who have had previous hospital admissions may require closer monitoring.
Economic evaluation of chronic lymphocytic leukemia from a hospital management perspective
Authors: Kron Florian , Kutsch Nadine , Kostenko Anna , Dohle Ines , Glossmann Jan‐Peter , Müller Dirk , Heimann Sebastian M. , Bahlo Jasmin , von Bergwelt‐Baildon Michael , Eichhorst Barbara , Wolf Jürgen , Hallek Michael , Zander Thomas
Published: October 2016

Objectives

Treatment of chronic lymphocytic leukemia (CLL) is currently undergoing dramatic changes. We analyzed economic risks in hospitalized patients with CLL from a management perspective.

Methods

One hundred and twelve patients with CLL hospitalized in 2013 and 2014 at the University Hospital of Cologne were analyzed. To assess profit margins (PMs) per case, diagnosis‐related group (DRG) reimbursement data were merged with an internal cost accounting scheme depending on age, prognostic factors, and DRG key performance indicators.

Results

In 112 patients, 284 cases coded by 19 different DRG with strongly fluctuating cost revenue ratios were found with an overall negative PM of €137 147. The DRG R61H was identified as the one most commonly coded (174 cases, 61.3%) with a deficit per case of €814. Subanalysis demonstrated that the payments were not cost covering due to excessive length of stay and staff costs. Significant differences in PM per case concerning age, length of stay and number of operation and procedure key (OPS) codes (P < 0.05) were found.

Conclusion

In our research‐driven tertiary care hospital, inpatient treatment of patients with CLL is not cost covering. This analysis demonstrates the need for novel care/reimbursement structures in CLL. From a hospital management perspective, cost revenue controlling is crucial to avoid major economic risks.
Coupling between spontaneous pupillary fluctuations and brain activity relates to inattentiveness
Authors: Breeden A. L. , Siegle G. J. , Norr M. E. , Gordon E. M. , Vaidya C. J.
Published: October 2016

Autonomic activity in neurological and psychiatric disorders is often dysregulated, particularly in the context of attentional behaviors. This suggests that interplay between the autonomic nervous system and aspects of the central nervous system subserving attention may be disrupted in these conditions. Better understanding these interactions and their relationship with individual variation in attentional behaviors could facilitate development of mechanistic biomarkers. We identified brain regions defined by trait‐sensitive central–autonomic coupling as a first step in this process. As spontaneous neural activity measured during the resting state is sensitive to phenotypic variability, unconfounded by task performance, we examined whether spontaneous fluctuations in brain activity and an autonomic measure, pupil diameter, were coupled during the resting state, and whether that coupling predicted individual differences in attentional behavior. By employing concurrent pupillometry andfMRIduring the resting state, we observed positive coupling in regions comprising cingulo‐opercular, default mode, and fronto‐parietal networks, as well as negative coupling with visual and sensorimotor regions. Individuals less prone to distractibility in everyday behavior demonstrated stronger positive coupling in cingulo‐opercular regions often associated with sympathetic activity. Overall, our results suggest that individuals less prone to distractibility have tighter intrinsic coordination between specific brain areas and autonomic systems, which may enable adaptive autonomic shifts in response to salient environmental cues. These results suggest that incorporating autonomic indices in resting‐state studies should be useful in the search for biomarkers for neurological and psychiatric disorders.
The rhythm of the executive gate of speech: subthalamic low‐frequency oscillations increase during verbal generation
Authors: Wojtecki Lars , Elben Saskia , Vesper Jan , Schnitzler Alfons
Published: October 2016

We investigated neurophysiological mechanisms of subthalamic nucleus involvement in verbal fluency through a verbal generation task. The subthalamic nucleus is thought to act as a behavioural go/no‐go instance by means of oscillatory communication in the theta band with the prefrontal cortex. Because subthalamic alpha‐theta frequency stimulation has been shown to exert beneficial effects on verbal fluency in Parkinson′s disease, we hypothesized that an alpha‐theta oscillatory network involving the subthalamic nucleus underlies verbal generation task performance as a gating instance for speech execution. Postoperative subthalamic local field potential recordings were performed during a verbal generation compared to a control task. Time‐frequency analysis revealed a significant alpha‐theta power increase and enhanced alpha‐theta coherence between the subthalamic nucleus and the frontal surface EEG during the verbal generation task. Beta and gamma oscillations were not significantly modulated by the task. Power increase significantly correlated with verbal generation performance. Our results provide experimental evidence for local alpha‐theta oscillatory activity in the subthalamic nucleus and coherence to frontal associative areas as a neurophysiological mechanism underlying a verbal generation task. Thus, verbal fluency improvement during subthalamic alpha‐theta stimulation in Parkinson′s disease is likely due to an enhancement of alpha‐theta oscillatory network activity. Alpha‐theta oscillations can be interpreted as the rhythmic gating signature in a speech executing subthalamic‐prefrontal network.
Science, Realism and Correlationism. A Phenomenological Critique of Meillassoux' Argument from Ancestrality
Authors: Wiltsche Harald A.
Published: October 2016

Quentin Meillassoux has recently launched a sweeping attack against ‘correlationism’. Correlationism is an umbrella term for any philosophical system that is based on ‘the idea [that] we only ever have access to the correlation between thinking and being, and never to either term considered apart from the other’ (Meillassoux 2012: 5). Thus construed, Meillassoux' critique is indeed a sweeping one: It comprises major parts of the philosophical tradition since Kant, both in its more continental and in its more analytical outlooks. In light of this critique, the aim of this paper is twofold: On the one hand, I shall defend phenomenology against Meillassoux' main argument, the ‘argument from ancestrality’. On the other hand, I will argue that this argument, albeit unsuccessful in its original form, can be modified to pose a more serious threat. Although this modified version can also be circumvented, it forces phenomenologists to clarify their stance towards the natural sciences.
Use of 1H NMR to identify nitrogen and carbon metabolites associated with mineralizable N in grassland soil
Authors: McDonald N. T. , Graham S. F. , Watson C. J. , Gordon A. , Lalor S. T. J. , Laughlin R. J. , Elliott C. T. , Wall D. P.
Published: October 2016

Improved understanding of the metabolites linked to the mineralization processes of nitrogen (N) and carbon (C) in soil is important for optimum management, and to realize the soil's production potential to minimize associated environmental risks. A novel approach for investigating soil with proton nuclear magnetic resonance spectroscopy (1H NMR) was used to detect metabolites present in 35 contrasting grassland soil types in Ireland. Soil samples were analysed for a range of chemical, biological and physical properties including mineralizable N (MN) with a 7‐day anaerobic incubation (AI‐7). We identified and quantified by multivariate and regression analyses seven soil metabolites related to MN, namely glucose, trimethylamine, glutamic acid, serine, aspartic acid, 4‐aminohippuric acid and citric acid. Glucose explained the largest percentage of the variation in MN (R2 = 0.72). The amino acids, aspartic acid, 4‐aminohippuric acid, glutamic acid and serine explained 39, 38, 27 and 19% of the variation in MN, respectively. These results suggest that a labile carbon source (seven possible metabolites) appears to be an important factor for soil microbial biomass (SMB) to regulate quantities of 7‐day mineralizable N from soil organic matter N (SOM‐N) pools in these grassland soils for potential plant uptake. The results also demonstrate the analytical ability of 1H NMR as a potential practical platform to analyse the complex metabolite profiles in soil related to short‐term C and N mineralization. However, evaluation of 1H NMR against other analytical techniques, such as high performance anion exchange chromatography and pulsed amperometric detection (HPAEC‐PAD), to profile soil metabolites is recommended.

Highlights

Knowledge of metabolites linked to C and N cycling in soil would help improve nutrient use efficiency.

1H NMR was investigated as a novel approach for profiling metabolites in grassland soil.

Seven soil metabolites that correlated with mineralizable N were identified.

1H NMR is effective for simultaneous soil metabolite profiling, but spectral libraries need to be developed.
Transcranial sonography in dopa‐responsive dystonia
Authors: Svetel M. , Tomić A. , Mijajlović M. , Dobričić V. , Novaković I. , Pekmezović T. , Brajković L. , Kostić V. S.
Published: October 2016

Background and purpose

Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa‐responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder.

Methods

Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinsonʼs disease (PD); (iii) 30 patients diagnosed as isolated adult‐onset focal dystonia; and (iv) 45 healthy controls (HCs).

Results

Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group.

Conclusions

We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long‐lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.
Quality indicators for the adult epilepsy monitoring unit
Authors: Sauro Khara M. , Wiebe Samuel , Macrodimitris Sophie , Jetté Nathalie ,   the EMU Quality Improvement Team
Published: October 2016

Objective

Quality and safety in epilepsy monitoring units (EMUs) are of great importance because patients’ seizures are induced rather than prevented in this hospital setting. However, the measurement and evaluation of quality and safety in EMUs are heterogeneous, as are practices and processes of care. To improve the measurement of quality and safety in EMUs, we sought to develop evidence‐based and consensus‐driven quality indicators, adhering to previously described methodologic standards.

Methods

Candidate quality indicators were identified using a recent systematic review on quality and safety indicators in EMUs. These were supplemented by expert opinion to identify other indicators that had not been reported previously. The candidate quality indicators were then evaluated using a modified Delphi technique among a multidisciplinary EMU quality improvement team. Candidate indicators identified as important and feasible through the Delphi technique were then developed into quality metrics.

Results

Thirty‐four candidate indicators were abstracted from 135 studies included in the earlier systematic review, and two additional candidate indicators were suggested through consensus from experts. Consensus was reached after two modified Delphi rounds for 25 quality indicators identified as important. These 25 indicators were then developed into quality metrics using a standardized data collection form and were deployed in an online database for systematic data capture and further analyses.

Significance

These quality indicators have the potential to improve the reporting of quality and safety in EMUs through standardized measurement and evaluation of the quality and safety of care. The ultimate goal is improved patient care and clinical outcomes through safer and better care for people with epilepsy in the EMU.
MicroRNA‐139‐5p negatively regulates NR2A‐containing NMDA receptor in the rat pilocarpine model and patients with temporal lobe epilepsy
Authors: Alsharafi Walid A. , Xiao Bo , Li Jing
Published: October 2016

Objectives

Regulation of N‐methyl‐d‐aspartate (NMDA) subunits NR2A and NR2B expression during status epilepticus (SE) remains incompletely understood. Here we explored the role of brain‐enriched microRNA (miR)‐139‐5p in this process.

Methods

miRNA microarray was performed to examine changes in miRNA expression in the rat pilocarpine model following NMDA‐receptor blockade. The dynamic expression patterns of miR‐139‐5p, NR2A, and NR2B levels were measured in rats during the three phases of temporal lobe epilepsy (TLE) development using quantitative reverse transcription polymerase chain reaction (qRT‐PCR) and Western blot. Similar expression methods were applied to hippocampi obtained from patients with TLE and from normal controls. Moreover, miR‐139‐5p agomir and antagomir were utilized to explore the role of miR‐139‐5p in determining NMDA‐receptor subunit expression patterns.

Results

We identified 18 miRNAs that were significantly altered in the rat pilocarpine model following NMDA‐receptor blockade. Of these, miR‐139‐5p was significantly up‐regulated and Grin2A was predicted as its potential putative target. In patients with TLE, miR‐139‐5p expression was significantly down‐regulated, whereas NR2A and NR2B levels were significantly up‐regulated. In the rat model of SE, miR‐139‐5p expression was down‐regulated while NR2A was up‐regulated in the acute and chronic phases, but not in the latent phase. NR2B expression was up‐regulated during the three phases of TLE development. Overexpression of miR‐139‐5p decreased, whereas depletion of miR‐139‐5p enhanced the expression levels of NR2A, but not NR2B, induced by pilocarpine treatment. Of interest, NMDA nonselective antagonist and NR2A selective antagonist enhanced miR‐139‐5p levels suppressed by pilocarpine treatment, whereas the NR2B selective antagonist was ineffective.

Significance

These findings elucidate the potential role of miR‐139‐5p in NMDA‐receptor involvement in TLE development and may provide novel therapeutic targets for the future treatment of TLE.