bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical Smartphone Applications Across Different Platforms
Authors: Kulendran Myutan , Lim Marcus , Laws Georgia , Chow Andre , Nehme Jean , Darzi Ara , Purkayastha Sanjay
Published: April 2014

Introduction. There are a vast array of smartphone applications that could benefit both surgeons and their patients. To review and identify all relevant surgical smartphone applications available for the Apple iPhone iOS and Google Android platform based on their user group and subspecialty for which they were designed. Method. Both the literature using PubMed and Google Scholar were searched using the following terms: application$, smartphone$, app$, app*, surgery, surgical, surg*, general surgery, general surg*, bariatric$, urology and plastic surgery, ortho*, orthop(a)edic, cardiac surgery, cardiothoracic, neurosurgery, and ophthalmology. Results. The search yielded 38 articles of which 23 were eligible. Each of the key specialties was searched in the Apple iTunes App Store for iPhone iOS and the Google Play Android application store. In total, there were 621 surgical applications for Apple iPhone iOS and 97 identified on Android’s Google Play. There has been a 9-fold increase in the number of surgical applications available for the Apple iPhone iOS from 2009 to 2012. Of these applications there were 126 dedicated to plastic surgery, 79 to orthopedics, 41 to neurosurgical, 180 to general surgery, 36 to cardiac surgery, 121 to ophthalmology, and 44 to urology. There was a wide range of applications ranging from simple flashcards to be used for revision to virtual surgery applications that provided surgical exposure and familiarization with common operative procedures. Conclusions. Despite the plethora of surgical applications available for smartphones, there is no taxonomy for medical applications. Only 12% were affiliated with an academic institution or association, which highlights the need for greater regulation of surgical applications.
Advance care planning
Authors: Gowing Alice , Robinson Louise
Published: April 2014

GPs play an important role in caring for patients at the end of their life. To facilitate patient autonomy, care providers are encouraged to give patients the opportunity to discuss their priorities and preferences for future care in anticipation of a loss of capacity. This process is called advance care planning. This is an area of increasing interest and importance, made even more pertinent by the enactment of the Mental Capacity Act 2005 ; however, it can be confusing and daunting to health professionals. This article aims to summarise the key aspects of advance care planning.
The clinic-pathological characteristics of prostate cancer in an Irish subpopulation with a serum PSA less than 4.0ng/ml
Authors: O’Kelly F , McGuire BB , Flynn RJ , Grainger R , McDermott TED , Thornhill JA
Published: April 2014

Background:

Prostate specific antigen (PSA) has been used as a biomarker for prostate cancer for the last 20 years. Traditionally, a serum PSA <4 ng/ml has been used as a general cut-off between normal and abnormal readings. There is evidence to demonstrate that men with a normal serum PSA can develop prostate cancer. The aim of this study was to investigate the clinico-pathological features of prostate cancer in a non-screened Irish cohort with serum PSA <4 ng/ml.

Methods:

A retrospective analysis was performed of all patients who underwent radical retropubic prostatectomy (RRP) in a tertiary referral unit over a 10-year period (2000–2010). Clinico-pathological characteristics were collated including those from trans-rectal ultrasound-guided (TRUS) prostate biopsies and radical prostatectomy specimens.

Results:

Between 2000 and 2010, 651 men underwent an RRP, with 43 (6.6%) having a serum PSA <4 ng/ml. The median PSA was 3.2 ng/ml (range 0.8–4.0). Nineteen (44.2%) had palpable disease on direct rectal examination (DRE). Following prostatectomy, 28 (65.12%) had Gleason 6 disease, 14 (32.56%) had Gleason 7 disease and one (2.32%) had Gleason 8 disease. Five (11.63%) patients were upgraded from TRUS biopsy to final histopathology. Six (13.95%) patients had pathological evidence of extracapsular extension on final pathology. Three (6.98%) patients experienced biochemical recurrence and received salvage radiation therapy after a median time of 24 months. The median follow-up was 106 months (range 36–158). Twenty (46.51%) patients had a first-degree family history of prostate cancer.

Conclusions:

A PSA cut-off of 4 ng/ml has commonly been used in the detection of prostate cancer. Our study emphasizes that this cut-off is inappropriate and that no specific level of PSA can be used. Management decisions need to be individualized based on index of suspicion with concomitant counselling and rectal examination.
pth moment stability in stochastic neutral Volterra-Levin equation with Lévy noise and variable delays
Authors: Yin Hongwei , Xiao Shuiming , Xiao Xiaoyong , Wen Xiaoqing
Published: April 2014

In this paper, we study a class of stochastic neutral Volterra-Levin equations which are equipped with Lévy noise and variable delay and we obtain p th moment exponential stability. Some well-known results are improved and generalized.
Laboratory assessment of molluscicidal and cercariacidal effects of Glinus lotoides fruits
Authors: Kiros Gebrehiwot , Erko Berhanu , Giday Mirutse , Mekonnen Yalemtsehay
Published: April 2014

Background

The negative impact of synthetic molluscicides on the environment and their high cost necessitated search for an alternative approach of using plant extracts for the control of schistosomiasis. The objective of this study was, therefore, to evaluate aqueous and ethyl acetate crude extracts of Glinus lotoides fruits for their cercariacidal activity and molluscicidal effect against schistosome snail intermediate hosts.

Methods

Assessment of the molluscicidal activity against Biomphalaria pfeifferi was made by immersion method in accordance with WHO guideline. The results of mortality were statistically analyzed using probit analysis. The attenuating effect of the plant on Schistosoma mansoni cercariae was determined using establishment of adult worms as a parasitological parameter post exposure.

Results

The 24 and 48 hour-LC50 values for the aqueous extract of G. lotoides fruits were 47.1 and 44.1 mg/L, respectively, whereas that of ethyl acetate were 66.1 and 59.6 mg/L, respectively. The 24 and 48 hour LC90 values for the aqueous extract of G. lotoides fruits were 56.96 and 51.0 mg/L, respectively, while that of ethyl acetate were 77.2 and 70.0 mg/L, respectively. The in vitro cercariacidal activity was determined after 2 hrs of exposure to the aqueous plant extract. It was found out that the LC50 and LC90 values were 18.7 and 41.7 mg/L, respectively. Besides, infectivity of Schistosoma mansoni cercariae to mice was determined by exposing mice to cercariae pre-treated with the sub-lethal concentrations (3.7, 11.6 and 18.7 mg/L) of the aqueous extract. A significant reduction in worm burden in mice was obtained at 11.6 mg/L (p < 0.05). Moreover, the reduction in number of worms recovered was highly significant at 18.7 mg/L (p < 0.001).

Conclusions

The results showed that G. lotoides has molluscicidal activity against B. pfeifferi snails and cercariacidal activity against S. mansoni. Yet, further comprehensive evaluation is recommended for the possible use of G. lotoides against B. pfeifferi and the schistosome parasite.
Predictors of exacerbation frequency in chronic obstructive pulmonary disease
Authors: Yang Hui , Xiang Pingchao , Zhang Erming , Guo Wei’An , Shi Yanwei , Zhang Shuo , Tong Zhaohui
Published: April 2014

Background

Exacerbations of chronic obstructive pulmonary disease (COPD) are sporadic, acute worsening of symptoms. Identifying predictors of exacerbation frequency may facilitate medical interventions that reduce exacerbation frequency and severity. The objective of this study was to determine predictors of exacerbation frequency and mortality.

Methods

A total of 227 COPD patients were enrolled in a prospective clinical study between January 2000 and December 2011. Reported exacerbations were recorded for the year preceding enrollment and annually thereafter, and patients were grouped by median annual exacerbation frequency into those experiencing infrequent exacerbations (less than one exacerbation annually) and frequent exacerbations (one or more exacerbation annually). Patients experiencing frequent exacerbations were further divided into those experiencing moderately frequent exacerbations (fewer than two exacerbations per year) and severely frequent exacerbations (two or more exacerbations per year). The rate of clinical relapse and survival was recorded over a 10-year period. The mean of follow-up time was 5.15 years per patient.

Results

For patients experiencing infrequent, moderately frequent, and severely frequent exacerbations, median exacerbations in the year preceding enrollment were 0.0, 0.5, 1.0, respectively, and more frequent exacerbations correlated with lower baseline forced expiratory volume in one second (FEV1) (0.81 L, 0.75 L, and 0.66 L, respectively), higher comorbidity (70.7%, 75.0%, and 89.4%, respectively), and greater NPPV use during hospitalization (16.4%, 35.9% and 51.1%, respectively). FEV1 declined and mortality increased with increasing exacerbation frequency.

Conclusions

Exacerbation frequency can be used to generate discreet patient subpopulations, supporting the hypothesis that multiple COPD phenotypes exist and can be used in patient risk stratification.
Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis?
Authors: Masi Alfonse T
Published: April 2014

Ankylosing spondylitis and axial spondyloarthropathy have characteristic age- and sex-specific onset patterns, typical entheseal lesions, and marked heritability, but the integrative mechanisms causing the pathophysiological and structural alterations remain largely undefined. Myofascial tissues are integrated in the body into webs and networks which permit transmission of passive and active tensional forces that provide stabilizing support and help to control movements. Axial myofascial hypertonicity was hypothesized as a potential excessive polymorphic trait which could contribute to chronic biomechanical overloading and exaggerated stresses at entheseal sites. Such a mechanism may help to integrate many of the characteristic host, pathological, and structural features of ankylosing spondylitis and axial spondyloarthritis. Biomechanical stress and strain were recently documented to correlate with peripheral entheseal inflammation and new bone formation in a murine model of spondyloarthritis. Ankylosing spondylitis has traditionally been classified by the modified New York criteria, which require the presence of definite radiographic sacroiliac joint lesions. New classification criteria for axial spondyloarthritis now include patients who do not fulfill the modified New York criteria. The male-to-female sex ratios clearly differed between the two patient categories - 2:1 or 3:1 in ankylosing spondylitis and 1:1 in non-radiographic axial spondyloarthritis - and this suggests a spectral concept of disease and, among females, milder structural alterations. Magnetic resonance imaging of active and chronic lesions in ankylosing spondylitis and axial spondyloarthritis reveals complex patterns, usually interpreted as inflammatory reactions, but shows similarities to acute degenerative disc disease, which attributed to edema formation following mechanical stresses and micro-damage. A basic question is whether mechanically induced microinjury and immunologically mediated inflammatory mechanisms operate in both ankylosing spondylitis and degenerative disc disease but differ in relative degrees. The hypothesized biomechanical properties raised in this commentary require documentation of their association with the onset risk and course of ankylosing spondylitis and axial spondyloarthritis. If particular subsets of ankylosing spondylitis and axial spondyloarthritis patients are confirmed to have altered axial myofascial properties, their biological basis and underlying biomechanical mechanisms promise to become clarified. Understanding how biomechanical and physical properties can affect symptomatic and structural manifestations of these disorders could also improve their management.
Ultrasonographic assessment reveals detailed distribution of synovial inflammation in Blau syndrome
Authors: Ikeda Kei , Kambe Naotomo , Takei Syuji , Nakano Taiji , Inoue Yuzaburo , Tomiita Minako , Oyake Natsuko , Satoh Takashi , Yamatou Tsuyoshi , Kubota Tomohiro , Okafuji Ikuo , Kanazawa Nobuo , Nishikomori Ryuta , Shimojo Naoki , Matsue Hiroyuki , Nakajima Hiroshi
Published: April 2014

Introduction

Arthritis is the most frequent manifestation of Blau syndrome, an autoinflammatory disorder caused by the genetic mutation of NOD2. However, detailed information on arthritis in Blau syndrome on which the therapeutic strategy should be based on is lacking. This multi-center study aimed to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome.

Methods

Patients who had been diagnosed with Blau syndrome by genetic analysis of NOD2 were recruited. A total of 102 synovial sites in 40 joints were assessed semiquantitatively by ultrasound for gray-scale synovitis and synovial power Doppler (PD) signal.

Results

In total, 10 patients whose age ranged from 10 months to 37 years enrolled in this study. Although only 4 joints (0.8%) were tender on physical examination, 81 joints (16.9%) were clinically swollen. Moreover, 240 (50.0%), and 124 (25.8%) joints showed gray-scale (GS) synovitis and synovial PD signal on ultrasound, respectively. Importantly, GS synovitis was present in 168 out of 399 non-swollen joints, in which 61 also exhibited synovial PD signal. Among 40 joint regions, the ankle, the wrist, and the proximal interphalangeal joints were the most frequently and severely affected joints. Comparisons between different synovial tissues demonstrated a significantly higher proportion of the joints with tenosynovitis as compared with that with intra-articular synovitis (41.5% versus 27.9%, P < 0.0001). In respect of age and treatment, synovial PD signals were minimal in the youngest patient and in the oldest two patients, and were relatively mild in patients receiving treatment with methotrexate plus TNF antagonists. In two patients who underwent the second ultrasound examination, total PD scores markedly decreased after initiating the treatment with a tumor necrosis factor (TNF) antagonist.

Conclusions

The detailed information on synovial inflammation obtained by ultrasound confirms the dissociation between pain and inflammation and the frequently involved joint regions and synovial tissue in the arthritis of Blau syndrome. Our data also demonstrate that ultrasonography can be a potent tool in monitoring the activity of synovial inflammation and in investigating the pathophysiology of arthritis in this rare but archetypical autoinflammatory condition.
Mammographic texture resemblance generalizes as an independent risk factor for breast cancer
Authors: Nielsen Mads , Vachon Celine M , Scott Christopher G , Chernoff Konstantin , Karemore Gopal , Karssemeijer Nico , Lillholm Martin , Karsdal Morten A
Published: April 2014

Introduction

Breast density has been established as a major risk factor for breast cancer. We have previously demonstrated that mammographic texture resemblance (MTR), recognizing the local texture patterns of the mammogram, is also a risk factor for breast cancer, independent of percent breast density. We examine if these findings generalize to another population.

Methods

Texture patterns were recorded in digitalized pre-diagnosis (3.7 years) film mammograms of a nested case–control study within the Dutch screening program (S1) comprising of 245 breast cancers and 250 matched controls. The patterns were recognized in the same study using cross-validation to form resemblance scores associated with breast cancer. Texture patterns from S1 were examined in an independent nested case–control study within the Mayo Mammography Health Study cohort (S2) of 226 cases and 442 matched controls: mammograms on average 8.5 years prior to diagnosis, risk factor information and percent mammographic density (PD) estimated using Cumulus were available. MTR scores estimated from S1, S2 and S1 + S2 (the latter two as cross-validations) were evaluated in S2. MTR scores were analyzed as both quartiles and continuously for association with breast cancer using odds ratios (OR) and adjusting for known risk factors including age, body mass index (BMI), and hormone usage.

Results

The mean ages of S1 and S2 were 58.0 ± 5.7 years and 55.2 ± 10.5 years, respectively. The MTR scores on S1 showed significant capability to discriminate cancers from controls (area under the operator characteristics curve (AUC) = 0.63 ± 0.02, P <0.001), which persisted after adjustment for PD. S2 showed an AUC of 0.63, 0.61, and 0.60 based on PD, MTR scores trained on S2, and MTR scores trained on S1, respectively. When adjusted for PD, MTR scores of S2 trained on S1 showed an association with breast cancer for the highest quartile alone: OR in quartiles of controls as reference; 1.04 (0.59 to 1.81); 0.95 (0.52 to 1.74); 1.84 (1.10 to 3.07) respectively. The combined continuous model with both PD and MTR scores based on S1 had an AUC of 0.66 ± 0.03.

Conclusions

The local texture patterns associated with breast cancer risk in S1 were also an independent risk factor in S2. Additional textures identified in S2 did not significantly improve risk segregation. Hence, the textural patterns that indicated elevated risk persisted under differences in X-ray technology, population demographics, follow-up time and geography.
Multilevel competing risk models to evaluate the risk of nosocomial infection
Authors: Wolkewitz Martin , Cooper Ben S , Palomar-Martinez Mercedes , Alvarez-Lerma Francisco , Olaechea-Astigarraga Pedro , Barnett Adrian G , Harbarth Stephan , Schumacher Martin
Published: April 2014

Introduction

Risk factor analyses for nosocomial infections (NIs) are complex. First, due to competing events for NI, the association between risk factors of NI as measured using hazard rates may not coincide with the association using cumulative probability (risk). Second, patients from the same intensive care unit (ICU) who share the same environmental exposure are likely to be more similar with regard to risk factors predisposing to a NI than patients from different ICUs. We aimed to develop an analytical approach to account for both features and to use it to evaluate associations between patient- and ICU-level characteristics with both rates of NI and competing risks and with the cumulative probability of infection.

Methods

We considered a multicenter database of 159 intensive care units containing 109,216 admissions (813,739 admission-days) from the Spanish HELICS-ENVIN ICU network. We analyzed the data using two models: an etiologic model (rate based) and a predictive model (risk based). In both models, random effects (shared frailties) were introduced to assess heterogeneity. Death and discharge without NI are treated as competing events for NI.

Results

There was a large heterogeneity across ICUs in NI hazard rates, which remained after accounting for multilevel risk factors, meaning that there are remaining unobserved ICU-specific factors that influence NI occurrence. Heterogeneity across ICUs in terms of cumulative probability of NI was even more pronounced. Several risk factors had markedly different associations in the rate-based and risk-based models. For some, the associations differed in magnitude. For example, high Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were associated with modest increases in the rate of nosocomial bacteremia, but large increases in the risk. Others differed in sign, for example respiratory vs cardiovascular diagnostic categories were associated with a reduced rate of nosocomial bacteremia, but an increased risk.

Conclusions

A combination of competing risks and multilevel models is required to understand direct and indirect risk factors for NI and distinguish patient-level from ICU-level factors.
Excision of viral reprogramming cassettes by Cre protein transduction enables rapid, robust and efficient derivation of transgene-free human induced pluripotent stem cells
Authors: Kadari Asifiqbal , Lu Min , Li Ming , Sekaran Thileepan , Thummer Rajkumar P , Guyette Naomi , Chu Vi , Edenhofer Frank
Published: April 2014

Integrating viruses represent robust tools for cellular reprogramming; however, the presence of viral transgenes in induced pluripotent stem cells (iPSCs) is deleterious because it holds the risk of insertional mutagenesis leading to malignant transformation. Here, we combine the robustness of lentiviral reprogramming with the efficacy of Cre recombinase protein transduction to derive iPSCs devoid of transgenes. By genome-wide analysis and targeted differentiation towards the cardiomyocyte lineage, we show that transgene-free iPSCs are superior to iPSCs before Cre transduction. Our study provides a simple, rapid and robust protocol for the generation of clinical-grade iPSCs suitable for disease modeling, tissue engineering and cell replacement therapies.
Phase I Trial of a Novel Anti-GD2 Monoclonal Antibody, Hu14.18K322A, Designed to Decrease Toxicity in Children With Refractory or Recurrent Neuroblastoma
Authors: Navid Fariba , Sondel Paul M. , Barfield Raymond , Shulkin Barry L. , Kaufman Robert A. , Allay Jim A. , Gan Jacek , Hutson Paul , Seo Songwon , Kim KyungMann , Goldberg Jacob , Hank Jacquelyn A. , Billups Catherine A. , Wu Jianrong , Furman Wayne L. , McGregor Lisa M. , Otto Mario , Gillies Stephen D. , Handgretinger Rupert , Santana Victor M.
Published: April 2014

Purpose

The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis.

Patients and Methods

Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m2per day for 4 consecutive days every 28 days (one course).

Results

Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non–dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and β (terminal phase) half-lives were 1.74 and 21.1 days, respectively.

Conclusion

The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m2per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.
IGH@ Translocations Are Prevalent in Teenagers and Young Adults With Acute Lymphoblastic Leukemia and Are Associated With a Poor Outcome
Authors: Russell Lisa J. , Enshaei Amir , Jones Lisa , Erhorn Amy , Masic Dino , Bentley Helen , Laczko Karl S. , Fielding Adele K. , Goldstone Anthony H. , Goulden Nicholas , Mitchell Christopher D. , Wade Rachel , Vora Ajay , Moorman Anthony V. , Harrison Christine J.
Published: April 2014

Purpose

To determine the prevalence and prognostic association of immunoglobulin heavy chain (IGH@) translocations in acute lymphoblastic leukemia (ALL).

Patients and Methods

The cohort comprised 3,269 patients treated on either the UKALL2003 trial for children and adolescents (1 to 24 years old) or the UKALLXII trial for adolescents and adults (15 to 59 years old). High-throughput fluorescent in situ hybridization was used to detect IGH@ translocations.

Results

We identified IGH@ translocations in 5% of patients with ALL (159 of 3,269 patients), in patients with both B-cell (148 of 2,863 patients) and T-cell (11 of 408 patients) disease. Multiple partner genes were identified including CRLF2 (n = 35), five members of the CEPB gene family (n = 17), and ID4 (n = 11). The level of the IGH@-positive clone varied and indicated that some IGH@ translocations were primary events, whereas others were secondary aberrations often associated with other established aberrations. The age profile of patients with IGH@ translocations was distinctive, with a median age of 16 years and peak incidence of 11% among 20- to 24-year-old patients. Among patients with B-cell precursor ALL who were Philadelphia chromosome negative, those with an IGH@ translocation had an inferior overall survival compared with other patients (UKALL2003: hazard ratio, 2.37; 95% CI, 1.34 to 4.18; P = .003; UKALLXII: hazard ratio, 1.73; 95% CI, 1.22 to 2.47; P = .002). However, this adverse effect was not independent of age or minimal residual disease status and did not seem to be driven by an increased risk of relapse.

Conclusion

IGH@ translocations define a genetic feature that is frequent among adolescents and young adults with ALL. Although associated with an adverse outcome in adults, it is not an independent prognostic factor in children and adolescents.
Patients With Apparently Nonfunctioning Adrenal Incidentalomas May Be at Increased Cardiovascular Risk Due to Excessive Cortisol Secretion
Authors: Androulakis Ioannis I. , Kaltsas Gregory A. , Kollias Georgios E. , Markou Athina C. , Gouli Aggeliki K. , Thomas Dimitrios A. , Alexandraki Krystallenia I. , Papamichael Christos M. , Hadjidakis Dimitrios J. , Piaditis George P.
Published: April 2014

Context:

Although adrenal incidentalomas (AIs) are associated with a high prevalence of cardiovascular risk (CVR) factors, it is not clear whether patients with nonfunctioning AI (NFAI) have increased CVR.

Objective:

Our objective was to investigate CVR in patients with NFAI.

Design and Setting:

This case-control study was performed in a tertiary general hospital.

Subjects:

Subjects included 60 normotensive euglycemic patients with AI and 32 healthy controls (C) with normal adrenal imaging.

Main Outcome Measures:

All participants underwent adrenal imaging, biochemical and hormonal evaluation, and the following investigations: 1) measurement of carotid intima-media thickness (IMT) and flow-mediated dilatation, 2) 2-hour 75-gram oral glucose tolerance test and calculation of insulin resistance indices (homeostasis model assessment, quantitative insulin sensitivity check, and Matsuda indices), 3) iv ACTH stimulation test, 4) low-dose dexamethasone suppression test, and 5) NaCl (0.9%) post-dexamethasone saline infusion test.

Results:

Based on cutoffs obtained from controls, autonomous cortisol secretion was documented in 26 patients (cortisol-secreting AI [CSAI] group), whereas 34 exhibited adequate cortisol and aldosterone suppression (NFAI group). IMT measurements were higher and flow-mediated vasodilatation was lower in the CSAI group compared with both NFAI and C and in the NFAI group compared with C. The homeostasis model assessment index was higher and quantitative insulin sensitivity check index and Matsuda indices were lower in the CSAI and NFAI groups compared with C as well as in CSAI compared with the NFAI group. The area under the curve for cortisol after ACTH stimulation was higher in the CSAI group compared with the NFAI group and C and in the NFAI group compared with C. In the CSAI group, IMT correlated with cortisol, urinary free cortisol, and cortisol after a low-dose dexamethasone suppression test, whereas in the NFAI group, IMT correlated with area under the curve for cortisol after ACTH stimulation and urinary free cortisol.

Conclusions:

Patients with CSAI without hypertension, diabetes, and/or dyslipidemia exhibit adverse metabolic and CVR factors. In addition, NFAIs are apparently associated with increased insulin resistance and endothelial dysfunction that correlate with subtle but not autonomous cortisol excess.
Universal Genetic Screening Uncovers a Novel Presentation of an SDHAF2 Mutation
Authors: Casey Ruth , Garrahy Aoife , Tuthill Antoinette , O'Halloran Domhnall , Joyce Caroline , Casey Mary B. , O'Shea Paula , Bell Marcia
Published: April 2014

Context:

Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner.

Objective:

Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL.

Methods:

In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications.

Results:

A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation.

Conclusion:

This study supports the value of universal genetic screening for all patients with PC/PGL.
Msx1 and Msx2 act as essential activators of Atoh1 expression in the murine spinal cord
Authors: Duval Nathalie , Daubas Philippe , Bourcier de Carbon Céline , St Cloment Cécile , Tinevez Jean-Yves , Lopes Miguel , Ribes Vanessa , Robert Benoît
Published: April 2014

Dorsal spinal neurogenesis is orchestrated by the combined action of signals secreted from the roof plate organizer and a downstream transcriptional cascade. Within this cascade, Msx1 and Msx2, two homeodomain transcription factors (TFs), are induced earlier than bHLH neuralizing TFs. Whereas bHLH TFs have been shown to specify neuronal cell fate, the function of Msx genes remains poorly defined. We describe dramatic alterations of neuronal patterning in Msx1/Msx2 double-mutant mouse embryos. The most dorsal spinal progenitor pool fails to express the bHLH neuralizing TF Atoh1, which results in a lack of Lhx2-positive and Barhl2-positive dI1 interneurons. Neurog1 and Ascl1 expression territories are dorsalized, leading to ectopic dorsal differentiation of dI2 and dI3 interneurons. In proportion, the amount of Neurog1-expressing progenitors appears unaffected, whereas the number of Ascl1-positive cells is increased. These defects occur while BMP signaling is still active in the Msx1/Msx2 mutant embryos. Cell lineage analysis and co-immunolabeling demonstrate that Atoh1-positive cells derive from progenitors expressing both Msx1 and Msx2. In vitro, Msx1 and Msx2 proteins activate Atoh1 transcription by specifically interacting with several homeodomain binding sites in the Atoh1 3′ enhancer. In vivo, Msx1 and Msx2 are required for Atoh1 3′ enhancer activity and ChIP experiments confirm Msx1 binding to this regulatory sequence. These data support a novel function of Msx1 and Msx2 as transcriptional activators. Our study provides new insights into the transcriptional control of spinal cord patterning by BMP signaling, with Msx1 and Msx2 acting upstream of Atoh1.
Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state
Authors: Chakkalakal Joe V. , Christensen Josef , Xiang Wanyi , Tierney Mathew T. , Boscolo Francesca S. , Sacco Alessandra , Brack Andrew S.
Published: April 2014

Across different niches, subsets of highly functional stem cells are maintained in a relatively dormant rather than proliferative state. Our understanding of proliferative dynamics in tissue-specific stem cells during conditions of increased tissue turnover remains limited. Using a TetO-H2B-GFP reporter of proliferative history, we identify skeletal muscle stem cell, or satellite cells, that retain (LRC) or lose (nonLRC) the H2B-GFP label. We show in mice that LRCs and nonLRCs are formed at birth and persist during postnatal growth and adult muscle repair. Functionally, LRCs and nonLRCs are born equivalent and transition during postnatal maturation into distinct and hierarchically organized subsets. Adult LRCs give rise to LRCs and nonLRCs; the former are able to self-renew, whereas the latter are restricted to differentiation. Expression analysis revealed the CIP/KIP family members p21cip1 (Cdkn1a) and p27kip1 (Cdkn1b) to be expressed at higher levels in LRCs. In accordance with a crucial role in LRC fate, loss of p27kip1 promoted proliferation and differentiation of LRCs in vitro and impaired satellite cell self-renewal after muscle injury. By contrast, loss of p21cip1 only affected nonLRCs, in which myogenic commitment was inhibited. Our results provide evidence that restriction of self-renewal potential to LRCs is established early in life and is maintained during increased tissue turnover through the cell cycle inhibitor p27kip1. They also reveal the differential role of CIP/KIP family members at discrete steps within the stem cell hierarchy.
Pulses of Notch activation synchronise oscillating somite cells and entrain the zebrafish segmentation clock
Authors: Soza-Ried Cristian , Öztürk Emre , Ish-Horowicz David , Lewis Julian
Published: April 2014

Formation of somites, the rudiments of vertebrate body segments, is an oscillatory process governed by a gene-expression oscillator, the segmentation clock. This operates in each cell of the presomitic mesoderm (PSM), but the individual cells drift out of synchrony when Delta/Notch signalling fails, causing gross anatomical defects. We and others have suggested that this is because synchrony is maintained by pulses of Notch activation, delivered cyclically by each cell to its neighbours, that serve to adjust or reset the phase of the intracellular oscillator. This, however, has never been proved. Here, we provide direct experimental evidence, using zebrafish containing a heat-shock-driven transgene that lets us deliver artificial pulses of expression of the Notch ligand DeltaC. In DeltaC-defective embryos, in which endogenous Notch signalling fails, the artificial pulses restore synchrony, thereby rescuing somite formation. The spacing of segment boundaries produced by repetitive heat-shocking varies according to the time interval between one heat-shock and the next. The induced synchrony is manifest both morphologically and at the level of the oscillations of her1, a core component of the intracellular oscillator. Thus, entrainment of intracellular clocks by periodic activation of the Notch pathway is indeed the mechanism maintaining cell synchrony during somitogenesis.
The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease
Authors: Varelas Xaralabos
Published: April 2014

Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.
Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis
Authors: Korn Claudia , Scholz Beate , Hu Junhao , Srivastava Kshitij , Wojtarowicz Jessica , Arnsperger Tabea , Adams Ralf H. , Boutros Michael , Augustin Hellmut G. , Augustin Iris
Published: April 2014

Multiple cell types involved in the regulation of angiogenesis express Wnt ligands. Although β-catenin dependent and independent Wnt signaling pathways have been shown to control angiogenesis, the contribution of individual cell types to activate these downstream pathways in endothelial cells (ECs) during blood vessel formation is still elusive. To investigate the role of ECs in contributing Wnt ligands for regulation of blood vessel formation, we conditionally deleted the Wnt secretion factor Evi in mouse ECs (Evi-ECKO). Evi-ECKO mice showed decreased microvessel density during physiological and pathological angiogenesis in the postnatal retina and in tumors, respectively. The reduced microvessel density resulted from increased vessel regression accompanied by decreased EC survival and proliferation. Concomitantly, survival-related genes were downregulated and cell cycle arrest- and apoptosis-inducing genes were upregulated. EVI silencing in cultured HUVECs showed similar target gene regulation, supporting a mechanism of EC-derived Wnt ligands in controlling EC function. ECs preferentially expressed non-canonical Wnt ligands and canonical target gene expression was unaffected in Evi-ECKO mice. Furthermore, the reduced vascularization of Matrigel plugs in Evi-ECKO mice could be rescued by introduction of non-canonical Wnt5a. Treatment of mouse pups with the non-canonical Wnt inhibitor TNP470 resulted in increased vessel regression accompanied by decreased EC proliferation, thus mimicking the proliferation-dependent Evi-ECKO remodeling phenotype. Taken together, this study identified EC-derived non-canonical Wnt ligands as regulators of EC survival, proliferation and subsequent vascular pruning during developmental and pathological angiogenesis.
Functional phylogenetic analysis of LGI proteins identifies an interaction motif crucial for myelination
Authors: Kegel Linde , Jaegle Martine , Driegen Siska , Aunin Eerik , Leslie Kris , Fukata Yuko , Watanabe Masahiko , Fukata Masaki , Meijer Dies
Published: April 2014

The cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution.
New Fisheries-related data from the Mediterranean Sea (April 2014)
Authors: STERGIOU K. , BOBORI D.C. , EKMEKÇİ F.G. , GÖKOĞLU M. , KARACHLE P.K. , MINOS G. , ÖZVAROL Y. , SALVARINA I. , TARKAN A.S. , VILIZZI L.
Published: April 2014

As part of its policy, Mediterranean Marine Science started from 2014 to publish a new series of collective article with fisheries-related data from the Mediterranean Sea. In this first collective article we present length frequencies and weight-length relationships for the northern brown shrimp Farfantepenaeus aztecus in the eastern Mediterranean, length-weight relationships for 10 fish species in the North Aegean Sea, the feeding habits for 11 sparid fishes in the North Aegean Sea, a review of the existing literature on the feeding and reproduction of common carp Cyprinus carpio in Anatolia (Turkey) and mouth dimensions and the relationships between mouth area and length for seven freshwater fishes from Lake Volvi (Northern Greece).
Corporate Social Responsibility in the Wood Products Industry: US and Chinese Consumers' Perceptions
Authors: Cai Zhen , Aguilar Francisco X.
Published: April 2014

This study examined US and Chinese consumers' perceptions of the economic, ethical, legal, and philanthropic responsibilities that wood products companies should be held responsible for. Survey data collected in the United States and China in 2011 were analyzed to determine whether this four-component corporate social responsibility (CSR) model was valid and to explore differences between the two countries. Results suggest that economic, ethical, legal, and philanthropic dimensions fit well a model of CSR. Responsibilities related to sound forest management were embedded in legal and ethical expectations. Wood products consumers from both nations self-reported higher expectations for companies' legal and ethical responsibilities than for economic and philanthropic responsibilities. US respondents' expectations for ethical and philanthropic responsibilities in the wood products industry had positive and significant effects on their stated preferences to purchase wood products. In China, only respondents' expectations for philanthropic responsibilities were found to have a positive and significant impact on stated purchasing preferences. The premise that wood products companies' primary objective is to attain economic profits may not be representative of consumers' expectations. Economic expectations seem axiomatic, and consumers instead deem this and likely other natural resource–based industries should exercise greater legal, ethical, and philanthropic practices.
Intrauterine Growth Restriction Impairs Small Intestinal Mucosal Immunity in Neonatal Piglets
Authors: Dong Li , Zhong Xiang , Ahmad Hussain , Li Wei , Wang Yuanxiao , Zhang Lili , Wang Tian
Published: April 2014

Intrauterine growth restriction (IUGR) is a very common problem in both piglet and human neonate populations. We hypothesized that IUGR neonates have impaired intestinal mucosal immunity from birth. Using neonatal piglets as IUGR models, immune organ weights, the weight and length of the small intestine (SI), intestinal morphology, intraepithelial immune cell numbers, levels of cytokines and immunoglobulins, and the relative gene expression of cytokines in the SI were investigated. IUGR neonatal piglets were observed to have lower absolute immune organ weight and SI length, decreased relative weights of the thymus, spleen, mesenteric lymph node, and thinner but longer SIs. Damaged and jagged villi, shorter microvilli, presence of autophagosomes, swelled mitochondria, and decreased villus surface areas were also found in the SIs of IUGR neonatal piglets. We also found a smaller number of epithelial goblet cells and lymphocytes in the SIs of IUGR neonates. In addition, we detected reduced levels of the cytokines TNF-α and IFN-γ and decreased gene expression of cytokines in IUGR neonates. In conclusion, IUGR was shown to impair the mucosal immunity of the SI in neonatal piglets, and the ileum was the major site of impairment.
The Clinical Use of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) in Australia
Authors: Kinsella-Ritter Angela , Gibson Frances L. , Wyver Shirley
Published: April 2014

The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) is a standardised assessment used to assess the developmental functioning of infants and young children from 1 month to 42 months of age (Bayley, 2006a). The Bayley scales are recognised internationally as one of the most comprehensive developmental assessment instruments (Sattler & Hoge, 2006) used to examine the major facets of a young child's development (Bayley, 2006a). The primary purpose of the Bayley-III is to identify children with developmental delay and to provide information for intervention implementation (Bayley, 2006a). The domains of early development covered increased from two to five including cognition, language, motor, social-emotional and adaptive behaviour with the publication of the third edition (Bayley, 2006a). While the original Bayley scales were predominately used by psychologists, publication of later editions led to accredited use, within the Australian and New Zealand context, by developmental paediatricians, occupational therapists, physiotherapists and speech pathologists (Bayley, 1969; Bayley 1992; Pearson Clinical and Talent Assessment, 2009). Although the Bayley-III is more comprehensive and a broader range of professionals now use the scales little is known about the clinical application. The current study aimed to explore the use of the Bayley-III in practice and views on the current US norms. An online survey was conducted and the findings revealed that the majority of respondents were interested in Australian local norms; the predominant age range assessed was the 24- to 42-month-old group and the most common clinical group seen and assessed was children presenting with global developmental delay. While the majority of the respondents used the Bayley-III approximately once a month or more, at least one third used it less often. However anticipated use over the next 12 months indicated a notable increase from 30% currently using it once or twice weekly up to 65%.
Tourism Reform, Policy and Development in Queensland, 1989–2011
Authors: Dredge Dianne
Published: April 2014

Tourism has been a major driver of economic and social development in Queensland since the end of World War II. In 2011, tourism's direct contribution to the economy was estimated to be $7.8 billion, and it generated direct employment of an estimated 118,000 full-time equivalent jobs (Queensland Tourism 2011). The multiplier effects of tourism account for another $9.2 billion, making it the most important component of the state's service sector. These figures suggest that the approach adopted by the Labor government over the last two decades to manage and develop Queensland tourism has generally been positive. However, a closer examination of recent trends and criticisms reveals that visitor demand has flat-lined: the industry is struggling under the weight of global and local pressures, investment has slowed, and there are issues of stagnating demand, competitiveness, service quality, industry capacity and innovation. Moreover, Queensland is losing international market share compared with New South Wales and Victoria (Tourism Research Australia 2011). Given that governments have a key role to play in creating and maintaining policy conditions that contribute to both a healthy economy and social well-being, what have been the Queensland Labor government's contributions to tourism, and what are the key challenges into the future?