bluuebunny/crossref_metadata_2025 huggingface dataset:
What is the influence of parents' myopia on their children's myopic progression? A 22‐year follow‐up study
Authors: Pärssinen Olavi , Kauppinen Markku
Published: April 2016

Purpose

To study the connection between parental myopia and their children's myopia from school age to adulthood.

Methods

Two hundred and forty myopic schoolchildren (119 boys, 121 girls, mean age 10.9 years) with no previous spectacles for myopia were recruited to a 3‐year treatment trial with different use of spectacles. Follow‐ups were performed at mean ages of 13.9, 23.7 and 33.2 years for 238, 176 and 170 subjects respectively. Subjective refraction was calibrated to the spherical equivalent at corneal level (SEcor). Corneal refractive power (CR) and axial length (AL) were measured. Parental myopia was assessed with a questionnaire and the children assigned accordingly to one of three hereditary groups: both parents myopic H++, one myopic parent = H+− and no myopic parents = H−.

Results

At baseline, no significant gender differences in age or SEcor were found in the different hereditary groups. Among girls, CR was significantly higher in hereditary group H++ (45.20 ± 1.08 D) than in group H+− (44.19 ± 1.28 D; p = 0.006) or H– (43.84 ± 1.18 D; p < 0.001). Among boys, the differences in CR between the hereditary groups were smaller and significant at follow‐up 2 only. At follow‐up end, among males, no significant differences between the hereditary groups were found in SEcor, CR, AL or myopic progression. Among females, myopic progression was 4.21 ± 1.81 D if one or both parents were myopic and −3.19 ± 1.36 D if neither parent was myopic (p = 0.035), but no significant difference was observed in AL.

Conclusions

The main difference between the hereditary groups was higher CR and myopic progression among females with myopic parents than non‐myopic parents, but with no significant difference in AL with respect to parental myopia at study end.
Chronic nonbacterial osteomyelitis may be associated with renal disease and bisphosphonates are a good option for the majority of patients
Authors: Pastore Serena , Ferrara Giovanna , Monasta Lorenzo , Meini Antonella , Cattalini Marco , Martino Silvana , Alessio Maria , Torre Francesco La , Teruzzi Barbara , Gerloni Valeria , Breda Luciana , Taddio Andrea , Lepore Loredana
Published: April 2016

Aim

The aim of this Italian study was to describe the clinical features, treatment options and outcomes of a cohort of patients with chronic nonbacterial osteomyelitis (CNO).

Methods

This was a retrospective cohort study. Laboratory data, diagnostic imaging, histological features and clinical course are reported.

Results

We enrolled 47 patients diagnosed with CNO. Bone pain was the leading symptom, and multifocal disease was present in 87% of the patients. The majority of the bone lesions were located in the appendicular skeleton (58%). Extraosseous manifestations were present in 34% of the patients, and renal involvement was detected in four patients. Inflammatory indices were increased in 80%, and bone x‐rays were negative in 15% of the patients. Nonsteroidal anti‐inflammatory drugs (NSAIDs) were the first therapy for all patients, achieving clinical remission in 27%. A good response to NSAIDs was significantly associated with a better prognosis. Bisphosphonates were used in 26 patients, with remission in 73%. Only six patients (13%), all with spine involvement, developed sequelae.

Conclusion

We found a possible association between CNO and renal disease. Bisphosphonates were more likely to lead to clinical remission when NSAIDs and corticosteroids had failed. Vertebral localisation was the only risk factor for potential sequelae.
Multiple and bilateral kidney tumors with clear cells of three different histotypes: A case report with clinicopathologic and molecular study
Authors: Raspollini Maria Rosaria , Castiglione Francesca , Martignoni Guido , Lapini Alberto , Cheng Liang , Montironi Rodolfo , Lopez‐Beltran Antonio
Published: April 2016

We describe a rare multicentric neoplastic disease arising bilteraly in the kidney. The patient was a 70‐year‐old man, who, during a period of 3 years, was treated for five independent tumors of three histotypes (three multilocular cystic clear cell renal cell neoplasms of low malignant potential, one clear cell renal cell carcinoma, and one clear cell papillary renal cell carcinoma, respectively). Pathologic diagnosis of the reported tumors was confirmed by immunohistochemical analyses, including CD10, CA IX, CK7, AMACR/RACEMASE, and 34 beta E12. Molecular detection of KRAS, BRAF, NRAS, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET, and EGFR gene mutational analysis was also performed in all tumors.
Hepatic venous outflow tract obstruction: treatment outcomes and development of a new prognostic score
Authors: Shalimar  , Kumar A. , Kedia S. , Sharma H. , Gamanagatti S. R. , Gulati G. S. , Nayak B. , Thakur B. , Acharya S. K.
Published: April 2016

Background

Results of endovascular interventions in hepatic venous outflow tract obstruction (HVOTO) have been reported from limited studies. Treatment outcomes and prognostic scores need further validation.

Aim

To evaluate treatment outcomes and prognostic scores for hepatic venous outflow tract obstruction in an Indian population.

Methods

Consecutive patients with hepatic venous outflow tract obstruction diagnosed at a tertiary centre were included. Technical success and clinical response after endovascular interventional therapy were documented. Predictors of survival were assessed with Cox‐proportional model. A new score was derived from the factors significant on multivariate analysis and compared with Child–Turcotte–Pugh, model for end‐stage liver disease (MELD), Rotterdam prognostic index (PI) and Budd‐Chiari syndrome‐transjugular intrahepatic portosystemic shunt ( BCS‐TIPSS) PI.

Results

Three hundred and thirty‐four patients (56.6% males), median age 24 (3–62) years were included. Hepatic vein was the commonest site of block‐isolated hepatic vonous block in 48%, combined hepatic venous‐inferior vena cava block in 46%. Endovascular interventional therapy was performed in 233/334 (70%) with 90% technical success. Clinical response was complete in 166 (71.2%), partial in 58 (24.9%) and no response in nine (3.9%). Majority of cases with HV block did not require TIPSS and could be treated with angioplasty (with/without stenting). On Cox‐proportional multivariate analysis, Child class C and response to intervention were independent predictors of outcome and used to derive the All India Institute of Medical Sciences (AIIMS) hepatic venous outflow tract obstruction score. The 5‐year survival was 92% (95% CI, 81–97%) for score ≤3, 79% (95%CI, 63–88%) for score >3 and ≤4, and 39% (95% CI, 21–57%) for score >4. The performance of AIIMS hepatic venous outflow obstruction score was superior to other prognostic indices.

Conclusions

Advanced Child class and no response to intervention are associated with poor outcomes. The All India Institute of Medical Sciences hepatic venous outflow tract obstruction score predicts survival better than other prognostic scores.
Review article: emerging anti‐fibrotic therapies in the treatment of non‐alcoholic steatohepatitis
Authors: Noureddin M. , Anstee Q. M. , Loomba R.
Published: April 2016

Background

Non‐alcoholic fatty liver disease (NAFLD) can lead to non‐alcoholic steatohepatitis (NASH) and cirrhosis. Fibrosis predicts worse outcomes and mortality. New treatments targeting fibrosis are being investigated to reverse disease progression.

Aim

To review the new pipeline therapeutic agents targeting fibrosis in NASH patients, with particular focus on clinical trials in which reversing fibrosis and portal hypertension are the primary outcomes.

Methods

The literature was searched in PubMed between January 2000 and January 2016 using search terms non‐alcoholic fatty liver disease and NASH, with filters of ‘English language’. We focused on fibrosis improvement as the key outcome. We also searched the ClinicalTrials.gov for promising agents that target fibrosis in NASH patients.

Results

Significant advances have been made on approaches targeting fibrosis in NASH patients. Many therapeutic agents are already in development, some of which have shown promising results in preclinical and phase I studies. Novel therapies have entered phase II and III studies targeting fibrosis reversal and/or improvement in portal hypertension. Innovative studies have also started looking into combining these agents, aiming at different mechanisms to maximise therapeutic outcomes. We found five clinical trials in phase II and one in phase III focusing on fibrosis in NASH patients as key outcomes. One of the phase II trials is using combination therapy to target fibrosis.

Conclusions

Ongoing research studies are already investigating new pathways aimed at reversing fibrosis in NASH patients. Novel therapeutic agents are in development and are expected to offer unique options to NASH patients with advanced fibrosis.
Nested case–control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance
Authors: Gounder P. P. , Bulkow L. R. , Snowball M. , Negus S. , Spradling P. R. , Simons B. C. , McMahon B. J.
Published: April 2016

Background

Hepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear.

Aim

To compare HCC risk between Alaska Native (AN) patients with and without hepatitis B surface antigen (HBsAg) seroclearance.

Methods

We selected persons with (case‐patients) and without (control‐patients) HBsAg seroclearance from a cohort of 1346 chronically HBV‐infected AN patients followed during 1982‒2013. We attempted to match two control‐patients/case‐patient on sex, HBV genotype, and age. Person‐years of follow‐up for case‐patients began on the date of HBsAg resolution and for control‐patients began on the date equivalent to the cohort entry date plus the years of HBsAg duration for their corresponding case‐patient. We compared HCC risk using a Cox proportional hazards model.

Results

The 238 case‐patients (4 with HCC) and 435 control‐patients (9 with HCC) were similar in age [P‐value (P) = 0.30], sex (P = 0.53) and HBV genotype (P = 0.99). Case‐patients had longer person‐years of follow‐up than control‐patients (11.7 vs. 10.1 years; P = 0.04). The HCC rate/100 000 persons was similar between case‐ (132) and control‐patients (178; P = 0.65). The adjusted hazard ratio comparing case‐ and control‐patients was similar for HCC [0.7; 95% confidence interval (CI): 0.2–2.4], increased for each 1‐year increment for age (1.1; CI: 1.0–1.1; P < 0.01), and was greater if the initial HBeAg was positive (3.5; CI: 1.1–11.0; P = 0.03).

Conclusions

Hepatitis B surface antigen seroclearance was not associated with reduced HCC risk; the HCC risk estimates are limited by wide 95% confidence intervals. Persons meeting HCC surveillance indications prior to HBsAg seroclearance could benefit from continued surveillance after seroclearance.
Prescribing pattern of antipsychotic drugs during the years 1996–2010: a population‐based database study in Europe with a focus on torsadogenic drugs
Authors: Oteri Alessandro , Mazzaglia Giampiero , Pecchioli Serena , Molokhia Mariam , Ulrichsen Sinna Pilgaard , Pedersen Lars , Poluzzi Elisabetta , De Ponti Fabrizio , Garbe Edeltraut , Schink Tania , Herings Ron , Bezemer Irene D. , Sturkenboom Miriam C. J. M. , Trifirò Gianluca
Published: April 2016

Introduction

Antipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs.

Aim

The aim of the current study was to evaluate the use of APDs in five European countries during the years 1996–2010.

Methods

A cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals.

The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona‐CERT list. All analyses were stratified by age, gender and calendar year.

Results

A total of 559 276 person‐years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients.

Conclusions

Substantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.
Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson's disease
Authors: Renoux Christel , Dell'Aniello Sophie , Khairy Paul , Marras Connie , Bugden Shawn , Turin Tanvir Chowdhury , Blais Lucie , Tamim Hala , Evans Charity , Steele Russell , Dormuth Colin , Ernst Pierre ,   the Canadian Network for Observational Drug Effect Studies (CNODES) investigators
Published: April 2016

Aim

Domperidone is preferentially used over other antiemetic agents to treat digestive symptoms in Parkinson's disease (PD). Concerns have been raised regarding an increased risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD) associated with domperidone in the general population. However, the risk in PD is unknown.

Methods

We conducted a multicentre retrospective cohort study using administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink. Using a nested case–control analysis, we estimated the rate ratios (RRs) of VT/SCD associated with domperidone use compared to no use in patients newly‐diagnosed with PD. VT/SCD events were identified using administrative medical records and vital statistics with a manual review of all potential cases. Meta‐analytic methods were used to estimate overall effects across sites.

Results

Among 214 962 patients with PD, 2907 cases of VT/SCD were identified during 886 581 person‐years of follow‐up (incidence rate 3.28 per 1000 persons per year). Current use of domperidone was associated with a non‐statistically significant 22% increased risk of VT/SCD (RR 1.22; 95% CI 0.99–1.50) compared with no use. The risk was significantly elevated in those with a history of cardiovascular disease (RR 1.38; 95% CI 1.07–1.78), but not in those without (RR 1.21; 95% CI 0.81–1.81). Dose and duration of use did not affect the magnitude of the risk.

Conclusion

Domperidone use may increase the risk of VT/SCD in patients with PD, particularly those with a history of cardiovascular disease. This risk may be underestimated because of imprecision in identifying VT/SCD events.
COMPARE: Pharmacokinetic profiles of subcutaneous peginterferon beta‐1a and subcutaneous interferon beta‐1a over 2 weeks in healthy subjects
Authors: Hu Xiao , Shang Shulian , Nestorov Ivan , Hasan Jawad , Seddighzadeh Ali , Dawson Katherine , Sperling Bjørn , Werneburg Brian
Published: April 2016

Aim

Subcutaneous (s.c.) peginterferon beta‐1a injected once every 2 weeks and s.c. interferon beta‐1a injected three times per week (Rebif®) have demonstrated efficacy in relapsing–remitting multiple sclerosis, but direct comparisons of pharmacological activity and tolerability between the two products are lacking. COMPARE was an open label, crossover, pharmacokinetic (PK) study evaluating drug exposure and the safety and tolerability of s.c. peginterferon beta‐1a and s.c. interferon beta‐1a, over 2 weeks in healthy subjects.

Methods

Thirty healthy subjects received one dose of peginterferon beta‐1a (125 μg s.c.) or six doses of interferon beta‐1a (44 μg s.c.) over 2 weeks, followed by the alternate treatment after a 2 week washout period. Drug concentrations were measured using an enzyme‐linked immunosorbent assay (ELISA) and PK parameters including cumulative area under the concentration–time curve (AUC0‐336h) over 2 weeks and maximum observed serum concentrations (Cmax) were estimated using a non‐compartmental analysis.

Results

The PK analysis population comprised 26 subjects for each treatment. Drug exposure (AUC0‐336h) was 60% higher with s.c. peginterferon than with s.c. interferon beta‐1a (117.4 ng ml−1h, 95% confidence interval 95.6, 144.3 vs. 73.1 ng ml−1 h, 95% confidence interval 61.2, 87.3, respectively; P < 0.0001). Injection‐site reactions (ISRs) were the most common adverse events (AEs) observed with both treatments. Numerically lower frequencies and incidence rates of ISRs, headache, myalgia and chills were observed with s.c. peginterferon beta‐1a.

Conclusions

One dose of s.c. peginterferon delivered significantly greater drug exposure than s.c. interferon beta‐1a three times a week over 2 weeks, and a lower frequency of AEs.
High prevalence of risk factors in elderly patients using drugs associated with acquired torsades de pointes chronically in Colombia
Authors: Moreno‐Gutiérrez Paula Andrea , Gaviria‐Mendoza Andrés , Cañón Mauricio Montoya , Machado‐Alba Jorge Enrique
Published: April 2016

Aims

Medication is one of the main causes of long QT syndrome (LQTS) and torsades de pointes (TdP), and the older adult population is at particularly high risk. The aim of the present study was to describe the prescription patterns of drugs with a risk of TdP in the Colombian older adult population.

Methods

Patients older than 65 years who received medication with a risk of TdP during three consecutive months were selected. The medication was obtained and classified according to the QT Drug List from Crediblemeds.org. The data were analysed using SPSS‐22.

Results

A total of 55 932 patients were chronically receiving QT‐prolonging drugs; 61.9% (n = 34 ,632) were women and the mean age of the sample was 75.6 years. Drugs with a conditional risk were consumed by 95.2% of patients, 5.3% received drugs with a known risk and 2.9% received drugs with a possible risk. Two or more QT‐prolonging drugs were consumed by 10.3% of the patients (n = 5786). Most of the sample (96.8%, n = 54 170) had at least one additional risk factor for LQTS, with a mean of 3.1 ± 0.9 risk factors. Patients receiving QT‐prolonging drugs for psychiatric and neurological disease were at a higher risk of major polypharmacy [odds ratio (OR) 3.0; 95% confidence interval (CI) 2.80, 3.22) and of receiving high doses of QT‐prolonging drugs (OR 3.8; 95% CI 3.52, 4.05).

Conclusions

The widespread use of medication that causes TdP and the high prevalence of additional risks in the older adult population raise the need for accurate prediction of risk and constant patient monitoring. Patients taking psychiatric drugs are at a higher risk of TdP.
Measurement of Rhodamine 123 in Three‐Dimensional Organoids: A Novel Model for P‐Glycoprotein Inhibitor Screening
Authors: Zhang Yuanjin , Zeng Zhiyang , Zhao Junfang , Li Dali , Liu Mingyao , Wang Xin
Published: April 2016

P‐glycoprotein (P‐gp), as the most important efflux transporter in intestines, plays the key role to determine the bioavailability of many drugs. The three‐dimensional (3D) organoid model is suitable to imitate small intestinal epithelium. In this study, a rapid, sensitive and efficient method to measure rhodamine 123 (Rh123, P‐gp substrate) in 3D organoids was developed to analyse P‐gp‐mediated drug transport. Ultrasonic cell disruptor was used to smash the organoid, and automatic microplate reader was used for detecting the concentration of Rh123 (λex/λem= 485/520 nm). Moreover, verapamil, quinidine and mitotane were used to make validation about this newly developed approach. All three P‐gp inhibitors significantly inhibited the transport of Rh123 into 3D organoids. Therefore, the above‐mentioned method could serve as a new model for P‐gp inhibitor screening in a high‐throughput way.
Agmatine Reverses Sub‐chronic Stress induced Nod‐like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats
Authors: Sahin Ceren , Albayrak Ozgur , Akdeniz Tuğba F. , Akbulut Zeynep , Yanikkaya Demirel Gulderen , Aricioglu Feyza
Published: April 2016

The activation of Nod‐like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)‐1β and IL‐18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant‐like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down‐regulated the gene expressions of all stress‐induced NLRP3 inflammasome components (NLRP3, NF‐κB, PYCARD, caspase‐1, IL‐1β and IL‐18) in the hippocampus and prefrontal cortex (PFC) and reduced pro‐inflammatory cytokine levels not only in both brain regions, but also in serum. Stress‐reduced levels of IL‐4 and IL‐10, two major anti‐inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress‐activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant‐like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.
TERT rs2736100 A>C SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms – a multicentric study on 529 patients
Authors: Trifa Adrian P. , Bănescu Claudia , Tevet Mihaela , Bojan Anca , Dima Delia , Urian Laura , Török‐Vistai Tünde , Popov Viola M. , Zdrenghea Mihnea , Petrov Ljubomir , Vasilache Anca , Murat Meilin , Georgescu Daniela , Popescu Mihaela , Pătrinoiu Oana , Balea Marius , Costache Roxana , Coleș Elena , Șaguna Carmen , Berbec Nicoleta , Vlădăreanu Ana‐Maria , Mihăilă Romeo G. , Bumbea Horia , Cucuianu Andrei , Popp Radu A.
Published: April 2016

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) represent typical myeloproliferative neoplasms (MPN), usually characterized by specific somatic driver mutations (JAK2 V617F, CALR and MPL). JAK2 46/1 haplotype and telomerase reverse transcriptase gene (TERT) rs2736100 A>C single nucleotide polymorphism (SNP) could represent a large fraction of the genetic predisposition seen in MPN. The rs10974944 C>G SNP, tagging the JAK2 46/1 haplotype, and the TERT rs2736100 A>C SNP were genotyped in 529 MPN patients with known JAK2 V617F, CALR and MPL status, and 433 controls. JAK2 46/1 haplotype strongly correlated to JAK2 V617F‐positive MPN and, to a lesser extent, CALR‐positive MPN. The TERT rs2736100 A>C SNP strongly correlated to all MPN, regardless of the phenotype (PV, ET or PMF) and major molecular subtype (JAK2 V617F‐ or CALR‐positive). While both variants have a significant contribution, they have nuanced consequences, with JAK2 46/1 predisposing essentially to JAK2 V617F‐positive MPN, and TERT rs2736100 A>C having a more general, non‐specific effect on all MPN, regardless of phenotype or major molecular subtype.
Sphingosine‐1‐phosphate receptor 1 as a prognostic biomarker and therapeutic target for patients with primary testicular diffuse large B‐cell lymphoma
Authors: Koresawa Risa , Yamazaki Kazuto , Oka Daigo , Fujiwara Hideyo , Nishimura Hirotake , Akiyama Takashi , Hamasaki Shuji , Wada Hideho , Sugihara Takashi , Sadahira Yoshito
Published: April 2016

Sphingosine‐1‐phosphate (S1P) is a potent lipid mediator that is produced during the metabolism of sphingolipid by sphingosine kinase. S1P has been implicated in the migration and trafficking of lymphocytes and several lymphoid malignancies through S1P receptors. Moreover, the overexpression of sphingosine‐1‐phosphate receptor 1 (S1PR1) has been correlated with the constitutive activation of signal transducer and activator of transcription (STAT)3 and poor prognosis of diffuse large B‐cell lymphoma (DLBCL). Thus, in this study, we examined the expression of S1PR1 in 198 DLBCL samples collected from nodal and various extranodal sites and sub‐classified formalin‐fixed paraffin‐embedded tissue samples into germinal centre B‐cell‐like (GCB) and non‐GCB subgroups using immunohistochemistry. These analyses showed S1PR1 overexpression in 15·7% of all cases with DLBCL and in 54·2% of 24 cases with primary testicular (PT)‐DLBCL; S1PR1 expression correlated with S1PR1mRNA expression and STAT3 phosphorylation in fresh samples. Analyses of data from a single institution suggested that S1PR1 overexpression was an independent negative prognostic marker in 68 patients with DLBCL of clinical stages I and II. The present high prevalence of S1PR1 overexpression warrants the consideration of PT‐DLBCL as a distinct disease subtype and suggests the potential of the S1P/S1PR1 axis as a therapeutic target.
Interplay between the kinin B1 receptor and inducible nitric oxide synthase in insulin resistance
Authors: Haddad Youssef , Couture Réjean
Published: April 2016

Background and Purpose

Kinins are vasoactive and pro‐inflammatory peptides whose biological effects are mediated by two GPCRs, named B1 and B2 receptors. While the B2 receptor plays a protective role in the cardiovascular system via the activation of endothelial NOS, the B1 receptor is associated with vascular inflammation, insulin resistance and diabetic complications. Because the B1 receptor is a potent activator of the inducible form of NOS (iNOS), this study has addressed the role of iNOS in the deleterious effects of B1 receptors in insulin resistance.

Experimental Approach

Male Sprague–Dawley rats (50–75 g) had free access to a drinking solution containing 10% d‐glucose or tap water (control) for 9 weeks. During the last week, a selective iNOS inhibitor (1400W, 1 mg·kg−1 twice daily) or its vehicle was administered s.c.

Key Results

Prolonged glucose treatment caused insulin resistance and several hallmarks of type 2 diabetes. Whereas the treatment with 1400W had no impact on the elevated systolic blood pressure and leptin levels in glucose‐fed rats, it significantly reversed or attenuated hyperglycaemia, hyperinsulinaemia, insulin resistance (HOMA index), body weight gain, peroxynitrite formation (nitrotyrosine expression) and the up‐regulation of biomarkers of inflammation (B1 receptor, carboxypeptidase M, iNOS and IL‐1β) in renal cortex and aorta and to some extent in the liver.

Conclusions and Implications

Pharmacological blockade of iNOS prevents the formation of peroxynitrite, which amplifies the pro‐inflammatory effects of B1 receptors through a positive feedback mechanism. Hence, targeting iNOS can prevent the deleterious effects of B1 receptors in insulin resistance and peripheral inflammation.
Permian exhumation of the Montagne Noire core complex recorded in the Graissessac‐Lodève Basin, France
Authors: Pfeifer Lily S. , Soreghan Gerilyn S. , Pochat Stéphane , Van Den Driessche Jean , Thomson Stuart N.
Published: April 2016

The paleogeographic reconstruction of the Variscan Mountains during late Carboniferous‐Permian post‐orogenic extension remains poorly understood, owing to the subsequent erosion and/or burial of most associated sedimentary basins during the Mesozoic. The Graissessac‐Lodève Basin (southern France) preserves a thick and exceptionally complete record of continental sedimentation spanning late Carboniferous through late Permian time. This section records the localized tectonic and paleogeographic evolution of southern France in the context of the low‐latitude Variscan Belt of Western Europe. This study presents new detrital zircon and framework mineralogy data that address the provenance of siliciclastic strata exposed in the basin. The ages and compositions of units that constitute the Montagne Noire metamorphic core complex (west of the basin) dictate the detrital zircon age populations and sandstone compositions in Permian strata, recording rapid exhumation and unroofing of the Montagne Noire dome. Cambrian‐Archean zircons and metamorphic lithic‐rich compositions record derivation from recycled detritus of the earliest Paleozoic sedimentary cover and Neoproterozoic‐early Cambrian metasedimentary Schistes X, which formerly covered the Montagne Noire dome. Ordovician zircons and subarkosic framework compositions indicate erosion of orthogneiss units that formed a large part of the dome. The youngest zircon population (320–285 Ma) reflects derivation from late Carboniferous‐early Permian granite units in the axial zone of the Montagne Noire. This population appears first in the early Permian, persists throughout the Permian section and is accompanied by sandstone compositions dominated by feldspar, polycrystalline quartz and metamorphic lithic fragments. The most recent migmatization, magmatism and deformation occurred ca. 298 ± 2 Ma, at ca. 17 km depth (based on peak metamorphic conditions). Accordingly, these new provenance data, together with zircon fission‐track thermochronology, demonstrate that exhumation of the Montagne Noire core complex was rapid (1–17 mm year−1) and early (300–285 Ma), reflecting deep‐seated uplift in the southern Massif Central during post‐orogenic extension.
Using detrital zircon U‐Pb ages to calculate Late Cretaceous sedimentation rates in the Magallanes‐Austral basin, Patagonia
Authors: Schwartz Theresa M. , Fosdick Julie C. , Graham Stephan A.
Published: April 2016

Determining both short‐ and long‐term sedimentation rates is becoming increasingly important in geomorphic (exhumation and sediment flux), structural (subsidence/flexure) and natural resource (predictive modelling) studies. Determining sedimentation rates for ancient sedimentary sequences is often hampered by poor understanding of stratigraphic architecture, long‐term variability in large‐scale sediment dispersal patterns and inconsistent availability of absolute age data. Uranium–Lead (U‐Pb) detrital zircon (DZ) geochronology is not only a popular method to determine the provenance of siliciclastic sedimentary rocks but also helps delimit the age of sedimentary sequences, especially in basins associated with protracted volcanism. This study assesses the reliability of U‐Pb DZ ages as proxies for depositional ages of Upper Cretaceous strata in the Magallanes‐Austral retroarc foreland basin of Patagonia. Progressive younging of maximum depositional ages (MDAs) calculated from young zircon populations in the Upper Cretaceous Dorotea Formation suggests that the MDAs are potential proxies for absolute age, and constrain the age of the Dorotea Formation to be ca. 82–69 Ma. Even if the MDAs do not truly represent ages of contemporaneous volcanic eruptions in the arc, they may still indicate progressive‐but‐lagged delivery of increasingly younger volcanogenic zircon to the basin. In this case, MDAs may still be a means to determine long‐term (≥1–2 Myr) average sedimentation rates. Burial history models built using the MDAs reveal high aggradation rates during an initial, deep‐marine phase of the basin. As the basin shoaled to shelfal depths, aggradation rates decreased significantly and were outpaced by progradation of the deposystem. This transition is likely linked to eastward propagation of the Magallanes fold‐thrust belt during Campanian‐Maastrichtian time, and demonstrates the influence of predecessor basin history on foreland basin dynamics.
Hill function‐based models of transcriptional switches: impact of specific, nonspecific, functional and nonfunctional binding
Authors: Bottani Samuel , Veitia Reiner A.
Published: April 2016

We explore minimalist models of transcription in which we take into account that a cis‐regulatory sequence is embedded in, and interacts with, a complex genome. The classical Hill equation is the simplest way to represent a transcriptional response. However, it may overlook the fact that a transcription factor (TF) establishes specific and nonspecific nonfunctional interactions with chromatin. Classical papers have shown that nonfunctional binding (not leading to transcription) may influence gene expression. We examine how the presence of additional binding sites for a TF, besides those on the gene(s) of interest, affect the shape and parameters of the transcriptional response. We consider two conditions: at equilibrium and at steady‐state. In many cases the TF level is determined by the position of the cell within a spatial or temporal gradient. We show that such gradients can be adjusted by evolutionary selection to compensate for the alteration of the gene transcription response by the presence of nonfunctional binding sites. Finally, we analyse how the transcriptional response is affected by a decrease in TF concentration, as in cases of haploinsufficiency. We show that the nonlinearity of the transcriptional response as a function of [TF] exacerbates the effect of a decrease in the latter, at least for weakly expressed TFs. Although decades of work on TFs have led to the impression that almost everything is known about the control of gene expression, we show that even the simplest models of transcription control have not delivered all their secrets yet.
Fault bars in bird feathers: mechanisms, and ecological and evolutionary causes and consequences
Authors: Jovani Roger , Rohwer Sievert
Published: April 2016

Fault bars are narrow malformations in feathers oriented almost perpendicular to the rachis where the feather vein and even the rachis may break. Breaks in the barbs and barbules result in small pieces of the feather vein being lost, while breaks in the rachis result in loss of the distal portion of the feather. Here, we provide a comprehensive review of 74 papers on fault bar formation in hopes of providing a clearer approach to their study. First, we review the evidence that the propensity to develop fault bars is modified by natural selection. Given that fault bars persist in the face of survival costs, we conclude that they must be an unfortunate consequence of some alternative adaptation that outweighs the fitness costs of fault bars. Second, we summarize evidence that the development of fault bars is triggered by psychological stress such as that of handling or predation attempts, and that they persist because the sudden contractions of the muscles in the feather follicle that control fright moults also causes the development of fault bars in growing feathers. Third, we review external and physiological (e.g. corticosterone) agents that may affect the likelihood that an acute stress will result in a growing feather exhibiting a fault bar. These modifying factors have often been treated as fundamental causes in the earlier literature on fault bars. Fourth, we then use this classification to propose a tentative model where fault bars of different severity (from light to severe) are the outcome of the interaction between the propensity to produce fault bars (which differs between species, individuals and feather follicles within individuals) and the intensity of the perturbation. This model helps to explain contradictory results in the literature, to identify gaps in our knowledge, and to suggest further studies. Lastly, we discuss ways in which better understanding of fault bars can inform us about other aspects of avian evolutionary ecology, such as the physiology of moult, the integration of moult into avian life cycles, and the strategies used to minimize stress during moult. Moreover, the study of fault bars may be relevant to understanding the aerodynamics of flight and the early evolution of flight.
The early Eocene birds of the Messel fossil site: a 48 million‐year‐old bird community adds a temporal perspective to the evolution of tropical avifaunas
Authors: Mayr Gerald
Published: April 2016

Birds play an important role in studies addressing the diversity and species richness of tropical ecosystems, but because of the poor avian fossil record in all extant tropical regions, a temporal perspective is mainly provided by divergence dates derived from calibrated molecular analyses. Tropical ecosystems were, however, widespread in the Northern Hemisphere during the early Cenozoic, and the early Eocene German fossil site Messel in particular has yielded a rich avian fossil record. The Messel avifauna is characterized by a considerable number of flightless birds, as well as a high diversity of aerial insectivores and the absence of large arboreal birds. With about 70 currently known species in 42 named genus‐level and at least 39 family‐level taxa, it approaches extant tropical biotas in terms of species richness and taxonomic diversity. With regard to its taxonomic composition and presumed ecological characteristics, the Messel avifauna is more similar to the Neotropics, Madagascar, and New Guinea than to tropical forests in continental Africa and Asia. Because the former regions were geographically isolated during most of the Cenozoic, their characteristics may be due to the absence of biotic factors, especially those related to the diversification of placental mammals, which impacted tropical avifaunas in Africa and Asia. The crown groups of most avian taxa that already existed in early Eocene forests are species‐poor. This does not support the hypothesis that the antiquity of tropical ecosystems is key to the diversity of tropical avifaunas, and suggests that high diversification rates may be of greater significance.
Producing anxiety in the neoliberal university
Authors: Berg Lawrence D. , Huijbens Edward H. , Larsen Henrik Gutzon
Published: April 2016

Key Messages

This article investigates processes of neoliberalization of the academy.

It argues that neoliberalism entails shifts from exchange to competition, from equality to inequality, and turns academics into human capital.

It suggests that auditing systems are key mechanisms of neoliberalization that produce unhealthy levels of anxiety and stress in the academy.
A school consultation intervention for adolescents with ADHD: barriers and implementation strategies
Authors: Sibley Margaret H. , Olson Sandra , Morley Candance , Campez Mileini , Pelham William E.
Published: April 2016

Background

Academic impairment is among the most troubling domains of impairment for adolescents with Attention Deficit/Hyperactivity Disorder (ADHD).

Method

This investigation presents results of a yearlong academic intervention delivered to adolescents with ADHD (N = 218) by engaging school staff as interventionists through behavioral consultation with an outside mental health professional.

Results

The intervention was coordinated successfully in some cases, but not in others. The principal challenge to intervention coordination was sustaining monthly contact between consultants and interventionists (38.5% success rate) and scheduling in‐person consultation meetings with interventionists (40.0% success rate). Implementation of the intervention was enhanced when the student (a) attended a public (vs. private) school, (b) had an IEP or Section 504 plan in place, (c) was in middle school (vs. high school), (d) had a parent who communicated regularly with the school, and (e) had a special education support staff member or counselor (vs. teacher or administrator) as a school interventionist.

Conclusions

Considering these data, recommendations are provided for effective coordination of academic interventions for adolescents with ADHD.
Design, Synthesis, and Biological Evaluation of a Novel Water‐soluble Prodrug of Docetaxel with Amino Acid as a Linker
Authors: Ma Huan , Chen Gang , Wang Tao , Li Qingeng , Liu Yan
Published: April 2016

The synthesis and preliminary evaluation of derivatives of docetaxel with novel amino acid as a linker named as LK‐193˜LK‐196 was described. The C2′‐modified compound LK‐196 behaves as a prodrug; that is, docetaxel is generated upon exposure to human plasma. The compound was also found to have greatly improved water solubility. The pharmacodynamic results showed LK‐196 had the self‐evident inhibitory effect on tumor growth in vivo, which is a promising candidate for further biological evaluation.
Enhanced Loading and Release of Non‐Steroidal Anti‐Inflammatory Drugs from Silica‐Based Nanoparticle Carriers
Authors: Mohammadzadeh Mostafa , Nourbakhsh Mohammad Sadegh , Khodaverdi Elham , Hadizadeh Farzin , Omid Malayeri Sina
Published: April 2016

Silica nanoparticles can be potentially considered the carriers of controlled drug systems. In this research, non‐steroidal anti‐inflammatory drugs were used. Diclofenac sodium and piroxicam were loaded on the considered nanosilica using solvent evaporation method. To prove drug encapsulation on the nanosilica and its rate, infrared spectroscopy, X‐ray diffraction, and BET were used, and after proving the existence of the drug in the nanosilica matrix and determining the amount of loading, dissolution test was performed in an environment similar to that of stomach and intestine in terms of pH. Drug loading percentage showed that over 90% of drugs were loaded on nanosilica. Dissolution tests in stomach pH environment showed the control samples (drug without SBA‐15) released considerable amount of drugs (about 90%) within first 15 min, when it was about 10–20% for the matrixes. Furthermore, release rate of drugs from matrixes has shown slower rate in comparison with control samples. It was indicated nanosilica has the ability of retaining the drugs in acidic pH and prevented their release. Furthermore, the drugs were released in a controlled manner in small intestine, which is the main absorption site.
Design, synthesis, and biological evaluation of novel 5‐Alkyl‐6‐Adamantylmethylpyrimidin‐4(3H)‐ones as HIV‐1 non‐nucleoside reverse‐transcriptase inhibitors
Authors: Li Wenxin , Huang Boshi , Kang Dongwei , De Clercq Erik , Daelemans Dirk , Pannecouque Christophe , Zhan Peng , Liu Xinyong
Published: April 2016

A series of novel 5‐alkyl‐6‐Adamantylmethylpyrimidin‐4(3H)‐ones bearing various substituents at the C‐2 position of the pyrimidinone ring were synthesized using a facile route and evaluated for their anti‐HIV activity in MT‐4 cells. The biological results demonstrated that the majority of the newly designed compounds possessed moderate efficiency in inhibiting the replication of the wild‐type (WT) HIV‐1 strain (IIIB) with EC50 values in the range from 0.10 to 5.39 μm. Among them, 5b1 and 5b3 proved to be the two most active inhibitors against WT HIV‐1 with EC50 values of 0.10 and 0.12 μm, respectively, which were more active than nevirapine (NVP) in the same assay. In addition, HIV‐1 reverse‐transcriptase (RT) inhibition assay indicated that the representative compound 5b1 showed affinity to WT HIV‐1 RT, and inhibited the activity of RT with an IC50 value superior to the reference drug NVP. Moreover, the preliminary structure–activity relationship (SAR) and the molecular modeling analysis of these new derivatives are also discussed.
An Investigation of the Differential Effects of Ursane Triterpenoids from Centella asiatica, and Their Semisynthetic Analogues, on GABAA Receptors
Authors: Hamid Kaiser , Ng Irene , Tallapragada Vikram J. , Váradi Linda , Hibbs David E. , Hanrahan Jane , Groundwater Paul W.
Published: April 2016

The ursane triterpenoids, asiatic acid 1 and madecassic acid 2, are the major pharmacological constituents of Centella asiatica, commonly known as Gotu Kola, which is used traditionally for the treatment of anxiety and for the improvement of cognition and memory. Using the two‐electrode voltage‐clamp technique, these triterpenes, and some semisynthetic derivatives, were found to exhibit selective negative modulation of different subtypes of the GABAA receptor expressed in Xenopus laevis oocytes. Despite differing by only one hydroxyl group, asiatic acid 1 was found to be a negative modulator of the GABA‐induced current at α1β2γ2L, α2β2γ2L and α5β3γ2L GABAA receptors, while madecassic acid 2 was not. Asiatic acid 1 exhibited the greatest effect at α1β2γ2L (IC50 37.05 μm), followed by α5β3γ2L (IC50 64.05 μm) then α2β2γ2L (IC50 427.2 μm) receptors. Conversion of the carboxylic acid group of asiatic acid 1 to a carboxamide group (2α,3β,23‐trihydroxy‐urs‐12‐en‐28‐amide 5) resulted in enhanced inhibition at both the α1β2γ2L (IC50 14.07 μm) and α2β2γ2L receptor subtypes (IC50 28.41 μm). The results of this study, and the involvement of α5‐containing GABAA receptors in cognition and memory, suggest that asiatic acid 1 may be a lead compound for the enhancement of cognition and memory.
Rational Evolution of Antimicrobial Peptides Containing Unnatural Amino Acids to Combat Burn Wound Infections
Authors: Xiong Meng , Chen Ming , Zhang Jue
Published: April 2016

Antimicrobial peptides have long been raised as a promising strategy to combat bacterial infection in burn wounds. Here, we attempted to rationally design small antimicrobial peptides containing unnatural amino acids by integrating in silico analysis and in vitro assay. Predictive quantitative sequence‐activity models were established and validated rigorously based on a large panel of nonamer antimicrobial peptides with known antibacterial activity. The best quantitative sequence‐activity model predictor was employed to guide genetic evolution of a peptide population. In the evolution procedure, a number of unnatural amino acids with desired physicochemical properties were introduced, resulting in a genetic evolution‐improved population, from which seven peptide candidates with top scores, containing 1–3 unnatural amino acids, and having diverse structures were successfully identified, and their antibacterial potencies against two antibiotic‐resistant bacterial strains isolated from infected burn wounds were measured using in vitro susceptibility test. Consequently, four (WL‐Orn‐LARKIV‐NH2, ARKRWF‐Dab‐FL‐NH2, KFI‐Hag‐IWR‐Orn‐R‐NH2 and YW‐Hag‐R‐Cit‐RF‐Orn‐N‐NH2) of the seven tested peptides were found to be more potent than reference Bac2A, the smallest naturally occurring broad spectrum antimicrobial peptide. Molecular dynamics simulations revealed that the designed peptides can fold into amphipathic helical structure that allows them to interact directly with microbial membranes.
Flexible Concern: The Development of Multidetermined and Context‐Dependent Empathic Responding
Authors: Vaish Amrisha
Published: April 2016

Research on empathic development, though extensive, has largely overlooked two vital facets of flexible empathic responding—multideterminism (which is elicited in response to various cues) and context dependence (i.e., empathic responding that can be regulated depending on contextual factors). Within a dual‐process account of empathic responding (in which both bottom‐up and top‐down processes contribute), such flexible empathic responding relies heavily on top‐down processes. Yet most developmental research has not systematically considered the role of top‐down processes in bringing about multidetermined and context‐dependent empathic responding; as such, it provides a narrow view of early empathic responding. Recent research has begun to fill these gaps and suggests that top‐down processes are involved even in early flexible empathic responding. But much more work is needed, particularly on developmental mechanisms and the development of top‐down processes, to understand fully the origins of flexible concern.