bluuebunny/crossref_metadata_2025 huggingface dataset:
Activation of AMP‐activated protein kinase by retinoic acid sensitizes hepatocellular carcinoma cells to apoptosis induced by sorafenib
Authors: Ishijima Naoki , Kanki Keita , Shimizu Hiroki , Shiota Goshi
Published: February 2015

To improve the outcome of cancer chemotherapy, strategies to enhance the efficacy of anticancer drugs are required. Sorafenib is the only drug to prolong overall survival of the patients with hepatocellular carcinoma (HCC), however, the outcome is still not satisfactory. Retinoids, vitamin A derivatives, have been known to exhibit inhibitory effects on various cancers including HCC. In this study, we investigated the effects of combined treatment using sorafenib and retinoids including all‐trans retinoic acid (ATRA), NIK‐333, and Am80 on HCC cells. Cell viability assays in six HCC cell lines, HepG2, PLC/PRF/5, HuH6, HLE, HLF, and Hep3B, revealed that 5 and 10 μM ATRA, concentrations that do not exert cytotoxic effects, enhanced the cytotoxicity of sorafenib, being much more effective than NIK‐333 and Am80. We found that ATRA induced AMP‐activated protein kinase activation, which was followed by reduced intracellular ATP level. Gene expression analysis revealed that ATRA decreased the expression of glycolytic genes such as GLUT‐1 and LDHA. In the combination treatment using ATRA and sorafenib, increased apoptosis, followed by the activation of p38 MAPK and JNK, the upregulation and translocation of Bax to mitochondria, and the activation of caspase‐3, was observed. Suppression of AMP‐activated protein kinase by siRNA restored the viability of the cells treated with ATRA and sorafenib. Our results thus indicate that ATRA is useful for enhancing the cytotoxicity of sorafenib against HCC cells by regulating the energy metabolism of HCC cells.
4‐Aminoquinoline Derivatives as Potential Antileishmanial Agents
Authors: Antinarelli Luciana M. R. , Dias Rafael M. P. , Souza Isabela O. , Lima Wallace P. , Gameiro Jacy , da Silva Adilson D. , Coimbra Elaine S.
Published: February 2015

The leishmanicidal activity of a series of 4‐aminoquinoline (AMQ) derivatives was assayed against Leishmania amazonensis. This activity against the intracellular parasite was found stronger than for L. amazonensis promastigotes. Neither compound was cytotoxic against macrophages. The compound AMQ‐j, which exhibited a strong activity against promastigotes and amastigotes of L. amazonensis (IC50 values of 5.9 and 2.4 μg/mL, respectively) and similar leishmanicidal activity to reference drugs, was chosen for studies regarding its possible mechanism of action toward parasite death. The results showed that the compound AMQ‐j induced depolarization of the mitochondrial membrane potential in promastigotes and in L. amazonensis‐infected macrophages, but not in uninfected macrophages. Furthermore, the depolarization of the mitochondrial membrane potential was dose dependent in infected macrophages. We have established that promastigotes and L. amazonensis‐infected macrophages treated with AMQ‐j were submitted to oxidative stress. This is in line with the increase in the level of reactive oxygen species (ROS). Leishmania amazonensis‐infected macrophages treated with AMQ‐j did not show a significant increase in the production of nitric oxide. Our results indicate the effective and selective action of AMQ‐j against L. amazonensis, and its mechanism of action appears to be mediated by mitochondrial dysfunction associated with ROS production.
Children's and Adolescents' Accounts of Helping and Hurting Others: Lessons About the Development of Moral Agency
Authors: Recchia Holly E. , Wainryb Cecilia , Bourne Stacia , Pasupathi Monisha
Published: February 2015

This study examined children's and adolescents' narrative accounts of everyday experiences when they harmed and helped a friend. The sample included 100 participants divided into three age groups (7‐, 11‐, and 16‐year‐olds). Help narratives focused on the helping acts themselves and reasons for helping, whereas harm narratives included more references to consequences of acts and psychological conflicts. With age, however, youth increasingly described the consequences of helping. Reasons for harming others focused especially on the narrator's perspective whereas reasons for helping others were centered on others' perspectives. With age, youth increasingly drew self‐related insights from their helpful, but not their harmful, actions. Results illuminate how reflections on prosocial and transgressive experiences may provide distinct opportunities for constructing moral agency.
Developmental Differences in Memory During Early Childhood: Insights From Event‐Related Potentials
Authors: Riggins Tracy , Rollins Leslie
Published: February 2015

Age‐related differences in behavioral and electrophysiological indices of memory were examined in 3‐ to 6‐year‐old children (N = 76). Behaviorally, no differences were observed in children's ability to identify old items; however, 3‐year‐old children were less accurate in correctly rejecting new items, and 3‐ and 4‐year‐old children recalled fewer contextual details compared to 5‐ and 6‐year‐old children. Age‐related differences in electrophysiological measures (800–1,000 ms after stimulus onset) were observed both to items recalled with contextual details, which increased between 3 and 4 years, and items recalled without contextual details, which were greatest in 5‐year‐old children, even after adjusting for global age‐related differences. These findings, interpreted within a dual‐process framework, may suggest changes in both recollection and familiarity processes during early childhood.
Maternal and paternal contribution to intergenerational psychosocial transmission of paan chewing
Authors: Madathil Sreenath A. , Rousseau Marie‐Claude , Allison Paul , Netuveli Gopalakrishnan , Humphris Gerald M. , Varghese Ipe , Shiraz Shameena , Castonguay Genevieve , Thekkepurakkal Akhil‐Soman , Shahul Hameed P. , Nicolau Belinda
Published: February 2015

Objectives

Paan chewing is a recognized risk factor for oral cancer in the Asian population. However, there is currently little evidence about the intergenerational psychosocial transmission of paan chewing in South Indian families. We investigated the association between parental and participant's paan chewing in a South Indian population.

Methods

A subset of data was drawn from a hospital‐based case–control study on oral cancer, the HeNCe Life study, conducted at Government Dental and Medical Colleges of Kozhikode, South India. Analyses were based on 371 noncancer control participants having diseases unrelated to known risk factors for oral cancer. Demographics, behavioral habits (e.g., paan chewing, smoking), and indicators of socioeconomic position (SEP) of both participants and their parents were collected with the use of a questionnaire‐based interview and a life grid technique. Unconditional logistic regression assessed odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between parental and participant's paan chewing, adjusted for confounders.

Results

Over half of the participants were males (55.2%), and the mean age of participants was 59 (SD = 12) years. After adjusting for age, religion, parents’ SEP, parents’ education, smoking and alcohol consumption, and perceived parenting behavior, we observed that maternal paan chewing and paternal paan chewing were significantly associated with the participant's paan chewing ([OR = 2.40, 95% CI = 1.11–5.21] and [OR = 3.05, 95% CI = 1.48–6.27], respectively).

Conclusions

Intergenerational psychosocial transmission of the habit of paan chewing could occur through shared sociocultural or environmental factors.
Low programmed cell death-1 (PD-1) expression in peripheral CD4+ T cells in Japanese patients with autoimmune type 1 diabetes
Authors: Fujisawa R , Haseda F , Tsutsumi C , Hiromine Y , Noso S , Kawabata Y , Mitsui S , Terasaki J , Ikegami H , Imagawa A , Hanafusa T
Published: February 2015

Programmed cell death-1 (PD-1) is a co-stimulatory molecule that inhibits T cell proliferation. We aimed to clarify PD-1 expression in CD4+ T cells and the association between PD-1 expression and the 7785C/T polymorphism of PDCD1, with a focus on the two subtypes of type 1 diabetes, type 1A diabetes (T1AD) and fulminant type 1 diabetes (FT1D), in the Japanese population. We examined 22 patients with T1AD, 15 with FT1D, 19 with type 2 diabetes (T2D) and 29 healthy control (HC) subjects. Fluorescence-activated cell sorting (FACS) and real-time PCR were utilized to analyse PD-1 expression quantitatively. Genotyping of 7785C/T in PDCD1 was performed using the TaqMan method in a total of 63 subjects (21 with T1AD, 15 with FT1D and 27 HC). FACS revealed a significant reduction in PD-1 expression in CD4+ T cells in patients with T1AD (mean: 4·2 vs. 6·0% in FT1D, P = 0·0450; vs. 5·8% in T2D, P = 0·0098; vs. 6·0% in HC, P = 0·0018). PD-1 mRNA expression in CD4+ T cells was also significantly lower in patients with T1AD than in the HC subjects. Of the 63 subjects, PD-1 expression was significantly lower in individuals with the 7785C/C genotype than in those with the C/T and T/T genotypes (mean: 4·1 vs. 5·9%, P = 0·0016). Our results indicate that lower PD-1 expression in CD4+ T-cells might contribute to the development of T1AD through T cell activation.
Calcineurin inhibitors dampen humoral immunity by acting directly on naive B cells
Authors: De Bruyne R , Bogaert D , De Ruyck N , Lambrecht B N , Van Winckel M , Gevaert P , Dullaers M
Published: February 2015

Calcineurin inhibitors (CNI), used frequently in solid organ transplant patients, are known to inhibit T cell proliferation, but their effect on humoral immunity is far less studied. Total and naive B cells from healthy adult donors were cultured in immunoglobulin (Ig)A- or IgG/IgE-promoting conditions with increasing doses of cyclosporin, tacrolimus, rapamycin or methylprednisolone. The effect on cell number, cell division, plasmablast differentiation and class-switching was tested. To examine the effect on T follicular helper (Tfh) cell differentiation, naive CD4+ T cells were cultured with interleukin (IL)-12 and titrated immunosuppressive drug (IS) concentrations. Total B cell function was not affected by CNI. However, naive B cell proliferation was inhibited by cyclosporin and both CNI decreased plasmablast differentiation. Both CNI suppressed IgA, whereas only cyclosporin inhibited IgE class-switching. Rapamycin had a strong inhibitory effect on B cell function. Strikingly, methylprednisolone, increased plasmablast differentiation and IgE class-switching from naive B cells. Differentiation of Tfh cells decreased with increasing IS doses. CNI affected humoral immunity directly by suppressing naive B cells. CNI, as well as rapamycin and methylprednisolone, inhibited the in-vitro differentiation of Tfh from naive CD4+ T cells. In view of its potent suppressive effect on B cell function and Tfh cell differentiation, rapamycin might be an interesting candidate in the management of B cell mediated complications post solid organ transplantation.
Specific overexpression of tumour necrosis factor-α-induced protein (TNFAIP)9 in CD14+CD16− monocytes in patients with rheumatoid arthritis: comparative analysis with TNFAIP3
Authors: Takai C , Matsumoto I , Inoue A , Umeda N , Tanaka Y , Kurashima Y , Wada Y , Narita I , Sumida T
Published: February 2015

The tumour necrosis factor (TNF)-α-induced proteins (TNFAIP)9 and TNFAIP3 play an important pathogenic role in murine arthritis. To clarify their pathophysiological roles in patients with rheumatoid arthritis (RA), we examined their expression and localization in peripheral blood mononuclear cells (PBMC). TNFAIP9 and TNFAIP3 mRNA expression was determined in PBMC of RA patients and healthy subjects (control). Flow cytometry was used to analyse the main TNFAIP9- and TNFAIP3-expressing cell populations. TNFAIP9 and TNFAIP3 mRNA expression levels were examined in vitro on CD14+ cells stimulated with TNF-α and lipopolysaccharide (LPS). The expression levels of TNFAIP9 and TNFAIP3 mRNA were also measured before and 12 weeks after treatment with tocilizumab and abatacept. TNFAIP9 expression was significantly higher, while TNFAIP3 expression was lower in PBMC of RA (n = 36) than the control (n = 24) (each P < 0·05). TNFAIP9 was expressed on CD14+ cells, especially in human leucocyte antigen D-related (HLA-DR)+CD14brightCD16−cells, while TNFAIP3 was expressed mainly on CD3+ T cells. TNF-α and LPS induced TNFAIP9 and TNFAIP3 in human CD14+monocytes in vitro. Treatment with tocilizumab (n = 13), but not abatacept (n = 11), significantly reduced TNFAIP9 mRNA expression in PBMC, which was associated with reduction in the number of circulating CD14bright monocytes. The expression of TNFAIP9 in CD14+ cells was specifically elevated in patients with RA, regulated by TNF-α and LPS, and suppressed by tocilizumab, while TNFAIP3 in PBMC showed different localization and induction patterns.
Current landscape of direct‐to‐consumer genetic testing and its role in ophthalmology: a review
Authors: Sanfilippo Paul G , Kearns Lisa S , Wright Philip , Mackey David A , Hewitt Alex W
Published: February 2015

The sequencing of the human genome has seen the emergence of the direct‐to‐consumer (DTC) genetic‐testing market, which allows individuals to obtain information about their genetic profile and its many health and lifestyle implications. Genetics play an important role in the development of many eye diseases, however, little information is available describing the influence of the DTC industry in ophthalmology. In this review, we examined DTC companies providing genetic test products for eye disease. Of all eye conditions, the majority of DTC companies provided susceptibility testing or risk assessment for age‐related macular degeneration (AMD). For the 15 companies noted to offer products, we found considerable variation in the cost, scope and clarity of informational content of DTC genetic testing for ophthalmic conditions. The clinical utility of these tests remains in question, and the American Academy of Ophthalmology recommendations against routine testing for many conditions probably still apply.
Xq25 duplication: the crucial role of the STAG2 gene in this novel human cohesinopathy
Authors: Leroy C. , Jacquemont M.‐L. , Doray B. , Lamblin D. , Cormier‐Daire V. , Philippe A. , Nusbaum S. , Patrat C. , Steffann J. , Colleaux L. , Vekemans M. , Romana S. , Turleau C. , Malan V.
Published: February 2015

The Xq25 duplications syndrome has recently emerged as a distinct clinical entity. We report here on six new patients belonging to two unrelated families and harbouring an Xq25 microduplication detected by array CGH. Similarly to previously reported cases, the phenotype of our patients is characterized by delayed milestones, speech disturbance, intellectual disability, abnormal behaviours and a characteristic facial dysmorphism. The common duplicated interval allowed further refinement of the shortest region of overlap to 173 kb, including only one gene, STAG2, which encodes a component of the cohesin complex. We suggest that increased STAG2 gene copy number and dysregulation of its downstream target genes may be responsible for the specific clinical findings of this syndrome. Therefore, the Xq25 microduplication could be considered as a novel cohesinopathy, thus increasing the group of these disorders.
A break‐even analysis of major ear surgery
Authors: Wasson J.D. , Phillips J.S.
Published: February 2015

Objectives

To determine variables which affect cost and profit for major ear surgery and perform a break‐even analysis.

Design

Retrospective financial analysis.

Setting

UK teaching hospital.

Participants

Patients who underwent major ear surgery under general anaesthesia performed by the senior author in main theatre over a 2‐year period between dates of 07 September 2010 and 07 September 2012.

Main outcome measures

Income, cost and profit for each major ear patient spell. Variables that affect major ear surgery profitability.

Results

Seventy‐six patients met inclusion criteria. Wide variation in earnings, with a median net loss of £−1345.50 was observed. Income was relatively uniform across all patient spells; however, theatre time of major ear surgery at a cost of £953.24 per hour varied between patients and was the main determinant of cost and profit for the patient spell. Bivariate linear regression of earnings on theatre time identified 94% of variation in earnings was due to variation in theatre time (r = −0.969; P < 0.0001) and derived a break‐even time for major ear surgery of 110.6 min. Theatre time was dependent on complexity of procedure and number of OPCS4 procedures performed, with a significant increase in theatre time when three or more procedures were performed during major ear surgery (P = 0.015).

Conclusion

For major ear surgery to either break‐even or return a profit, total theatre time should not exceed 110 min and 36 s.
Restoring normoglycaemia by use of a very low calorie diet in long‐ and short‐duration Type 2 diabetes
Authors: Steven S. , Taylor R.
Published: February 2015

Aims

To establish whether an 8‐week very‐low‐calorie diet could improve glycaemic control in Type 2 diabetes of long duration.

Methods

A total of 29 people with Type 2 diabetes [short‐duration group (diabetes duration < 4 years), n = 15; long‐duration group (diabetes duration > 8 years), n = 14] completed an 8‐week very‐low‐calorie diet, with assessments of fasting anthropometry, blood tests and blood pressure at baseline and weeks 1, 4 and 8 of the diet.

Results

Similar weight loss was achieved in the short‐ and long‐duration groups (14.8 ± 0.8% and 14.4 ± 0.7% respectively; P = 0.662). The glucose response to acute calorie restriction was heterogeneous in the long‐duration group with some responding similarly to those in the short‐duration group, some responding, but only slowly, and others not responding at all. Overall, HbA1c concentration in the short‐ vs. long‐duration groups fell to 44 ± 2 vs. 64 ± 6 mmol/l (6.2 ± 0.2 vs. 8.0 ± 0.5%; P = 0.002). Fasting plasma glucose levels decreased to 5.8 ± 0.2 vs. 8.4 ± 1.1 mmol/l (P = 0.024) respectively. A total of 87% of the short‐duration group and 50% of the long‐duration group achieved non‐diabetic fasting plasma glucose levels at week 8. Clinically significant improvements in blood pressure and lipid profile were seen regardless of diabetes duration.

Conclusion

In people with Type 2 diabetes of > 8 years' duration, a therapeutic trial of a very‐low‐calorie diet may be undertaken with a 50% chance of achieving non‐diabetic fasting glucose levels off all antidiabetic therapies.
Practical approach to non‐alcoholic fatty liver disease in patients with diabetes
Authors: Tai F. W. D. , Syn W.‐K. , Alazawi W.
Published: February 2015

The prevalence of Type 2 diabetes is expected to increase in parallel with obesity rates and the ageing population. Recent studies show that Type 2 diabetes is associated with a twofold increase in the risk of non‐alcoholic fatty liver disease, a leading cause of chronic liver disease. Individuals with non‐alcoholic steatohepatitis, a more advanced stage of non‐alcoholic fatty liver disease, are specifically at risk of developing fibrosis/cirrhosis (end‐stage liver disease) and hepatocellular carcinoma; therefore, identifying individuals (with Type 2 diabetes) who are likely to develop hepatic complications is paramount. In the present clinical review, we discuss the potential impact of non‐alcoholic fatty liver disease diagnosis on Type 2 diabetes, and the putative risk factors for developing non‐alcoholic steatohepatitis and non‐alcoholic steatohepatitis fibrosis. We highlight the limitations of currently used tools in non‐alcoholic fatty liver disease diagnosis and staging, and provide an insight into future developments in the field. We present an example of a non‐alcoholic fatty liver disease screening protocol and discuss the therapeutic options currently available to our patients.
Normal pregnancy outcome after first‐trimester exposure to liraglutide in a woman with Type 2 diabetes
Authors: Greco D.
Published: February 2015

Background

Data from animal studies suggest that glucagon‐like peptide‐1 analogues should not be used in pregnancy, but there have been no reports to date of their effects in human pregnancy. The aim of the present report was to describe a case of exposure to liraglutide during the first trimester of pregnancy in a patient with Type 2 diabetes mellitus.

Case report

A 37‐year‐old woman with Type 2 diabetes mellitus who had been taking liraglutide for 2 years was admitted in the 13th week of gestation. Liraglutide was immediately discontinued and intensive insulin therapy instituted. The woman gave birth to a healthy child after completing an uneventful gestation period.

Conclusion

Although the present normal pregnancy outcome does not mean that glucagon‐like peptide‐1 analogues are safe to use in pregnancy, this report contributes to the limited knowledge regarding human exposure to these drugs during pregnancy in women with diabetes.
Negative appraisals of insulin therapy are common among adults with Type 2 diabetes using insulin: Results from Diabetes MILES – Australia cross‐sectional survey
Authors: Holmes‐Truscott E. , Skinner T. C. , Pouwer F. , Speight J.
Published: February 2015

Aim

To identify insulin therapy appraisals among adults with Type 2 diabetes using insulin and how negative appraisals relate to clinical, self‐care and psychosocial outcomes.

Methods

Diabetes MILES – Australia 2011 was a national survey of adults with diabetes, focused on behavioural and psychosocial issues. Subgroup analyses were conducted on the responses of 273 adults with Type 2 diabetes using insulin (46% women; mean ± sd age: 59 ± 9 years; diabetes duration: 12 ± 7 years; years using insulin: 4 ± 4). They completed validated measures of insulin therapy appraisals (ITAS), depression (PHQ–9), anxiety (GAD–7), diabetes distress (PAID) and diabetes‐specific self‐efficacy (DES–SF).

Results

Insulin was perceived to be very important, and its benefits (e.g. improves health) were endorsed by most (82%). Fifty‐one per cent believed that taking insulin means their diabetes has become worse; 51% that insulin causes weight gain; 39% that they have ‘failed to manage’ their diabetes. Those with the greatest and least ‘ITAS negative’ scores did not differ by diabetes duration or years using insulin, or by average number of insulin injections or blood glucose checks per day. Those with more negative insulin appraisals were significantly younger (Mean Diff. = 5 years, P < 0.001), less satisfied with recent blood glucose levels (P < 0.001, d = 0.63), had reduced diabetes‐specific self‐efficacy (P < 0.001, d = 0.7), and were more likely to report depressive symptoms, anxiety or diabetes distress (all P < 0.001, d = 0.65–1.1).

Conclusions

Negative insulin therapy appraisals are common among adults with Type 2 diabetes using insulin, and are associated with lower general and diabetes‐specific emotional well‐being, reduced diabetes‐specific self‐efficacy and satisfaction with blood glucose.
Gender‐based differences in glycaemic control and hypoglycaemia prevalence in patients with type 2 diabetes: results from patient‐level pooled data of six randomized controlled trials
Authors: Kautzky‐Willer A. , Kosi L. , Lin J. , Mihaljevic R.
Published: February 2015

Aims

To determine the impact of gender on glycaemic control and hypoglycaemia in insulin‐naïve patients with type 2 diabetes (T2DM).

Methods

Data were pooled from six randomized clinical trials of insulin glargine or NPH insulin in insulin‐naïve, inadequately controlled patients. Female [n = 1251; mean glycated haemoglobin (HbA1c) level 8.99%, age 56.91 years, diabetes duration 9.84 years] and male patients (n = 1349; mean HbA1c 8.9%, age 57.47 years, diabetes duration 10.13 years) were started on and treated with insulin glargine or NPH insulin for 24–36 weeks. HbA1c and fasting blood glucose levels, percent achieving HbA1c target of <7% and insulin dose change were recorded.

Results

For both men and women, HbA1c levels were significantly reduced over time (p < 0.001); a significantly greater HbA1c reduction was observed in men than in women (−1.36 vs. −1.22; p = 0.002). Significantly fewer women achieved target HbA1c of <7% (p < 0.001). At the study end, women had a significantly higher insulin dose/kg than men (0.47 vs. 0.42 U/kg; p < 0.001). The incidence rates of severe and severe nocturnal hypoglycaemia were significantly higher in women (3.28% vs. 1.85%; p < 0.05 and 2.24% vs. 0.59%; p < 0.001, respectively). Women were more likely to experience severe hypoglycaemia [odds ratio (OR) 1.80; 95% confidence interval (CI) 1.08, 3.00; p = 0.02] and severe nocturnal hypoglycaemia (OR: 3.80; 95% CI 1.72, 8.42; p = 0.001).

Conclusions

These observations confirm studies that found a smaller improvement in HbA1c and greater hypoglycaemia in women during insulin treatment. Physicians should be aware of the need to determine and closely monitor dosing, particularly in women, to optimize the balance between glycaemic control and hypoglycaemia risk.
Circulating and urinary microRNA profile in focal segmental glomerulosclerosis: a pilot study
Authors: Ramezani Ali , Devaney Joseph M. , Cohen Scott , Wing Maria R. , Scott Richard , Knoblach Susan , Singhal Rishi , Howard Lilian , Kopp Jeffrey B. , Raj Dominic S.
Published: February 2015

Background

MicroRNAs (miRNAs) are noncoding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigated whether patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) have distinct circulating and urinary miRNA expression profiles that could lead to potential development of noninvasive biomarkers of the disease.

Materials and methods

Exosome miRNAs were extracted from plasma and urine samples of patients with primary FSGS (n = 16) or MCD (n = 5) and healthy controls (n = 5). Differences in miRNA abundance were examined using Affymetrix GeneChip miRNA 3.0 arrays. QRT‐PCR was used to validate the findings from the array.

Results

Comparison analysis of FSGS versus MCD revealed 126 and 155 differentially expressed miRNAs in plasma and in urine, respectively. Only 38 of these miRNAs were previously cited, whereas the remaining miRNAs have not been described. Comparison analysis showed that a significant number of miRNAs were downregulated in both plasma and urine samples of patients with FSGS compared to those with MCD. Plasma levels of miR‐30b, miR‐30c, miR‐34b, miR‐34c and miR‐342 and urine levels of mir‐1225‐5p were upregulated in patients with MCD compared to patients with FSGS and controls (P < 0·001). Urinary levels of mir‐1915 and miR‐663 were downregulated in patients with FSGS compared to MCD and controls (P < 0·001), whereas the urinary levels of miR‐155 were upregulated in patients with FSGS when compared to patients with MCD and controls (P < 0·005).

Conclusions

Patients with FSGS and MCD have a unique circulating and urinary miRNA profile. The diagnostic and prognostic potential of miRNAs in FSGS and MCD warrants further studies.
Increasing rate of atrial fibrillation from 2003 to 2011 in patients with ischaemic stroke: results from 55 551 patients in a nationwide registry
Authors: Jespersen S. F. , Christensen L. M. , Christensen A. , Christensen H.
Published: February 2015

Background and purpose

The general awareness of atrial fibrillation is increasing. The key to prevent atrial fibrillation related stroke is oral anticoagulation therapy; however, it has often been proposed that oral anticoagulation therapy is under‐utilized despite indication. The aim of the study was to examine the trends in atrial fibrillation rate in patients after acute ischaemic stroke and to determine whether the use of oral anticoagulation therapy increased from 2003 to 2011.

Methods

In the nationwide Danish Stroke Registry 55 551 patients (≥18 years) admitted with acute ischaemic stroke were identified. Frequency analysis and linear regression were used to assess trends in atrial fibrillation diagnosis and oral anticoagulation therapy prescription.

Results

A total of 17.1% (n = 9482) of ischaemic stroke patients had atrial fibrillation. The relative frequency of atrial fibrillation increased significantly during the study period (16.3%–20.1%). The prescription rate of oral anticoagulation therapy had a yearly increase five times higher than the atrial fibrillation rate.

Conclusion

From 2003 to 2011 atrial fibrillation detection rate increased significantly, which was followed by a more marked increase in the use of oral anticoagulation therapy, most probably reflecting an increased awareness and questioning assumed current under‐use of oral anticoagulation therapy in secondary stroke prevention.
ICD coding for epilepsy: Past, present, and future—A report by the International League Against Epilepsy Task Force on ICD codes in epilepsy
Authors: Jette Nathalie , Beghi Ettore , Hesdorffer Dale , Moshé Solomon L. , Zuberi Sameer M. , Medina Marco T. , Bergen Donna
Published: February 2015

The World Health Organization (WHO) International Classification of Diseases (ICD) has been used to classify causes of morbidity and mortality such as epilepsy for more than 50 years. The aims of this critical commentary are to do the following: (1) Introduce the ICD classification, summarize the ICD‐9 and ICD‐10 codes for epilepsy and seizures, and discuss the challenges of mapping epilepsy codes between these two versions; (2) discuss how the ICD‐9 and ICD‐10 relate to the revised International League Against Epilepsy (ILAE) terminology and concepts for classification of seizures and epilepsies; (3) discuss how ICD‐coded data have been used for epilepsy care and research and briefly examine the potential impact of the international ICD‐10 clinical modifications on research; (4) discuss the upcoming ICD‐11 codes and the role of the epilepsy community in their development; and (5) discuss how the ICD‐11 will conform more closely to the current ILAE terminology and classification of the epilepsies and seizures and its potential impact on clinical care, surveillance, and public health and research.
Neuropeptide FF and prolactin‐releasing peptide decrease cortical excitability through activation of NPFF receptors
Authors: Buffel Ine , Meurs Alfred , Portelli Jeanelle , Raedt Robrecht , De Herdt Veerle , Sioncke Lynn , Wadman Wytse , Bihel Frederic , Schmitt Martine , Vonck Kristl , Bourguignon Jean‐Jacques , Simonin Frederic , Smolders Ilse , Boon Paul
Published: February 2015

Objective

Drugs with a novel mechanism of action are needed to reduce the number of people with epilepsy that are refractory to treatment. Increasing attention is paid to neuropeptide systems and several anticonvulsant neuropeptides have already been described, such as galanin, ghrelin, and neuropeptide Y (NPY). Many others, however, have not been investigated for their ability to affect epileptic seizures. In this study, the potential anticonvulsant activities of three members of the RF‐amide neuropeptide family, neuropeptide FF (NPFF), prolactin‐releasing peptide (PrRP), and kisspeptin (Kp) and other receptor ligands (NPFF1/2R, GPR10, and GRP54, respectively) were tested in the motor cortex stimulation model.

Methods

A train of pulses with increasing intensity (0–10 mA over 150 s, 50 Hz, pulse width 2 msec) was delivered to the motor cortex of rats. The threshold intensity for eliciting a motor response (i.e., motor threshold) was determined through behavioral observation and used as a measure for cortical excitability. The threshold was determined before, during, and after the intracerebroventricular (i.c.v.) administration of various NPFF1/2R, GPR10, and GPR54 receptor ligands.

Results

NPFF and PrRP significantly increased the motor threshold by a maximum of 143 ± 27 and 83 ± 13 μA, respectively, for the doses of 1 nmol/h (p < 0.05). The increase of motor threshold by NPFF and PrRP was prevented by pretreatment and co‐treatment with the NPFF1/2R antagonist RF9. Pretreatment with a selective NPFF1R antagonist also prevented the threshold increase induced by NPFF. Kp did not increase motor threshold.

Significance

Intracerebroventricular infusion of NPFF or PrRP decreases cortical excitability in rats through activation of NPFFRs. Furthermore, the NPFF1R is required for the NPFF‐induced decrease in cortical excitability.
Diagnosis and treatment of carpometacarpal desmopathy in a horse
Authors: Porter E. G. , Brokken M. T. , Holmes S. P.
Published: February 2015

A 9‐year‐old Warmblood gelding underwent magnetic resonance (MR) imaging of the carpal and proximal metacarpal regions for evaluation of prolonged right forelimb lameness. Magnetic resonance findings were indicative of desmopathy of the right lateral carpometacarpal ligament and the interosseous ligament between the third and fourth metacarpal bones. Based on the MR findings and lack of response to conservative therapy, surgery using a drilling technique was performed to facilitate fusion of the right carpometacarpal joint. After surgery and a 6‐month rest and rehabilitation programme, the horse returned to soundness. This case report describes a unique combination of lateral carpal/proximal metacarpal soft tissue injuries that resulted in prolonged lameness and were treated with facilitated arthrodesis of the carpometacarpal joint. These soft tissue injuries should be considered as a differential diagnosis in horses with lameness localised to the proximal metacarpal/distal carpal region.
Suture exostosis with concurrent nasal septum chondrosarcoma in a horse
Authors: Bonilla A. G. , Wilson K. , Santschi E. M.
Published: February 2015

A 15‐year‐old Hanoverian mare presented with a 10‐day history of facial swelling in the right maxillary and frontal regions, left epiphora and intermittent right epistaxis. Radiographs revealed suture exostosis of both nasofrontal sutures and a deviated and thickened nasal septum. Computed tomography (CT) of the skull revealed exostosis of the nasolacrimal sutures and ducts bilaterally of both nasofrontal sutures and of the right zygomatocomaxillary and lacrimomaxillary sutures. The mid‐to‐caudal aspect of the nasal septum was thickened and had multiple well demarcated hypoattenuated regions within the septum. Histological examination of biopsies taken from the right nasofrontal suture and the nasal septal mass revealed suture exostosis and nasal septum chondrosarcoma. The horse was treated with rest and anti‐inflammatories. The facial swelling and left epiphora were improved at 7 months telephone follow‐up. This report is the first to describe a nasal septum chondrosarcoma in a horse. Additionally, we suggest that the suture exostosis may have developed due to an alteration of the biomechanics of the skull sutures secondary to the septal tumour.
Treatment of a pulmonary granular cell tumour by repeated transendoscopic diode laser photoablation
Authors: Van Heesewijk N. , Knowles E. J. , Palgrave C. J. , Mair T. S.
Published: February 2015

A 27‐year‐old Shetland mare was examined for persistent coughing, increased respiratory rate and mild exercise intolerance. Over the previous 5 months, the mare had experienced a persistent cough nonresponsive to medical and environmental management. Upon endoscopic examination of the lower airways, a mass was seen within the left mainstem bronchus; biopsy identified a granular cell tumour. The tumour was successfully reduced by repeated transendoscopic diode laser photoablation over a period of 4 months with no evidence of recurrence at 10 months post treatment.
Structural and catalytic effects of proline substitution and surface loop deletion in the extended active site of human carbonic anhydrase II
Authors: Boone Christopher D. , Rasi Valerio , Tu Chingkuang , McKenna Robert
Published: February 2015

Bioengineering of a thermophilic enzyme starting from a mesophilic scaffold has proven to be a significant challenge, as several stabilizing elements have been proposed to be the foundation of thermal stability, including disulfide bridges, surface loop reduction, ionic pair networks, proline substitutions and aromatic clusters. This study emphasizes the effect of increasing the rigidity of human carbonic anhydrase II (HCA II; EC 4.2.1.1) via incorporation of proline residues at positions 170 and 234, which are located in surface loops that are able to accommodate restrictive main‐chain conformations without rearrangement of the surrounding peptide backbone. Additionally, the effect of the compactness of HCA II was examined by deletion of a surface loop (residues 230–240) that had been previously identified as a possible source of thermal stability for the hyperthermophilic carbonic anhydrase isolated from the bacterium Sulfurihydrogenibium yellowstonense YO3AOP1. Differential scanning calorimetry analysis of these HCA II variants revealed that these structural modifications had a minimum effect on the thermal stability of the enzyme, while kinetic studies showed unexpected effects on the catalytic efficiency and proton transfer rates. X‐ray crystallographic analysis of these HCA II variants showed that the electrostatic potential and configuration of the highly acidic loop (residues 230–240) play an important role in its high catalytic activity. Based on these observations and previous studies, a picture is emerging of the various components within the general structural architecture of HCA II that are key to stability. These elements may provide blueprints for rational thermal stability engineering of other enzymes.

Database

Structural data have been submitted to the Protein Data Bank under accession numbers 4QK1 (K170P), 4QK2 (E234P) and 4QK3 (Δ230—240).
Assessment of empirical formulas for prediction of the effects of projectile impact on concrete structures
Authors: Kosteski L. E. , Riera J. D. , Iturrioz I. , Singh R. K. , Kant T.
Published: February 2015

The prediction of the response of structures subjected to projectiles impact may often be accomplished by means of empirical or semi‐empirical formulas available in the technical literature, which address mainly cases of relevance in engineering practice in terms of the observed failure modes. The paper presents an evaluation of the performance of the equations most widely used in predictions of penetration, scabbing and perforation of concrete and rock structures by comparing the predicted results with experimentally observed response and with the results of detailed numerical analyses employing the truss‐like Discrete Element Method (DEM). Numerical DEM predictions were shown to be close to the experimentally determined responses of concrete plates subjected to impact throughout the range of velocities examined and were also consistent with the empirical formulas. In all cases the authors attempted to quantify the uncertainty inherent both in the predictions of empirical formulas and of the numerical analysis.
Non‐planar mixed‐mode growth of initially straight‐fronted surface cracks, in cylindrical bars under tension, torsion and bending, using the symmetric Galerkin boundary element method‐finite element method alternating method
Authors: Tian L. ‐G. , Dong L. ‐T. , Phan N. , Atluri S. N.
Published: February 2015

In this paper, the stress intensity factor (SIF) variations along an arbitrarily developing crack front, the non‐planar fatigue‐crack growth patterns, and the fatigue life of a round bar with an initially straight‐fronted surface crack, are studied by employing the 3D symmetric Galerkin boundary element method‐finite element method (SGBEM‐FEM) alternating method. Different loading cases, involving tension, bending and torsion of the bar, with different initial crack depths and different stress ratios in fatigue, are considered. By using the SGBEM‐FEM alternating method, the SIF variations along the evolving crack front are computed; the fatigue growth rates and directions of the non‐planar growths of the crack surface are predicted; the evolving fatigue‐crack growth patterns are simulated, and thus, the fatigue life estimations of the cracked round bar are made. The accuracy and reliability of the SGBEM‐FEM alternating method are verified by comparing the presently computed results to the empirical solutions of SIFs, as well as experimental data of fatigue crack growth, available in the open literature. It is shown that the current approach gives very accurate solutions of SIFs and simulations of fatigue crack growth during the entire crack propagation, with very little computational burden and human–labour cost. The characteristics of fatigue growth patterns of initially simple‐shaped cracks in the cylindrical bar under different Modes I, III and mixed‐mode types of loads are also discussed in detail.
Stable carbon isotope analysis reveals widespread drought stress in boreal black spruce forests
Authors: Walker Xanthe J. , Mack Michelle C. , Johnstone Jill F.
Published: February 2015

Unprecedented rates of climate warming over the past century have resulted in increased forest stress and mortality worldwide. Decreased tree growth in association with increasing temperatures is generally accepted as a signal of temperature‐induced drought stress. However, variations in tree growth alone do not reveal the physiological mechanisms behind recent changes in tree growth. Examining stable carbon isotope composition of tree rings in addition to tree growth can provide a secondary line of evidence for physiological drought stress. In this study, we examined patterns of black spruce growth and carbon isotopic composition in tree rings in response to climate warming and drying in the boreal forest of interior Alaska. We examined trees at three nested scales: landscape, toposequence, and a subsample of trees within the toposequence. At each scale, we studied the potential effects of differences in microclimate and moisture availability by sampling on northern and southern aspects. We found that black spruce radial growth responded negatively to monthly metrics of temperature at all examined scales, and we examined ∆13C responses on a subsample of trees as representative of the wider region. The negative ∆13C responses to temperature reveal that black spruce trees are experiencing moisture stress on both northern and southern aspects. Contrary to our expectations, ∆13C from trees on the northern aspect exhibited the strongest drought signal. Our results highlight the prominence of drought stress in the boreal forest of interior Alaska. We conclude that if temperatures continue to warm, we can expect drought‐induced productivity declines across large regions of the boreal forest, even for trees located in cool and moist landscape positions.
Testing local and global stressor impacts on a coastal foundation species using an ecologically realistic framework
Authors: Cheng Brian S. , Bible Jillian M. , Chang Andrew L. , Ferner Matthew C. , Wasson Kerstin , Zabin Chela J. , Latta Marilyn , Deck Anna , Todgham Anne E. , Grosholz Edwin D.
Published: February 2015

Despite the abundance of literature on organismal responses to multiple environmental stressors, most studies have not matched the timing of experimental manipulations with the temporal pattern of stressors in nature. We test the interactive effects of diel‐cycling hypoxia with both warming and decreased salinities using ecologically realistic exposures. Surprisingly, we found no evidence of negative synergistic effects on Olympia oyster growth; rather, we found only additive and opposing effects of hypoxia (detrimental) and warming (beneficial). We suspect that diel‐cycling provided a temporal refuge that allowed physiological compensation. We also tested for latent effects of warming and hypoxia to low‐salinity tolerance using a seasonal delay between stressor events. However, we did not find a latent effect, rather a threshold survival response to low salinity that was independent of early life‐history exposure to warming or hypoxia. The absence of synergism is likely the result of stressor treatments that mirror the natural timing of environmental stressors. We provide environmental context for laboratory experimental data by examining field time series environmental data from four North American west coast estuaries and find heterogeneous environmental signals that characterize each estuary, suggesting that the potential stressor exposure to oysters will drastically differ over moderate spatial scales. This heterogeneity implies that efforts to conserve and restore oysters will require an adaptive approach that incorporates knowledge of local conditions. We conclude that studies of multiple environmental stressors can be greatly improved by integrating ecologically realistic exposure and timing of stressors found in nature with organismal life‐history traits.
Plant and soil effects on bacterial communities associated with Miscanthus × giganteus rhizosphere and rhizomes
Authors: Li Dongfang , Voigt Thomas B. , Kent Angela D.
Published: February 2015

Bacterial assemblages, especially diazotroph assemblages residing in the rhizomes and the rhizosphere soil of Miscanthus × giganteus, contribute to plant growth and nitrogen use efficiency. However, the composition of these microbial communities has not been adequately explored nor have the potential ecological drivers for these communities been sufficiently studied. This knowledge is needed for understanding and potentially improving M. × giganteus – microbe interactions, and further enhancing sustainability of M. × giganteus production. In this study, cultivated M. × giganteus from four sites in Illinois, Kentucky, Nebraska, and New Jersey were collected to examine the relative influences of soil conditions and plant compartments on assembly of the M. × giganteus‐associated microbiome. Automated ribosomal intergenic spacer (ARISA) and terminal restriction fragment length polymorphism (T‐RFLP) targeting the nifH gene were applied to examine the total bacterial communities and diazotroph assemblages that reside in the rhizomes and the rhizosphere. Distinct microbial assemblages were detected in the endophytic and rhizosphere compartments. Site soil conditions had strong correlation with both total bacterial and diazotroph assemblages, but in different ways. Nitrogen treatments showed no significant effect on the composition of diazotroph assemblages in most sites. Endophytic compartments of different M. × giganteus plants tended to harbor similar microbial communities across all sites, whereas the rhizosphere soil of different plant tended to harbor diverse microbial assemblages that were distinct among sites. These observations offer insight into better understanding of the associative interactions between M. × giganteus and diazotrophs, and how this relationship is influenced by agronomic and edaphic factors.