bluuebunny/crossref_metadata_2025 huggingface dataset:
Adverse drug reactions in neonates and infants: a population‐tailored approach is needed
Authors: Allegaert Karel , van den Anker Johannes N.
Published: May 2014

Drug therapy is a powerful tool to improve outcome, but there is an urgent need to improve pharmacotherapy in neonates through tailored prevention and management of adverse drug reactions (ADRs). At present, infants commonly receive off‐label drugs, at dosages extrapolated from those in children or adults. Besides the lack of labelling, inappropriate formulations, (poly)pharmacy, immature organ function and multiple illnesses further raise the risk for ADRs in neonates and infants. Pharmacovigilance to improve the prevention and management of ADRs needs to be tailored to neonates and infants. We illustrate this using prevention strategies for drug prescription and administration errors (e.g. formulation, bedside manipulation, access), detection through laboratory signalling or clinical outlier data (e.g. reference laboratory values, overall high morbidity), assessment through algorithm scoring (e.g. Naranjo or population specific), as well as understanding of the developmental toxicology (e.g. covariates, developmental pharmacology) to avoid re‐occurrence and for development of guidelines. Such tailored strategies need collaborative initiatives to combine the knowledge and expertise of different disciplines, but hold promise to become a very effective tool to improve pharmacotherapy and reduce ADRs in infants.
Loss of Sparc in p53‐null Astrocytes Promotes Macrophage Activation and Phagocytosis Resulting in Decreased Tumor Size and Tumor Cell Survival
Authors: Thomas Stacey L. , Schultz Chad R. , Mouzon Ezekiell , Golembieski William A. , Naili Reima El , Radakrishnan Archanna , Lemke Nancy , Poisson Laila M. , Gutiérrez Jorge A. , Cottingham Sandra , Rempel Sandra A.
Published: May 2014

Both the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Both SPARC and p53 regulate glioma cell survival by inverse effects on apoptotic signaling. Therefore, during glioma formation, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival. This study determined whether the loss of Sparc in astrocytes that are null for p53 would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53‐null astrocytes resulted in an increase in cell proliferation, but a loss of tumorigenicity. At 7 days after intracranial implantation, Sparc‐null tumors had decreased tumor cell survival, proliferation and reduced tumor size. The loss of Sparc promoted microglia/macrophage activation and phagocytosis of tumor cells. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance.
Allergic contact dermatitis caused by acrylates and methacrylates – a 7‐year study
Authors: Ramos Leonor , Cabral Rita , Gonçalo Margarida
Published: May 2014

Backgound

Allergic contact dermatitis (ACD) caused by (meth)acrylates is traditionally an occupational disease among dentists, printers, and fibreglass workers. With the use of artificial nails, cases have been reported both in nail technicians and in users.

Objectives

The aims of this study were to characterize ACD caused by (meth)acrylates, identify the responsible allergens, and assess the sensitivity of the patch test with 2‐hydroxyethyl methacrylate (HEMA) for diagnosis.

Methods

An observational and retrospective study (January 2006–April 2013) was performed, evaluating and correlating epidemiological and clinical parameters and positive patch test results with (meth)acrylates.

Results

Among 2263 patch tested patients, 122 underwent aimed testing with an extended (meth)acrylate series, and 37 showed positive and relevant reactions. Twenty‐five cases (67.6%) were occupational. Hand eczema with pulpitis was observed in 32 patients. Twenty‐eight cases were related to artificial nails, 3 were related to dental materials, and 2 were industrial workers. Oral lesions associated with dental prostheses were observed in 4 patients. Thirty‐one patients reacted to more than one (meth)acrylate. In our sample, beauty technicians working with artificial nails were the most affected group (80% of occupational cases).

Conclusion

HEMA detected 80.6% of our cases, and may be considered a good screening allergen. However, to perform an accurate diagnosis, it is safer to use a broader series of allergens.
Clinical usefulness of novel tag‐less Agile patency capsule prior to capsule endoscopy for patients with suspected small bowel stenosis
Authors: Nakamura Masanao , Hirooka Yoshiki , Yamamura Takeshi , Miyahara Ryoji , Watanabe Osamu , Ando Takafumi , Ohmiya Naoki , Goto Hidemi
Published: May 2014

Background and Aim

The Agile patency capsule (PC; Given Imaging Ltd, Yoqneam, Israel) is used as a dummy prior to capsule endoscopy (CE) to avoid retention of the CE capsule. However, impaction of the PC's inner radio frequency identification (RFID) tag in a stricture could cause small‐bowel ileus. Recently, the RFID tag‐less PC was introduced into clinical practice. Herein, we aimed to retrospectively evaluate the usefulness of the tag‐less PC.

Methods

Of 154 patients who were scheduled to undergo CE, 100 consecutive patients (65%) who underwent PC evaluation were enrolled in the present study. Primary study end point was the retention rate of the CE capsule after successful passage of the PC. Secondary end point was analysis of the significant factors affecting the passage of the PC.

Results

In total, 87 patients (87%) had bowel patency confirmed by PC evaluation. There was no capsule retention in any of these 87 patients during CE. Abnormal findings were obtained from 60 CE, and 41 patients received new or modified treatment. Multivariate analysis of factors related to the confirmation of patency demonstrated that stenosis on imaging was the most influential factor (P = 0.002, odds ratio 16.387). The results confirmed that passage of the PC depends on stenosis on imaging.

Conclusions

Use of the tag‐less PC confirmed gastrointestinal tract patency for most of the patients who did not have stenosis on imaging and allowed estimation of the patency for patients who did have stenosis on imaging.
Non‐radiation endoscopic retrograde cholangiopancreatography in the management of choledocholithiasis during pregnancy
Authors: Wu Wenming , Faigel Douglas O. , Sun Gang , Yang Yunsheng
Published: May 2014

Gallstone diseases are common during pregnancy. In most cases, patients are asymptomatic and do not require any treatment. However, choledocholithiasis, cholangitis, and gallstone pancreatitis may potentially become life‐threatening for both mother and fetus and often require urgent intervention. Although endoscopic retrograde cholangiopancreatography (ERCP) has become the standard technique for removing common bile duct stones, it is associated with ionizing radiation that could carry teratogenic risk. Non‐radiationERCP(NR‐ERCP) is reported to be effective without incurring this risk. Two techniques have been described to confirm bile duct cannulation: bile aspiration and image guidance. With bile aspiration, biliary cannulation is confirmed by applying suction to the cannula to yield bile, thus confirming an intrabiliary position. Image guidance involves using ultrasound or direct visualization (choledochoscopy) to confirm selective biliary cannulation or duct clearance. Once cannulation is achieved, the stones are removed using standardERCPtechniques and tools. Case series and retrospective studies have reported success rates of up to 90% forNR‐ERCPwith complication rates similar to standardERCP. Pregnancy outcomes are not adversely affected byNR‐ERCP, but whether the avoidance of radiation carries benefit for the baby is unknown. Prospective comparative trials are lacking.NR‐ERCPis technically demanding and should be attempted only by skilled biliary endoscopists in properly equipped and staffed health‐care institutions, in a multidisciplinary setting.
Dipeptidyl peptidase‐4 inhibitors can minimize the hypoglycaemic burden and enhance safety in elderly people with diabetes
Authors: Avogaro A. , Dardano A. , de Kreutzenberg S. V. , Del Prato S.
Published: May 2014

The prevalence of type 2 diabetes mellitus (T2DM) among elderly people is increasing. Often associated with disabilities/comorbidities, T2DM lowers the chances of successful aging and is independently associated with frailty and an increased risk of hypoglycaemia, which can be further exacerbated by antihyperglycaemic treatment. From this perspective, the clinical management of T2DM in the elderly is challenging and requires individualization of optimum glycaemic targets depending on comorbidities, cognitive functioning and ability to recognize and self‐manage the disease. The lack of solid evidence‐based medicine supporting treatment guidelines for older people with diabetes further complicates the matter. Several classes of medicine for the treatment of T2DM are currently available and different drug combinations are often required to achieve individualized glycaemic goals. Many of these drugs, however, carry disadvantages such as the propensity to cause weight gain or hypoglycaemia. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors, a recent addition to the pharmacological armamentarium, have become widely accepted in clinical practice because of their efficacy, low risk of hypoglycaemia, neutral effect on body weight, and apparently greater safety in patients with kidney failure. Although more information is needed to reach definitive conclusions, growing evidence suggests that DPP‐4 inhibitors may become a valuable component in the pharmacological management of elderly people with T2DM. The present review aims to delineate the potential advantages of this pharmacological approach in the treatment of elderly people with T2DM.
Safety and efficacy of the dipeptidyl peptidase‐4 inhibitor linagliptin in elderly patients with type 2 diabetes: a comprehensive analysis of data from 1331 individuals aged ≥ 65 years
Authors: Schernthaner G. , Barnett A. H. , Patel S. , Hehnke U. , von Eynatten M. , Woerle H.‐J.
Published: May 2014

Aims

To investigate individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin across a range of glucose‐lowering regimens in a large elderly population with type 2 diabetes mellitus (T2DM).

Methods

Data were pooled from individuals aged ≥65 years, who participated in seven phase III, placebo‐controlled clinical trials of linagliptin (24–52 weeks). Safety was assessed by incidence and severity of adverse events (AEs) with a focus on hypoglycaemia. The primary efficacy endpoint was change in glycated haemoglobin (HbA1c).

Results

In total, 841 subjects received linagliptin 5 mg once a day and 490 received placebo. At baseline, the population had a mean ± s.d. age of 71.0 ± 4.6 years and a mean HbA1c concentration of 8.0 ± 0.8%; 63.5% of subjects received ≥2 antidiabetes drugs. Overall AEs and drug‐related AEs were experienced by similar proportions of patients (linagliptin 71.3, placebo 73.3; linagliptin 18.1, placebo 19.8%, respectively). The incidence of investigator‐reported hypoglycaemia was 21.4% with linagliptin and 25.7% with placebo. Severe hypoglycaemic events were rare and there were fewer in the linagliptin group (1.0 vs. 1.8%). At week 24, the placebo‐corrected adjusted mean ± s.e. reduction in HbA1c with linagliptin was −0.62 ± 0.06% (95% CI: −0.73, −0.51).

Conclusions

Data from this large cohort show that linagliptin is a well‐tolerated and efficacious therapy for elderly patients with T2DM. Treatment with linagliptin may support individualized treatment goals, while effectively managing the risk of hypoglycaemia or drug‐related side effects.
Orthogonal array design for optimization of an artificial medium for in vitro rearing of Trichogramma dendrolimi
Authors: Lü Xin , Han Shichou , De Clercq Patrick , Dai Jianqing , Li Liying
Published: May 2014

Successful complete development of Trichogramma species on artificial media is also related to the presence and proportions of ingredients other than host insect‐derived components. In this study, an orthogonal array with six factors at three levels was performed and parameters of parasitism, larval development, pupation, and adult emergence were monitored to reveal the most important components of an artificial medium and to improve the medium for in vitro mass rearing of Trichogramma dendrolimi Matsumura (Hymenoptera: Trichogrammatidae). Results indicated that biological parameters of T. dendrolimi were affected differently by six ingredients of the artificial medium: pupal hemolymph of Antheraea pernyi (Guérin‐Méneville) (Lepidoptera: Saturniidae), egg yolk, 10% malted milk solution, Neisenheimer's salt solution, trehalose, and sterile water. Statistical analysis indicated that trehalose and Neisenheimer's salt solution, 10% malted milk solution, and pupal hemolymph of A. pernyi were the main ingredients of the artificial medium based on rates of parasitism and pupation, the number of larvae developing in each artificial egg, adult emergence rate, and the number of normal adults produced. A follow‐up bioassay with a selection of optimized formulas confirmed the validity of the optimization as predicted by the orthogonal array analysis, indicating the usefulness of this method for selecting artificial diets for entomophagous insects. Adult emergence rate of the parasitoid and total number of normal adults produced per egg card (each containing 20 artificial eggs) averaged 88.8% and 956 females on the best performing optimized artificial medium, consisting of 3 ml pupal hemolymph of A. pernyi, 2.5 ml egg yolk, 1 ml 10% malted milk solution, 1 ml Neisenheimer's salt solution, 0.1 g trehalose, and 1.5 ml sterile water. The latter medium was superior to any formerly developed medium and may thus have potential for the in vitro mass rearing of T. dendrolimi.
Participants' perceived benefits of family intervention following a first episode of psychosis: a qualitative study
Authors: Nilsen Liv , Frich Jan C. , Friis Svein , Norheim Irene , Røssberg Jan Ivar
Published: May 2014

Aim

To explore the perceived benefits for patients and family members of psychoeducational family intervention following a first episode of psychosis.

Methods

A qualitative exploratory study using data from interviews with 12 patients and 14 family members who participated in a psychoeducational multi‐ or single‐family treatment programme. Semi‐structured interviews were digitally recorded and transcribed verbatim with slight modifications, after which they were analysed by systematic text condensation.

Results

Patients and family members reported benefits that could be classified in five categories: (i) developing insight and acceptance requires understanding of the fact that the patient has an illness, and recognizing the need for support; (ii) recognizing warning signs requires an understanding of early signs of deterioration in the patient; (iii) improving communication skills is linked to new understanding and better communication both within the family and in groups; (iv) Learning to plan and solve problems requires the ability to solve problems in new ways; (v) becoming more independent requires patients to take responsibility for their own life.

Conclusion

The study suggests that developing insight and acceptance, learning about warning signs, improving communications skills, learning to plan and solve problems, and becoming more independent are perceived as benefits of a psychoeducational family intervention.
Fixational saccade‐related activity of pedunculopontine tegmental nucleus neurons in behaving monkeys
Authors: Okada Ken‐ichi , Kobayashi Yasushi
Published: May 2014

Fixational saccades are small, involuntary eye movements that occur during attempted visual fixation. Recent studies suggested that several cognitive processes affect the occurrence probability of fixational saccades. Thus, there might be an interaction between fixational saccade‐related motor signals and cognitive signals. The pedunculopontine tegmental nucleus (PPTN) in the brainstem has anatomical connections with numerous saccade‐related and limbic areas. Previously, we reported that a group of PPTN neurons showed transient phasic bursts or a pause in activity during large visually guided and spontaneous saccades, and also showed sustained tonic changes in activity with task context. We hypothesised that single PPTN neurons would relay both fixational saccade‐related and task context‐related signals, and might function as an interface between the motor and limbic systems. We recorded the activity of PPTN neurons in behaving monkeys during a reward‐biased task, and analysed neuronal activity for small fixational saccades during visual fixation, and compared it with the activity for large visually guided targeting saccades and large spontaneous saccades during intertrial intervals. A population of PPTN neurons exhibited a fixational saccade‐related phasic increase in activity, and the majority of them also showed activity modulation with large targeting saccades. In addition, a group of these neurons showed a task‐related tonic increase in activity during the fixation period, and half of them relayed the saccade signal only when the neuron exhibited higher tonic activity during the task execution period. Thus, fixational saccade‐related signals of PPTN neurons overlap with tonic task‐related signals, and might contribute to the cognitive modulation of fixational saccades.
Long‐term safety of perampanel and seizure outcomes in refractory partial‐onset seizures and secondarily generalized seizures: Results from phase III extension study 307
Authors: Krauss Gregory L. , Perucca Emilio , Ben‐Menachem Elinor , Kwan Patrick , Shih Jerry J. , Clément Jean‐François , Wang Xuefeng , Bagul Makarand , Gee Michelle , Zhu Jin , Squillacote David
Published: May 2014

Objective

To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment.

Methods

Patients ≥12 years old with partial‐onset seizures despite treatment with 1–3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open‐label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions.

Results

Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy‐related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥1 year, 5.3% were seizure‐free for the entire year.

Significance

No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.

A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Cleaning Up After a Meal: The Consequences of Prey Disposal for Pit‐Building Antlion Larvae
Authors: Beponis Lucy M. , O'Dea Rose E. , Ohl Valérie‐Anne , Ryan Mitchell P. , Backwell Patricia R. Y. , Binning Sandra A. , Haff Tonya M.
Published: May 2014

Predators use a variety of strategies for capturing prey. Trap‐building predators can save on searching and encountering costs by investing in the construction and maintenance of traps such as webs and pits. However, what to do with partially consumed prey poses a potential problem. Antlion larvae (Myrmeleon acer) catch ants in conical pits, and dispose of partially consumed carcasses by flicking them a short distance away. We tested whether this prey‐disposal behaviour affects the effectiveness of antlion pits. We observed ant behaviour around artificially constructed pits and compared falls into pits with clean margins to those with conspecific ant carcasses or control objects around the pit edge. The presence of objects near pits affected the behaviour of live ants, and reduced the effectiveness of pits. Live ants spent the most time examining fresh ant carcasses, but the presence of any object near pits deterred pitfalls. Ants fell into pits significantly more often when pit edges were clean, suggesting that antlions could incur a prey capture cost from flicking carcasses from pits as well as from the accumulation of other debris around pit margins.
Infectious disease, shifting climates, and opportunistic predators: cumulative factors potentially impacting wild salmon declines
Authors: Miller Kristina M. , Teffer Amy , Tucker Strahan , Li Shaorong , Schulze Angela D. , Trudel Marc , Juanes Francis , Tabata Amy , Kaukinen Karia H. , Ginther Norma G. , Ming Tobi J. , Cooke Steven J. , Hipfner J. Mark , Patterson David A. , Hinch Scott G.
Published: May 2014

Emerging diseases are impacting animals under high‐density culture, yet few studies assess their importance to wild populations. Microparasites selected for enhanced virulence in culture settings should be less successful maintaining infectivity in wild populations, as once the host dies, there are limited opportunities to infect new individuals. Instead, moderately virulent microparasites persisting for long periods across multiple environments are of greatest concern. Evolved resistance to endemic microparasites may reduce susceptibilities, but as barriers to microparasite distributions are weakened, and environments become more stressful, unexposed populations may be impacted and pathogenicity enhanced. We provide an overview of the evolutionary and ecological impacts of infectious diseases in wild salmon and suggest ways in which modern technologies can elucidate the microparasites of greatest potential import. We present four case studies that resolve microparasite impacts on adult salmon migration success, impact of river warming on microparasite replication, and infection status on susceptibility to predation. Future health of wild salmon must be considered in a holistic context that includes the cumulative or synergistic impacts of multiple stressors. These approaches will identify populations at greatest risk, critically needed to manage and potentially ameliorate the shifts in current or future trajectories of wild populations.
Adherence to treatment in a Western European paediatric population with haemophilia: reliability and validity of theVERITAS‐Pro scale
Authors: Lock J. , Raat H. , Duncan N. , Shapiro A. , Beijlevelt M. , Peters M. , Tamminga R. Y. J. , Leebeek F. W. G. , Moll H. A. , Cnossen M. H.
Published: May 2014

Treatment adherence in haemophilia is strongly associated with quality of life and the cost–benefit of treatment. Therefore, it is important to quantify and monitor it. This study aimed to validate a translation of theVERITAS‐Pro cross‐culturally and analyse treatment adherence in a Dutch population of paediatric haemophilia patients. Children aged 1–18 years with haemophilia were included from three Haemophilia Treatment Centres, on prophylactic clotting factor replacement therapy for more than 1 year. Parents and adolescents were analysed separately. The adherence scale for prophylactic therapy (VERITAS‐Pro) was translated according to international guidelines. This instrument contains a total of six subscales (‘Time’, ‘Dose’, ‘Plan’, ‘Remember’, ‘Skip’ and ‘Communicate’) each with four items. Lower scores reflecthigheradherence. Overall response rate was 85%, leading to a study population of 60 children. Mean age was 10 years (SD4.1).Internal consistency reliability: Mean Cronbach's alphas were adequate (>0.70) for total score and the subscales ‘Skip’ and ‘Communicate’. Item‐own subscale correlations were stronger than most item‐other subscale correlations.Convergent validity: Total scores were higher for non‐adherent participants compared with adherent participants according to patient infusion logs (n = 48;P < 0.05). Test–retest correlations:Significant for all scales except ‘Dose’ (n = 58;P < 0.01). This study demonstrates applicability ofVERITAS‐Pro outside the United States, as total score and most subscales effectively quantified treatment adherence in a Dutch paediatric population on prophylactic therapy. Non‐adherent respondents’ total scores were significantly higher, demonstrating the ability ofVERITAS‐Pro to identify non‐adherent individuals.
Salvage of grafts with vascular thrombosis during live donor renal allotransplantation: A critical analysis of successful outcome
Authors: Harraz Ahmed M , Shokeir Ahmed A , Soliman Shady A , Osman Yasser , El‐Hefnawy Ahmed S , Zahran Mohamed H , Kamal Ahmed I , Kamal Mohamed M , Ali‐El‐Dein Bedeir
Published: May 2014

Objectives

To report a high‐volume institution experience with salvage techniques for vascular accidents during live donor renal allotransplantation.

Methods

Between March 1976 and January 2011, 2208 recipients underwent live donor renal allotransplantation. A retrospective review of recipients with vascular accidents – renal artery thrombosis and renal vein thrombosis – was carried out. Salvage procedures were recorded and their outcomes were assessed.

Results

A total of 23 (1%) vascular accidents occurred, including renal artery thrombosis and renal vein thrombosis in 19 (0.8%) and four (0.18%) recipients, respectively. All renal artery thrombosis patients were treated by open revascularization and the graft was salvaged in 12 patients (63%). Two renal vein thrombosis events were resolved by percutaneous catheter‐directed thrombolytic therapy. Of the other two allografts, one was salvaged by thrombectomy and revascularization, and the other was lost. On univariable analysis, older recipients (P = 0.003), pretransplant hypertension (P = 0.001), more human leukocyte antigen mismatches (≥3; P = 0.036), shorter ischemia time (≤45 min; P = 0.004) and longer time to diagnosis (>3.5 days; P = 0.013) were significantly associated with non‐salvage of the graft after vascular accidents. Nevertheless, none of these variables were significant on the multivariable analysis. Over a median follow up of 35 months, the median (range) serum creatinine was 2 mg/dL (range 0.8–8.8 mg/dL), and 11 (79%) recipients were living with functioning grafts.

Conclusions

Despite the devastating complications, vascular accidents are salvageable and revascularization is crucial for graft salvage. Angiographic percutaneous techniques are viable alternatives for renal vein thrombosis.
Mutation profile of differentiated thyroid tumours in an Australian urban population
Authors: Mond M. , Alexiadis M. , Fuller P. J. , Gilfillan C.
Published: May 2014

Background

The majority of differentiated thyroid cancers are characterised by one of several point mutations or gene rearrangements. Limited data are available on the prevalence and clinical correlations of these mutations in the Australian population.

Aims

The aim of the present study was to characterise the mutation profile of differentiated thyroid tumours in the local population.

Methods

The study involved 148 patients with differentiated thyroid cancer. The following tumours were examined: 109 papillary carcinomas (PTC), 27 follicular carcinomas (FC) and 12 Hurthle cell carcinomas (HCC). Polymerase chain reaction (PCR) was performed for BRAF and RAS mutations (RNA and DNA) as well as for RET/PTC rearrangements and PAX8‐PPARγ translocations (RNA). Clinicopathological parameters and outcome data were analysed according to BRAFV600E status in PTC and RAS mutation status in FC.

Results

BRAFV600E was identified in 74/109 (68%) PTC. BRAFV600E was not significantly correlated with clinicopathological features of aggressive disease. At a median follow up of 48 months, there was no significant difference between BRAFV600E and wild‐type BRAF PTC with respect to the rates of nodal recurrence, distant metastases or disease‐specific death. In FC, RAS mutations (five NRAS and three HRAS) were present in 8/27 (30%) tumours. RAS mutation was significantly associated with widely invasive histology (P = 0.01) and distant metastases (P = 0.01) on follow up.

Conclusion

In the present study, BRAF mutation was not associated with negative prognostic indicators or adverse outcomes in PTC. RAS mutation was positively correlated with aggressive features in FC suggesting potential prognostic utility, although confirmation is required from larger studies.
Lean mass modulates glomerular filtration rate in males of normal and extreme body composition
Authors: Chew‐Harris J. S.C. , Florkowski C. M. , Elmslie J. L. , Livesey J. , Endre Z. H. , George P. M.
Published: May 2014

Background

Understanding determinants of glomerular filtration rate (GFR) is important in aiding prediction and interpretation of kidney function. Body composition is known to affect GFR but is not included in current screening of kidney disease. We investigated the association between GFR and body composition in healthy young men with differing body mass but without known diabetes or kidney injury.

Methods

Three groups were recruited: normal BMI (n = 22) with a body mass index (BMI) <25 kg/m2, muscular (n = 23) with BMI ≥30 kg/m2 and bioelectrical impedance body fat ≤20% and obese (n = 22) with BMI ≥30 kg/m2 and bioelectrical impedance body fat ≥30%. Dietary analyses, GFR clearance by 99m Tc‐DTPA, urine protein and body composition by dual‐energy X‐ray absorptiometry were measured in all participants. Linear and nonlinear associations of constituents of body composition with GFR were assessed.

Results

Muscular men had a higher GFR (mean 186.4 mL/min; 95% CI 171.7–201.1) than normal BMI and obese groups (P = 0.0007). Urine protein and albumin excretion were not elevated in any participants. On multiple regression analysis (r2 = 0.60), the variables with strong associations with GFR were age (P = 0.0009) and lean mass (P = 0.0001). Fat mass, protein intake and smoking status were not associated. Skeletal muscle mass correlated significantly with GFR in all subgroups.

Conclusion

Age and lean mass were strong determinants of GFR. Estimates of GFR should therefore be indexed to an estimate of lean mass.
Interactive Effects of Sudden and Gradual Drought Stress and Foliar‐applied Glycinebetaine on Growth, Water Relations, Osmolyte Accumulation and Antioxidant Defence System in Two Maize Cultivars Differing in Drought Tolerance
Authors: Zhang L.‐X. , Lai J.‐H. , Liang Z.‐S. , Ashraf M.
Published: May 2014

Influence of sudden and gradual drought stress (DS) and foliar‐applied glycinebetaine (GB) on growth, water relations, osmolyte accumulation and antioxidant defence system were investigated in the plants of two maize (Zea mays L.) cultivars, that is, drought‐tolerant Shaandan 9 (S9) and drought‐sensitive Shaandan 911 (S911). Sudden DS caused less accumulation of GB and free proline, but a more accumulation of malondialdehyde (MDA), which resulted in a greater reduction in leaf relative water content (RWC) and dry matter (DM) in both cultivars compared with the gradual DS. Exogenous GB application caused a rise in DM, RWC, contents of GB and free proline as well as the activities of SOD, CAT and POD along with a decline in MDA content to various extent in both cultivars under both types of DS. A more pronounced effectiveness of GB application was observed in S911 than that in S9 under the same type of DS. It seemed that the more serious damage of DS was on maize plants, and the better positive role of GB was observed in terms of mitigating the adverse effects of DS. From this study, it was possible to propose that hardening for drought resistance by gradual DS treatment and GB application are effective to make plants robust to thrive under water‐deficit conditions.
High‐Probability Features of Primary Aldosteronism May Obviate the Need for Confirmatory Testing Without Increasing False‐Positive Diagnoses
Authors: Kline Gregory A. , Pasieka Janice L. , Harvey Adrian , So Benny , Dias Val C.
Published: May 2014

This retrospective review examined all primary aldosteronism (PA) adrenal vein sampling (AVS), diagnoses, and outcomes from an endocrine hypertension unit where confirmatory testing was abandoned in 2005 to determine the potential rate of false‐positive diagnoses. Patients with outcome‐verified PA (surgical patients) were compared with patients with high‐probability PA (nonsurgical but high aldosterone‐renin ratio, imaging abnormalities, and/or hypokalemia) or possible PA (nonsurgical, no features besides mild elevation of aldosterone‐renin ratio, a potential false diagnosis of PA). Of 83 patients, 58% had unilateral PA and 42% had bilateral aldosteronism. Less than 3% of the cohort showed bilateral aldosteronism without hypokalemia or computed tomographic findings, potentially representing the false‐positive PA diagnosis rate with omission of confirmatory tests in this population. In a hypertension referral unit enriched in high‐probability PA cases and where high AVS success is achieved, omission of a PA confirmatory test yields a high rate of surgical diagnosis with few potential false‐positive diagnoses.
‘To move or not to move’: a national survey among professionals on beliefs and considerations about the place of end‐of‐life care for people with intellectual disabilities
Authors: Bekkema N. , de Veer A. J. E. , Wagemans A. M. A , Hertogh C. M. P. M. , Francke A. L.
Published: May 2014

Background

The aim of this article was to investigate the beliefs and considerations of professionals concerning an appropriate environment for end‐of‐life care for people with intellectual disabilities (ID).

Method

A survey questionnaire was composed based on a scan of relevant literature and the results of group interviews with professionals, family members and people with ID. The questionnaire focused on the respondents' general beliefs about an appropriate environment for end‐of‐life care and their specific considerations regarding the place of care of the last client for whom the respondent provided end‐of‐life care. The questionnaire was sent to 294 care staff members recruited from a nationally representative panel of nurses and social workers, 273 ID physicians recruited from the members list of the Dutch professional association of ID physicians, and 1000 general practitioners (GPs) recruited from a nationally representative sample from a national registration of GPs.

Results

The overall response was 46%. Professionals predominantly believe that all efforts should be made to ensure that a person with ID receives end‐of‐life care in their own home environment, and that 24/7 care is available. Respondents indicated that most of the clients (79%) who had last received end‐of‐life care from an ID care service were able to stay in their own home environment. Decisions to keep the client in their own home environment were primarily based on the familiarity of the environment and the expertise of the team in end‐of‐life care. Insufficient expertise and a lack of adequate equipment were the main considerations in decisions to move a client. Despite the belief of care staff in particular that the wishes of the person with ID should always be leading when deciding on the place of end‐of‐life care, only 8% of the care staff and ID physicians explicitly mentioned that the client's wishes were taken into account in actual decision‐making.

Conclusions

Professionals agree that end‐of‐life care for people with ID should preferably take place in the client's home environment, even when nursing expertise, experience and adequate equipment are not (yet) in place. Nonetheless, a lack of expertise in end‐of‐life care is the foremost consideration in decisions to move a client. If ID care services want to promote end‐of‐life care in the client's own home, we recommend formulating a policy on how to realise end‐of‐life care in the client's own home environment and provide sufficient training and support for staff. To involve people with ID as much as possible, we recommend that professionals integrate more collaborative principles in decision‐making about the place of end‐of‐life care.
Neurokinin B Receptor Antagonism Decreases Luteinising Hormone Pulse Frequency and Amplitude and Delays Puberty Onset in the Female Rat
Authors: Li S. Y. , Li X. F. , Hu M. H. , Shao B. , Poston L. , Lightman S. L. , O'Byrne K. T.
Published: May 2014

The neural mechanisms controlling puberty onset remain enigmatic. Humans with loss of function mutations in TAC3 or TACR3, the genes encoding neurokinin B (NKB) or its receptor, neurokinin‐3 receptor (NK3R), respectively, present with severe congenital gonadotrophin deficiency and pubertal failure. Animal studies have shown ambiguous actions of NKB‐NK3R signalling with respect to controlling puberty onset. The present study aimed to determine the role of endogenous NKB‐NK3R signalling in the control of pulsatile luteinising hormone (LH) secretion and the timing of puberty onset, and also whether precocious pubertal onset as a result of an obesogenic diet is similarly regulated by this neuropeptide system. Prepubertal female rats, chronically implanted with i.c.v. cannulae, were administered SB222200, a NK3R antagonist, or artificial cerebrospinal fluid via an osmotic mini‐pump for 14 days. SB222200 significantly delayed the onset of vaginal opening and first oestrus (as markers of puberty) compared to controls in both normal and high‐fat diet fed animals. Additionally, serial blood sampling, via chronic indwelling cardiac catheters, revealed that the increase in LH pulse frequency was delayed and that the LH pulse amplitude was reduced in response to NK3R antagonism, regardless of dietary status. These data suggest that endogenous NKB‐NK3R signalling plays a role in controlling the timing of puberty and the associated acceleration of gonadotrophin‐releasing hormone pulse generator frequency in the female rat.
Looking Attractive until You Sell: Earnings Management, Lockup Expiration, and Venture Capitalists
Authors: Nam Dae‐il , Park Haemin Dennis , Arthurs Jonathan D.
Published: May 2014

Earnings management occurs when managerial discretion allows managers to influence reported earnings and thus mislead some investors about the underlying economic performance and quality of the firm. This study considers how potential investors may guard against earnings management by observing negative stock price reaction at the lockup expiration period of initial public offering (IPO) firms as a negative signal. Findings from a sample of 160 newly public firms show that earnings management behaviour is stronger inIPOfirms backed by venture capitalists (VCs). Moreover,VCreputation negatively moderates this relationship such thatIPOfirms backed by reputableVCs are less likely to manage earnings, suggesting that reputableVCs serve an auditing function following anIPO. Overall, we provide insights into signalling theory by examining negative signals arising from the behaviour of multiple agents in anIPOfirm.
Melatonin prevents maternal fructose intake‐induced programmed hypertension in the offspring: roles of nitric oxide and arachidonic acid metabolites
Authors: Tain You‐Lin , Leu Steve , Wu Kay L. H. , Lee Wei‐Chia , Chan Julie Y. H.
Published: May 2014

Fructose intake has increased globally and is linked to hypertension. Melatonin was reported to prevent hypertension development. In this study, we examined whether maternal high fructose (HF) intake causes programmed hypertension and whether melatonin therapy confers protection against the process, with a focus on the link to epigenetic changes in the kidney using next‐generation RNA sequencing (NGS) technology. Pregnant Sprague–Dawley rats received regular chow or chow supplemented with HF (60% diet by weight) alone or with additional 0.01% melatonin in drinking water during the whole period of pregnancy and lactation. Male offspring were assigned to four groups: control, HF, control + melatonin (M), and HF + M. Maternal HF caused increases in blood pressure (BP) in the 12‐wk‐old offspring. Melatonin therapy blunted the HF‐induced programmed hypertension and increased nitric oxide (NO) level in the kidney. The identified differential expressed gene (DEGs) that are related to regulation of BP included Ephx2, Col1a2, Gucy1a3, Npr3, Aqp2, Hba‐a2, and Ptgs1. Of which, melatonin therapy inhibited expression and activity of soluble epoxide hydrolase (SEH, Ephx2 gene encoding protein). In addition, we found genes in arachidonic acid metabolism were potentially involved in the HF‐induced programmed hypertension and were affected by melatonin therapy. Together, our data suggest that the beneficial effects of melatonin are attributed to its ability to increase NO level in the kidney, epigenetic regulation of genes related to BP control, and inhibition of SEH expression. The roles of DEGs by the NGS in long‐term epigenetic changes in the adult offspring kidney require further clarification.
Melatonin improves mitochondrial function in inguinal white adipose tissue of Zücker diabetic fatty rats
Authors: Jimenéz‐Aranda Aroa , Fernández‐Vázquez Gumersindo , Mohammad A‐Serrano María , Reiter Russel J. , Agil Ahmad
Published: May 2014

Mitochondrial dysfunction in adipose tissue may contribute to obesity‐related metabolic derangements such as type 2 diabetes mellitus (T2DM). Because mitochondria are a target for melatonin action, the goal of this study was to investigate the effects of melatonin on mitochondrial function in white (WAT) and beige inguinal adipose tissue of Zücker diabetic fatty (ZDF) rats, a model of obesity‐related T2DM. In this experimental model, melatonin reduces obesity and improves the metabolic profile. At 6 wk of age, ZDF rats and lean littermates (ZL) were subdivided into two groups, each composed of four rats: control (C‐ZDF and C‐ZL) and treated with oral melatonin in the drinking water (10 mg/kg/day) for 6 wk (M‐ZDF and M‐ZL). After the treatment period, animals were sacrificed, tissues dissected, and mitochondrial function assessed in isolated organelles. Melatonin increased the respiratory control ratio (RCR) in mitochondria from white fat of both lean (by 26.5%, P < 0.01) and obese (by 34.5%, P < 0.01) rats mainly through a reduction of proton leaking component of respiration (state 4) (28% decrease in ZL, P < 0.01 and 35% in ZDF, P < 0.01). However, melatonin treatment lowered the RCR in beige mitochondria of both lean (by 7%, P < 0.05) and obese (by 13%, P < 0.05) rats by maintaining high rates of uncoupled respiration. Melatonin also lowered mitochondrial oxidative status by reducing nitrite levels and by increasing superoxide dismutase activity. Moreover, melatonin treatment also caused a profound inhibition of Ca‐induced opening of mPTP in isolated mitochondria from both types of fat, white and beige, in both lean and obese rats. These results demonstrate that chronic oral melatonin improves mitochondrial respiration and reduces the oxidative status and susceptibility to apoptosis in white and beige adipocytes. These melatonin effects help to prevent mitochondrial dysfunction and thereby to improve obesity‐related metabolic disorders such as diabetes and dyslipidemia of ZDF rats.
Syntactic Memory in the Comprehension of Reflexive Dependencies: an Overview
Authors: Dillon Brian
Published: May 2014

The distribution of reflexive anaphors has long been of central importance in the development of syntactic theory. In a parallel fashion, research on the comprehension of reflexive anaphors is increasingly influential for theories of syntactic comprehension. In this article, I present the problem of selecting a reflexive's antecedent as a memory retrieval problem and illustrate why the comprehension of reflexives is of special interest for theories of the memory architecture of the sentence processor. I review a range of influential findings on reflexive comprehension, focusing on results that concern the speed and grammatical accuracy of antecedent retrieval. An emerging empirical generalization is that reflexives are relatively immune to retrieval interference, a property that sets them apart from superficially similar syntactic dependencies like subject–verb agreement. Existing data, across languages and across methodologies, suggest that comprehenders retrieve a reflexive's antecedent primarily on the basis of its syntactic position.
Teleosemantics: Intentionality, Productivity, and the Theory of Meaning
Authors: Leahy Brian
Published: May 2014

Since the publication of Ruth Millikan's Language, Thought, and Other Biological Categories in 1984, a great deal of literature has discussed her so‐called teleosemantic or biosemantic solution to the problem of intentionality. Only recently, though, has much attention been paid to her co‐ordinated solution to the problem of productivity. This article, first, clearly describes the problems of intentionality, productivity, and compositionality, and describes their relationships and their relevance for the theory of meaning. It then describes Millikan's proposal with respect to the problem of intentionality and shows how this buys her a novel solution to the problem of productivity. The article closes by discussing some alternative teleosemantic theories and some issues that will contribute to deciding between them.
A Meloidogyne incognita effector is imported into the nucleus and exhibits transcriptional activation activity in planta
Authors: Zhang Lei , Davies Laura J. , Elling Axel A.
Published: May 2014

Root‐knot nematodes are sedentary biotrophic endoparasites that maintain a complex interaction with their host plants. Nematode effector proteins are synthesized in the oesophageal glands of nematodes and secreted into plant tissue through a needle‐like stylet. Effectors characterized to date have been shown to mediate processes essential for nematode pathogenesis. To gain an insight into their site of action and putative function, the subcellular localization of 13 previously isolated Meloidogyne incognita effectors was determined. Translational fusions were created between effectors and EGFP‐GUS (enhanced green fluorescent protein‐β‐glucuronidase) reporter genes, which were transiently expressed in tobacco leaf cells. The majority of effectors localized to the cytoplasm, with one effector, 7H08, imported into the nuclei of plant cells. Deletion analysis revealed that the nuclear localization of 7H08 was mediated by two novel independent nuclear localization domains. As a result of the nuclear localization of the effector, 7H08 was tested for the ability to activate gene transcription. 7H08 was found to activate the expression of reporter genes in both yeast and plant systems. This is the first report of a plant‐parasitic nematode effector with transcriptional activation activity.