bluuebunny/crossref_metadata_2025 huggingface dataset:
Organization and mode of action of two component system signaling circuits from the various kingdoms of life
Authors: Alvarez Adrian F. , Barba‐Ostria Carlos , Silva‐Jiménez Hortencia , Georgellis Dimitris
Published: May 2016

Two‐component system (TCS) signaling circuits regulate numerous cellular processes in response to environmental cues in both prokaryotic and eukaryotic cells. These signaling circuits are all based on phosphoryl‐group transfers between histidine and aspartate containing modules of sensor kinase and response regulator proteins. Curiously, the architecture and organization of prokaryotic and eukaryotic two‐component systems reveal notable variations, raising the question of whether the input‐response specificity that governs the majority of prokaryotic TCSs also governs the eukaryotic ones. In this review, we contrast the TCS architecture and signaling circuits of prokaryotes and eukaryotes, and discuss their possible consequences on signaling specificity.
Physiological adjustments and transcriptome reprogramming are involved in the acclimation to salinity gradients in diatoms
Authors: Bussard Adrien , Corre Erwan , Hubas Cédric , Duvernois‐Berthet Evelyne , Le Corguillé Gildas , Jourdren Laurent , Coulpier Fanny , Claquin Pascal , Lopez Pascal Jean
Published: May 2016

Salinity regimes in estuaries and coastal areas vary with river discharge patterns, seawater evaporation, the morphology of the coastal waterways and the dynamics of marine water mixing. Therefore, microalgae have to respond to salinity variations at time scales ranging from daily to annual cycles. Microalgae may also have to adapt to physical alterations that induce the loss of connectivity between habitats and the enclosure of bodies of water. Here, we integrated physiological assays and measurements of morphological plasticity with a functional genomics approach to examine the regulatory changes that occur during the acclimation to salinity in the estuarine diatom Thalassiosira weissflogii. We found that cells exposed to different salinity regimes for a short or long period presented adjustments in their carbon fractions, silicon pools, pigment concentrations and/or photosynthetic parameters. Salinity‐induced alterations in frustule symmetry were observed only in the long‐term (LT) cultures. Whole transcriptome analyses revealed a down‐regulation of nuclear and plastid encoded genes during the LT response and identified only a few regulated genes that were in common between the ST and LT responses. We propose that in diatoms, one strategy for acclimating to salinity gradients and maintaining optimal cellular fitness could be a reduction in the cost of transcription.
Surface area–volume ratios in insects
Authors: Kühsel Sara , Brückner Adrian , Schmelzle Sebastian , Heethoff Michael , Blüthgen Nico
Published: May 2016

Body mass, volume and surface area are important for many aspects of the physiology and performance of species. Whereas body mass scaling received a lot of attention in the literature, surface areas of animals have not been measured explicitly in this context. We quantified surface area–volume (SA/V) ratios for the first time using 3D surface models based on a structured light scanning method for 126 species of pollinating insects from 4 orders (Diptera, Hymenoptera, Lepidoptera, and Coleoptera). Water loss of 67 species was measured gravimetrically at very dry conditions for 2 h at 15 and 30 °C to demonstrate the applicability of the new 3D surface measurements and relevance for predicting the performance of insects. Quantified SA/V ratios significantly explained the variation in water loss across species, both directly or after accounting for isometric scaling (residuals of the SA/V ∼ mass2/3 relationship). Small insects with a proportionally larger surface area had the highest water loss rates. Surface scans of insects to quantify allometric SA/V ratios thus provide a promising method to predict physiological responses, improving the potential of body mass isometry alone that assume geometric similarity.
Metatranscriptome of the protistan community in Reticulitermes flaviceps
Authors: Liu Xiao‐Jing , Che Min , Xie Lei , Zhan Shuai , Zhou Zhi‐Hua , Huang Yong‐Ping , Wang Qian
Published: May 2016

The hindgut of lower termites harbors various symbiotic protists, which perform varied functions in lignocellulose decomposition. As termites are social insects, the species and numbers of these flagellated protists in the termite gut vary among the different castes. Juvenile hormones (JHs) can regulate caste differentiation in termites. In this study, we used the juvenile hormone analog fenoxycarb to induce termite workers (Reticulitermes flaviceps) to differentiate into pre‐soldiers. A metatranscriptomic investigation of the protistan community was then performed by 454 pyrosequencing. From a thorough analysis based on 597 312 generated reads, we found that the starch and sucrose metabolism pathway was the most abundant pathway across the metatranscriptome. The current study demonstrates that the metatranscriptome of the protistan community in termites contains an abundance of lignocellulase, which plays a vital role in termite nutrition.
Survival analysis of veteran patients with pancreatic cancer
Authors: Kim David , Zhu Hong , Nassri Ammar , Mokdad Ali , Kukreja Sachin , Polanco Patricio , Huerta Sergio , Ramzan Zeeshan
Published: May 2016

Objective

For patients with pancreatic cancer, the identification of reliable predictors of their outcomes could be invaluable for directing the managements. This study aimed to identify clinical and laboratory factors that could be used to predict early (≤6 months) or late (>6 months) mortality.

Methods

Medical records of patients diagnosed with pancreatic cancer in the VA North Texas Health Care System from 2005 to 2010 were retrospectively reviewed. Univariate and multivariate analyses (MVA) were performed and the utility of cancer antigen 19‐9 (CA19‐9) test was explored.

Results

Altogether 109 patients with pancreatic cancer, 89.0% of whom were with adenocarcinoma, were divided into early (n = 62) and late (n = 47) mortality groups. Kaplan–Meier analysis revealed a median survival of 154 days [95% confidence interval (CI) 93–194 days]. On MVA, abdominal pain (OR = 10.6, P = 0.009) and large tumor size (OR = 2.4, P = 0.028) were significantly associated with early mortality, while palliative chemotherapy (OR = 0.048, P = 0.001) and neuroendocrine tumor (OR = 0.009, P = 0.024) were significantly associated with late mortality. Subgroup analyses of adenocarcinoma and late‐stage patients revealed similar results. Serum CA19‐9 performed poorly as a prognostic indicator in both groups (P = 0.43), in metastatic disease at diagnosis (P = 0.32) and after treatment (P = 0.65).

Conclusions

Abdominal pain and large tumor size portends a poor prognosis in patients with pancreatic cancer. Palliative chemotherapy and surgical intervention may prolong the patient's survival. CA19‐9 is not universally reliable for predicting metastasis, survival, or the responses to chemotherapy.
Lessons from genome skimming of arthropod‐preserving ethanol
Authors: Linard B. , Arribas P. , Andújar C. , Crampton‐Platt A. , Vogler A. P.
Published: May 2016

Field‐collected specimens of invertebrates are regularly killed and preserved in ethanol, prior to DNA extraction from the specimens, while the ethanol fraction is usually discarded. However, DNA may be released from the specimens into the ethanol, which can potentially be exploited to study species diversity in the sample without the need for DNA extraction from tissue. We used shallow shotgun sequencing of the total DNA to characterize the preservative ethanol from two pools of insects (from a freshwater habitat and terrestrial habitat) to evaluate the efficiency of DNA transfer from the specimens to the ethanol. In parallel, the specimens themselves were subjected to bulk DNA extraction and shotgun sequencing, followed by assembly of mitochondrial genomes for 39 of 40 species in the two pools. Shotgun sequencing from the ethanol fraction and read‐matching to the mitogenomes detected ~40% of the arthropod species in the ethanol, confirming the transfer of DNA whose quantity was correlated to the biomass of specimens. The comparison of diversity profiles of microbiota in specimen and ethanol samples showed that ‘closed association’ (internal tissue) bacterial species tend to be more abundant in DNA extracted from the specimens, while ‘open association’ symbionts were enriched in the preservative fluid. The vomiting reflex of many insects also ensures that gut content is released into the ethanol, which provides easy access to DNA from prey items. Shotgun sequencing of DNA from preservative ethanol provides novel opportunities for characterizing the functional or ecological components of an ecosystem and their trophic interactions.
Sex determination in the wild: a field application of loop‐mediated isothermal amplification successfully determines sex across three raptor species
Authors: Centeno‐Cuadros A. , Abbasi I. , Nathan R.
Published: May 2016

PCR‐based methods are the most common technique for sex determination of birds. Although these methods are fast, easy and accurate, they still require special facilities that preclude their application outdoors. Consequently, there is a time lag between sampling and obtaining results that impedes researchers to take decisions in situ and in real time considering individuals’ sex. We present an outdoor technique for sex determination of birds based on the amplification of the duplicated sex‐chromosome‐specific gene Chromo‐Helicase‐DNA binding protein using a loop‐mediated isothermal amplification (LAMP). We tested our method on Griffon Vulture (Gyps fulvus), Egyptian Vulture (Neophron percnopterus) and Black Kite (Milvus migrans) (family Accipitridae). We introduce the first fieldwork procedure for sex determination of animals in the wild, successfully applied to raptor species of three different subfamilies using the same specific LAMP primers. This molecular technique can be deployed directly in sampling areas because it only needs a voltage inverter to adapt a thermo‐block to a car lighter and results can be obtained by the unaided eye based on colour change within the reaction tubes. Primers and reagents are prepared in advance to facilitate their storage at room temperature. We provide detailed guidelines how to implement this procedure, which is simpler (no electrophoresis required), cheaper and faster (results in c. 90 min) than PCR‐based laboratory methods. Our successful cross‐species application across three different raptor subfamilies posits our set of markers as a promising tool for molecular sexing of other raptor families and our field protocol extensible to all bird species.
A high‐throughput detection method for invasive fruit fly (Diptera:Tephritidae) species based on microfluidic dynamic array
Authors: Jiang Fan , Fu Wei , Clarke Anthony R. , Schutze Mark Kurt , Susanto Agus , Zhu Shuifang , Li Zhihong
Published: May 2016

Invasive species can be detrimental to a nation's ecology, economy and human health. Rapid and accurate diagnostics are critical to limit the establishment and spread of exotic organisms. The increasing rate of biological invasions relative to the taxonomic expertise available generates a demand for high‐throughput,DNA‐based diagnostics methods for identification. We designed species‐specificqPCRprimer and probe combinations for 27 economically important tephritidae species in six genera (Anastrepha,Bactrocera,Carpomya,Ceratitis,DacusandRhagoletis) based on 935COI DNAbarcode haplotypes from 181 fruit fly species publically available inBOLD, and then tested the specificity for each primer pair and probe throughqPCRof 35 of those species. We then developed a standardization reaction system for detecting the 27 target species based on a microfluidic dynamic array and also applied the method to identify unknown immature samples from port interceptions and field monitoring. This method led to a specific and simultaneous detection for all 27 species in 7.5 h, using only 0.2 μL of reaction system in each reaction chamber. The approach successfully discriminated among species within complexes that had genetic similarities of up to 98.48%, while it also identified all immature samples consistent with the subsequent results of morphological examination of adults which were reared from larvae of cohorts from the same samples. We present an accurate, rapid and high‐throughput innovative approach for detecting fruit flies of quarantine concern. This is a new method which has broad potential to be one of international standards for plant quarantine and invasive species detection.
State‐and‐transition simulation models: a framework for forecasting landscape change
Authors: Daniel Colin J. , Frid Leonardo , Sleeter Benjamin M. , Fortin Marie‐Josée
Published: May 2016

A wide range of spatially explicit simulation models have been developed to forecast landscape dynamics, including models for projecting changes in both vegetation and land use. While these models have generally been developed as separate applications, each with a separate purpose and audience, they share many common features.

We present a general framework, called a state‐and‐transition simulation model (STSM), which captures a number of these common features, accompanied by a software product, called ST‐Sim, to build and run such models. The STSM method divides a landscape into a set of discrete spatial units and simulates the discrete state of each cell forward as a discrete‐time‐inhomogeneous stochastic process. The method differs from a spatially interacting Markov chain in several important ways, including the ability to add discrete counters such as age and time‐since‐transition as state variables, to specify one‐step transition rates as either probabilities or target areas, and to represent multiple types of transitions between pairs of states.

We demonstrate the STSM method using a model of land‐use/land‐cover (LULC) change for the state of Hawai'i, USA. Processes represented in this example include expansion/contraction of agricultural lands, urbanization, wildfire, shrub encroachment into grassland and harvest of tree plantations; the model also projects shifts in moisture zones due to climate change. Key model output includes projections of the future spatial and temporal distribution of LULC classes and moisture zones across the landscape over the next 50 years.

State‐and‐transition simulation models can be applied to a wide range of landscapes, including questions of both land‐use change and vegetation dynamics. Because the method is inherently stochastic, it is well suited for characterizing uncertainty in model projections. When combined with the ST‐Sim software, STSMs offer a simple yet powerful means for developing a wide range of models of landscape dynamics.
Stability of the Effect of a Standardized Meal on QTc
Authors: Täubel Jörg , Fernandes Sara , Ferber Georg
Published: May 2016

Background

The assessment of QTc changes after the intake of a standardized meal has been proposed as an alternative approach to prove assay sensitivity when the proarrhythimic potential of a drug is to be excluded in either TQT or intensive Phase I QT studies.

Methods

In this article, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method.

Results

The results show that the time‐effect attributed to food is stable over different study periods demonstrating consistency of the physiological response triggered by food.

Conclusions

Stability and reproducibility of the effect is comparable with moxifloxacin.
Functional and clinical outcomes following anterior hip replacement: a 5‐year comparative study versus posterior approach
Authors: Balasubramaniam Umatheepan , Dowsey Michelle , Ma Francis , Dunin Anthony , Choong Peter
Published: May 2016

Background

With the evolution of total hip joint replacement techniques, there has been a trend towards minimally invasive surgery. The anterior approach (AA) to total hip arthroplasty has been widely associated with less soft tissue damage. The aim of our study was to compare clinical and 1‐year functional outcomes for AA hip arthroplasty versus a posterior approach (PA).

Method

We retrospectively reviewed 92 (50 anterior and 42 posterior) total hip replacements performed at our centre between 2006 and 2011. Clinical outcomes were recorded from hospital medical records and clinical audit system. Range of motion analysis, Harris hip score (HHS) and Short Form‐12 score were recorded pre‐operatively and at the 12‐month follow‐up marks. Additionally, we reviewed operative time, length of stay, discharge destination, complications, return to theatre and readmission rates.

Results

The results of our study revealed significantly shorter average hospital length of stay for the AA versus PA (4.2 versus 6.0 days, P = 0.004). Interestingly, our study also showed significantly shorter operating time with the AA (83.0 versus 91.8 min, P = 0.048) and lower return to theatre rates (0 versus 9.5%, P = 0.026). Finally, multivariate analysis showed AA to be associated with higher HHS and pre‐operative body mass index to be associated with lower HHS at 12‐month post‐operation (P = 0.02 and <0.001, respectively).

Conclusions

Our study showed improved HHS at 12 months as well as reduced hospital length of stay, operating time and return to theatre with an AA when compared with a PA.
Variance components in confocal scanning laser tomography measurements of neuro‐retinal rim area and the effect of repeated measurements on the power to detect loss over time
Authors: Sandberg Melin Camilla , Nuija Eva , Alm Albert , Yu Zhaohua , Söderberg Per G.
Published: May 2016

Purpose

To estimate the variation in measurements of neuro‐retinal rim area (NRA) determined by confocal scanning laser tomography and consequences for clinical follow‐up.

Methods

Altogether, 24 healthy subjects were randomized on –320 μm, Moorfields and Standard NRA plane strategies. Additionally, NRA was measured in 32 glaucoma subjects. Variance components for subjects, visits and measurements were estimated with analysis of variance. Sample sizes required to detect a 6.0 × 10−2 mm2 NRA change were estimated assuming a significance level of 0.05 and a power of 0.8. Consequences for independent group, and paired comparison design, respectively, were analysed. Further, precision in estimates within subjects over time was investigated.

Results

The variation of NRA among subjects was considerably larger than the variation among visits and measurements. For glaucoma subjects, the variation among visits and measurements were of the same order but larger than in healthy subjects. It was found that independent group comparisons require inconveniently large sample sizes. Within‐subject paired comparisons over time require sample sizes of below 15 subjects. The estimated variations for glaucoma subjects imply that 54 months of follow‐up is required for detection of change from baseline.

Conclusions

The variance for subjects is substantial in relation to those for visits and measurements. Cross‐sectional independent group comparisons of levels of NRA are unsuitable, due to considerable subject variation. Levels of NRA differences within subjects between visits can be estimated with acceptable precision. Neuro‐retinal rim area (NRA) measurement can be used for long‐term follow‐up of glaucoma progression.
The role of corneal endothelial morphology in graft assessment and prediction of endothelial cell loss during organ culture of human donor corneas
Authors: Hermel Martin , Salla Sabine , Fuest Matthias , Walter Peter
Published: May 2016

Purpose

Endothelial assessment is crucial in the release of corneas for grafting. We retrospectively analysed the role of endothelial morphology parameters in predicting endothelial cell loss during organ culture.

Methods

Human donor corneas were cultured in minimal essential medium with 2% fetal calf serum and antibiotics. Initial endothelial morphology was assessed microscopically using score parameters polymegethism (POL), pleomorphism (PLE), granulation (GRA), vacuolization (VAC), segmentation of cell membranes (SEG), Descemet's folds (DF), trypan blue‐positive cells (TBPC) and endothelial cell‐free areas (ECFA). Some corneas were primarily rejected based on endothelial assessment. Endothelial cell density (ECD) was assessed at the beginning (I‐ECD) and end of culture. Corneas were then placed in dehydration medium (as above + 5% dextran 500). In a subgroup, ECD was reassessed after dehydration. Endothelial cell loss during culture (ECL@Culture) and culture+dehydration (ECL‐Culture&Dehydration) were calculated. Data were given as mean ± SD and analysed using multiple linear and logistic regression. Odds ratios (OR) and 95% confidence intervals (CI) were calculated.

Result

I‐ECD was 2812 ± 360/mm2 (n = 2356). The decision to reject a cornea due to endothelial assessment was associated negatively with I‐ECD (OR = 0.77/100 cells, CI 0.7–0.82) and positively with ECFA (OR = 2.7, CI 1.69–4.35), SEG (OR =1.3, CI 1.01–1.68) and donor age (OR = 1.26/decade, CI 1.33–1.41). ECL@Culture was 153 ± 201/mm2 (n = 1277), ECL@Culture&Dehydration was 169 ± 183/mm2 (n = 918). ECL@Culture was associated positively with donor age, I‐ECD, GRA and TBPC, and negatively with PLE, and DF. ECL@Culture&Dehydration was associated positively with age, sex, initial ECD, POL, PLE, VAC and TBPC.

Conclusion

Morphological parameters displayed associations with the exclusion of corneas from culture and with endothelial cell loss. Appropriate parameter selection for screening purposes may help improve graft quality.
Gebauer SLc Original and Moria One‐Use Plus automated microkeratomes for ultrathin Descemet's stripping automated endothelial keratoplasty preparation
Authors: Fuest Matthias , Salla Sabine , Hermel Martin , Plum Wolfgang Joachim , Rütten Stephan , Plange Niklas , Kuerten David , Schnitzler Anne Christine , Walter Peter
Published: May 2016

Purpose

We compared the SLc Original (SLc) and One‐Use Plus (OUP) microkeratomes for ultrathin Descemet's stripping automated endothelial keratoplasty (DSAEK) lamella preparation and storage, vis‐à‐vis accuracy, endothelial cell loss (ECL) and lamellar surface roughness (LSR).

Methods

Twenty‐five human corneas were dissected with single‐use heads of different sizes aiming for a posterior lamella (PL) thickness of 85 μm, after which they were incubated for 6 days in a 5% dextran medium. Before preparation (0 hr) and 1, 24, and 144 hr after dissection, ECL and corneal thickness (CCT) were measured by ultrasound pachymetry (USP) and optical coherence tomography (OCT). Lamellar surface roughness (LSR) was assessed by scanning electron microscopy (SEM) and evaluated by two masked observers.

Results

Prior to cutting, CCTs did not differ between OCT and USP measurements, with a high correlation between the two modalities (r2 = 0.8; p < 0.0001). Both systems succeeded in UT lamella preparation (CCT 40–130 μm) in 88% of cases. The OUP heads cut significantly deeper than the according SLc counterparts (p = 0.001), while the variance did not differ. The mean PL thickness increased significantly in the following incubation period (p = 0.01) with no difference between the keratome groups. Endothelial cell density (ECD) decreased significantly from before to 1 hr after preparation (−5.6%; p = 0.04), with no changes in the following 144‐hr incubation period and no differences between the OUP and SLc group. Lamellar surface roughness (LSR) did not differ between both systems.

Conclusions

The SLc and the OUP system are both suited for the preparation of UT‐DSAEK lamellae. Neither system differed significantly in variability, LSR or ECL, which did not increase during a 6‐day incubation period.
The functional brain connectome of the child and autism spectrum disorders
Authors: Mevel Katell , Fransson Peter
Published: May 2016

Brain connectomics is a relatively new field of research that maps the brain's large‐scale structural and functional networks at rest. The connectome of the human brain develops progressively from early infancy to late adolescence, and this review describes the theory behind the concept and its applicability to studying the development and dynamics of brain networks through graph theoretical metrics. We also describe how the brain connectome concept could further our understanding of autism spectrum disorders (ASD)

Conclusion

Further research into the functional child brain connectome concept could enhance our understanding of atypical brain connectivity patterns presumed to be linked to ASD.
The Role of the Mucosa in Normal and Abnormal Bladder Function
Authors: Fry Christopher H. , Vahabi Bahareh
Published: May 2016

The internal face of the detrusor smooth muscle wall of the urinary bladder is covered by a mucosa, separating muscle from the hostile environment of urine. However, the mucosa is more than a very low permeability structure and offers a sensory function that monitors the extent of bladder filling and composition of the urine. The mucosa may be considered as a single functional structure and comprises a tight epithelial layer under which is a basement membrane and lamina propria. The latter region itself is a complex of afferent nerves, blood vessels, interstitial cells and in some species including human beings a muscularis mucosae. Stress on the bladder wall through physical or chemical stressors elicits release of chemicals, such as ATP, acetylcholine, prostaglandins and nitric oxide that modulate the activity of either afferent nerves or the muscular components of the bladder wall. The release and responses are graded so that the mucosa forms a dynamic sensory structure, and there is evidence that the gain of this system is increased in pathologies such as overactive bladder and bladder pain syndrome. This system therefore potentially provides a number of drug targets against these conditions, once a number of fundamental questions are answered. These include how is mediator release regulated; what are the intermediate roles of interstitial cells that surround afferent nerves and blood vessels; and what is the mode of communication between urothelium and muscle – by diffusion of mediators or by cell‐to‐cell communication?
Cyclophosphamide‐induced Down‐Regulation of Uroplakin II in the Mouse Urinary Bladder Epithelium is Prevented by S‐Allyl Cysteine
Authors: Abdi Sayed Aliul Hasan , Najmi Abul Kalam , Raisuddin Sheikh
Published: May 2016

The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP‐induced HC. In this study, we studied the modulatory effect of the thiol‐rich compound S‐allyl cysteine (SAC) on the mRNA level of uroplakin II by real‐time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)‐induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP‐induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol‐rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP‐induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium.
Neuromuscular Effects of Rocuronium Bromide in Patients in Statin Therapy for at least Three Months
Authors: Ren Hongwei , Lv Huangwei
Published: May 2016

Statins cause skeletal muscle myopathy. However, the neuromuscular effects of non‐depolarizing neuromuscular‐blocking agent in patients in long‐term statin therapy remain unclear. Hence, we investigated the neuromuscular effects of rocuronium and muscle injury in patients in long‐term statin therapy. Eighteen statin users using statins for at least 3 months were included in the statin group and 18 non‐statin users were included in the non‐statin group. General anaesthesia was induced with intravenous midazolam, etomidate, sufentanil and rocuronium 0.9 mg/kg (3ED95) for intubation. Anaesthesia was maintained with 1% propofol and remifentanil. The onset time and duration 10% T1 and 25% T1 of rocuronium were recorded. Blood samples were obtained before induction and 5 min., 1 hr, 2 hr, 4 hr, 12 hr and 24 hr after rocuronium administration to measure creatine kinase (CK), myoglobin and potassium. Myalgia was determined at 2 and 24 hr after surgery. There were no significant differences in the basic clinical characteristics between the two groups. The onset time of the statin group was significantly shorter than that of the non‐statin group (p = 0.02), while the duration 10% T1 and duration 25% T1 of the statin group were significantly longer than those of the non‐statin group (p = 0.006; p = 0.045). The myoglobin and CK concentrations increased after rocuronium administration as compared to baseline in both groups. CK concentration in the statin group was significantly higher than in the non‐statin group just at 24 hr (p = 0.000003). However, myoglobin showed no significant difference between the two groups. The onset time of rocuronium decreases and its duration time increases in patients in long‐term statin therapy.
Acute risk factors for suicide attempts and death: prospective findings from the STEP‐BD study
Authors: Ballard Elizabeth D , Vande Voort Jennifer L , Luckenbaugh David A , Machado‐Vieira Rodrigo , Tohen Mauricio , Zarate Carlos A
Published: May 2016

Objectives

Suicide is unfortunately common in psychiatric practice, but difficult to predict. The present study sought to assess which clinical symptoms increase in the months before suicidal behavior in a sample of psychiatric outpatients with bipolar disorder.

Methods

Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD) trial were used. A total of 103 participants who attempted suicide or died by suicide during the trial were included; a 15% random sample of the remaining participants (n = 427) was used as a comparison sample. Linear mixed models in the six months before suicidal behavior were conducted for each of five proposed acute risk factors for suicidal behavior. Participants were assessed using the Clinical Monitoring Form (CMF) at each visit for the following potential acute risk factors for suicidal behavior: suicidal ideation, loss of interest, anxiety, psychomotor agitation, and high‐risk behavior.

Results

Each of the five symptoms was elevated overall in individuals who engaged in suicidal behavior (p < 0.05). The severity of both suicidal ideation and loss of interest significantly increased in the months before suicidal behavior (p < 0.001). Anxiety demonstrated comparable effect sizes across multiple models. Psychomotor agitation and high‐risk behavior were not significantly elevated before suicidal behavior.

Conclusions

Suicidal ideation, loss of interest and, to a lesser extent, anxiety may represent acute suicide risk factors up to four months before suicidal behavior in outpatients with bipolar disorder. Further investigation of these potential acute risk factors in prospective analyses is warranted.
Intersection of mitochondrial fission and fusion machinery with apoptotic pathways: Role of Mcl‐1
Authors: Morciano Giampaolo , Pedriali Gaia , Sbano Luigi , Iannitti Tommaso , Giorgi Carlotta , Pinton Paolo
Published: May 2016

Mitochondria actively contribute to apoptotic cell death through mechanisms including the loss of integrity of the outer mitochondrial membrane, the release of intermembrane space proteins, such as cytochrome c, in the cytosol and the caspase cascade activation. This process is the result of careful cooperation not only among members of the Bcl‐2 family but also dynamin‐related proteins. These events are often accompanied by fission of the organelle, thus linking mitochondrial dynamics to apoptosis. Emerging evidences are suggesting a fine regulation of mitochondrial morphology by Bcl‐2 family members and active participation of fission–fusion proteins in apoptosis. The debate whether in mitochondrial morphogenesis the role of Bcl‐2 family members is functionally distinct from their role in apoptosis is still open and, above all, which morphological changes are associated with cell death sensitisation. This review will cover the findings on how the mitochondrial fission and fusion machinery may intersect apoptotic pathways focusing on recent advances on the key role played by Mcl‐1.
Notch4+ cancer stem‐like cells promote the metastatic and invasive ability of melanoma
Authors: Lin Xian , Sun Baocun , Zhu Dongwang , Zhao Xiulan , Sun Ran , Zhang Yanhui , Zhang Danfang , Dong Xueyi , Gu Qiang , Li Yanlei , Liu Fang
Published: May 2016

Sphere formation in conditioned serum‐free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor (tumorospheres) is considered useful for the enrichment of cancer stem‐like cells, also known as tumor‐initiating cells. We used a gene expression microarray to investigate the gene expression profile of melanoma cancer stem‐like cells (MCSLCs). The results showed that MCSLCs highly expressed the following Notch signaling pathway molecules: Notch3 (NM_008716), Notch4 (NM_010929), Dtx4 (NM_172442), and JAG2 (NM_010588). Immunofluorescence staining showed tumorosphere cells highly expressed Notch4. Notch4high B16F10 cells were isolated by FACS, and Western blotting showed that high Notch4 expression is related to the expression of epithelial–mesenchymal transition (EMT)‐associated proteins. Reduced invasive and migratory properties concomitant with the downregulation of the EMT markers Twist1, vimentin, and VE‐cadherin and the overexpression of E‐cadherin was observed in human melanoma A375 and MUM‐2B cells. In these cells, Notch4 was also downregulated, both by Notch4 gene knockdown and by application of the γ‐secretase inhibitor, DAPT. Mechanistically, the re‐overexpression of Twist1 by the transfection of cells with a Twist1 expression plasmid led to an increase in VE‐cadherin expression and a decrease in E‐cadherin expression. Immunohistochemical analysis of 120 human melanoma tissues revealed a significant correlation between the high expression of Notch4 and the metastasis of melanoma. Taken together, our findings indicate that Notch4+ MCSLCs trigger EMT and promote the metastasis of melanoma cells.
PXD101 analogs with L‐phenylglycine‐containing branched cap as histone deacetylase inhibitors
Authors: Li Jingyao , Li Xiaoyang , Wang Xue , Hou Jinning , Zang Jie , Gao Shuai , Xu Wenfang , Zhang Yingjie
Published: May 2016

Histone deacetylases (HDACs) allow histones to wrap DNA more tightly and finally lead to the repression of some tumor suppressor genes. Histone deacetylase inhibitors (HDACIs) have been proved to have effects on tumorigenesis and tumor progression. In this study, we reported the design, synthesis, and in vitro activity evaluation of novel PXD101 analogs with L‐phenylglycine‐containing cap as HDACIs. Our results showed that HDACs inhibitory activities of compounds 10k, 10r, and 10s were not only superior to the first approved HDACI SAHA, but also comparable to their parent compound PXD101, a recently approved HDACI in 2014. However, all 6 selected PXD101 analogs exhibited moderate in vitro antiproliferative activities, less potent than PXD101 and SAHA. Representative compound 10s showed similar HDACs isoform selective profile to PXD101, which demonstrated that introduction of L‐phenylglycine‐containing branched cap group could not change the isoform selectivity of PXD101 dramatically.
Implications of oncocytic change in papillary thyroid cancer
Authors: Hong Jun Hwa , Yi Hyon‐Seung , Yi Shinae , Kim Hyeon‐Woo , Lee Junguee , Kim Koon Soon
Published: May 2016

Objective

Although the presence of oncocytic change in less than 75% of a tumour is not considered to indicate oncocytic variants of papillary thyroid carcinoma (PTC), we frequently observe partial oncocytic change, especially in obese PTC patients. Thus, we sought to investigate the relationship between the presence of oncocytic change of PTC and its prognosis.

Design, setting and participants

We retrospectively studied 142 patients with PTC who had undergone surgery between 2000 and 2005, and re‐evaluated their PTC slides to record the proportion of oncocytic change in 10% increments from 0% to 100%.

Major outcome measure

We analysed the relationship between the proportion of oncocytic change and clinicopathological prognostic factors.

Results

Oncocytic change was found in 45·8% (65/142) of PTC patients. The proportion of patients with oncocytic change was higher in obese patients than in lean patients and showed a significant correlation with the BMI (r = 0·195, P = 0·020). The PTC patients with oncocytic change showed a higher recurrence rate than PTC patients without oncocytic change (30·8% vs 11·7%, respectively; P = 0·005). The presence of oncocytic change in PTC patients was associated with a shorter disease‐free survival in a Kaplan–Meier analysis after a mean follow‐up of 8·9 years.

Conclusion

The patients with PTC with oncocytic change presented with a higher recurrence rate and were more likely to be obese. These findings suggest that presence of oncocytic change is a poor prognostic factor in PTC patients, even if the oncocytic change involves less than 75% of a tumour.
Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population
Authors: Fattahi Z. , Kalhor Z. , Fadaee M. , Vazehan R. , Parsimehr E. , Abolhassani A. , Beheshtian M. , Zamani G. , Nafissi S. , Nilipour Y. , Akbari M.R. , Kahrizi K. , Kariminejad A. , Najmabadi H.
Published: May 2016

Neuromuscular diseases (NMDs) include a broad range of disorders affecting muscles, nerves and neuromuscular junctions. Their overlapping phenotypes and heterogeneous genetic nature have created challenges in diagnosis which calls for the implementation of massive parallel sequencing as a candidate strategy to increase the diagnostic yield. In this study, total of 45 patients, mostly offspring of consanguineous marriages were examined using whole exome sequencing. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes which led to identification of causal variants for 33 out of 45 patients (73.3%) in the following known genes: CAPN3, Col6A1, Col6A3, DMD, DYSF, FHL1, GJB1, ISPD, LAMA2, LMNA, PLEC1, RYR1, SGCA, SGCB, SYNE1, TNNT1 and 22 novel pathogenic variants were detected. Today, the advantage of whole exome sequencing in clinical diagnostic strategies of heterogeneous disorders is clear. In this cohort, a diagnostic yield of 73.3% was achieved which is quite high compared to the overall reported diagnostic yield of 25% to 50%. This could be explained by the consanguineous background of these patients and is another strong advantage of offering clinical exome sequencing in diagnostic laboratories, especially in populations with high rate of consanguinity.
Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology
Authors: Charzewska A. , Wierzba J. , Iżycka‐Świeszewska E. , Bekiesińska‐Figatowska M. , Jurek M. , Gintowt A. , Kłosowska A. , Bal J. , Hoffman‐Zacharska D.
Published: May 2016

Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect proper formation of the myelin sheath in the central nervous system. They are characterized by developmental delay, hypotonia, spasticity, and variable intellectual disability. In the past various classification systems for HLDs have been used, based on imaging findings, clinical manifestation, and organelle‐specific disorders. Here we present a molecular insight into HLDs based on a defect in specific gene engaged in myelination. We discuss recent findings on pathogenesis, clinical presentation, and imaging related to these disorders. We focus on HLDs that are in use in differential diagnostics of Pelizaeus–Merzbacher disease (PMD), with a special emphasis on Allan–Herndon–Dudley syndrome (AHDS), an X‐linked condition with delayed myelination due to thyroid transport disturbances. On the background of previously published patients we describe a proband initially considered as presenting with a severe PMD, whose diagnosis of AHDS due to a novel nonsense SLC16A2 mutation unraveled two previously undiagnosed generations of affected males who died in infancy from unexplained reasons. Since AHDS is found to be a relatively frequent cause of X‐linked intellectual disability, we emphasize the need for determining the whole thyroid profile especially in hypotonic males with a delay of psychomotor development.
The problem of estimating recent genetic connectivity in a changing world
Authors: Samarasin Pasan , Shuter Brian J. , Wright Stephen I. , Rodd F. Helen
Published: May 2016

Accurate understanding of population connectivity is important to conservation because dispersal can play an important role in population dynamics, microevolution, and assessments of extirpation risk and population rescue. Genetic methods are increasingly used to infer population connectivity because advances in technology have made them more advantageous (e.g., cost effective) relative to ecological methods. Given the reductions in wildlife population connectivity since the Industrial Revolution and more recent drastic reductions from habitat loss, it is important to know the accuracy of and biases in genetic connectivity estimators when connectivity has declined recently. Using simulated data, we investigated the accuracy and bias of 2 common estimators of migration (movement of individuals among populations) rate. We focused on the timing of the connectivity change and the magnitude of that change on the estimates of migration by using a coalescent‐based method (Migrate‐n) and a disequilibrium‐based method (BayesAss). Contrary to expectations, when historically high connectivity had declined recently: (i) both methods over‐estimated recent migration rates; (ii) the coalescent‐based method (Migrate‐n) provided better estimates of recent migration rate than the disequilibrium‐based method (BayesAss); (iii) the coalescent‐based method did not accurately reflect long‐term genetic connectivity. Overall, our results highlight the problems with comparing coalescent and disequilibrium estimates to make inferences about the effects of recent landscape change on genetic connectivity among populations. We found that contrasting these 2 estimates to make inferences about genetic‐connectivity changes over time could lead to inaccurate conclusions.
Impact of surgeon laparoscopic training and case volume of laparoscopic surgery on conversion during elective laparoscopic colorectal surgery
Authors: Massarotti H. , Rodrigues F. , O'Rourke C. , Chadi S. A. , Wexner S.
Published: May 2016

Aim

The study aimed to determine whether laparoscopic volume and type of training influence conversion during elective laparoscopic colorectal surgery.

Method

An Institutional Review Board‐approved prospective database was reviewed for patients who underwent colorectal resection, performed by six colorectal surgeons, for all diagnoses from 2009 to 2014. Surgeons were designated as laparoscopic‐ or open‐trained based on formal laparoscopic colorectal surgery training, and were classified as low laparoscopic volume (LLV) (i.e. had performed < 100 laparoscopic procedures) or high laparoscopic volume (HLV) (i.e. had performed ≥ 100 laparoscopic procedures). Technique was laparoscopic, open or converted (pre‐emptive or reactive). Conversion was compared among three groups: LLV, laparoscopic trained (group A); LLV, open trained (group B); and HLV, open trained (group C).

Results

In total, 159/567 procedures were open and 408 laparoscopic procedures were attempted. Of the 408 laparoscopic procedures, 73 were converted. Among the 567 patients [mean age: 56 ± 17 years (44% male)], the overall conversion rate was 13% (73/567), including 75% pre‐emptive and 25% reactive. Conversion rates for groups A, B and C were 17.9%, 42.6% and 14.3%, respectively. Significantly higher conversion was seen in group B compared with group C (P = 0.01), but not between group A and group C (P = 0.85) or between group B and group A (P = 0.11). Converted patients were older (P < 0.001), with lower rates of proctectomy (P = 0.007), higher rates of anastomosis (P < 0.001) and higher body mass index (BMI) (P < 0.001). After adjusting for patient and surgeon factors, training type was not associated with conversion (P = 0.15). Compared with successful laparoscopy, converted patients had a significantly higher incidence of ileus (P < 0.001), length of stay (P = 0.002), time to flatus (OR = 3.21, P < 0.001) and time to solids (P < 0.001). Converted patients experienced increased morbidity.

Conclusion

Training is not associated with conversion. Rather, HLV surgeons, regardless of training, convert less frequently than do LLV surgeons.
Epidermotropic metastasis of primary lung adenocarcinoma
Authors: Scott Gregory D. , Kwong Bernice Y. , Novoa Roberto A.
Published: May 2016

Cutaneous metastasis of lung cancer is a rare event and usually portends a grim prognosis. Several cases of lung cancer with cutaneous metastasis have been reported, but these have been largely limited to the dermis. Here we describe a unique case of cutaneous metastatic lung adenocarcinoma largely limited to the epidermis, mimicking Paget's disease or a cutaneous adnexal tumor.
Randomized double‐blind clinical trial comparing basal insulin peglispro and insulin glargine, in combination with prandial insulin lispro, in patients with type 2 diabetes: IMAGINE 4
Authors: Blevins T. , Pieber T. R. , Colón Vega G. , Zhang S. , Bastyr E. J. , Chang A. M. ,   on behalf of the IMAGINE 4 Investigators
Published: May 2016

Aims

To evaluate the efficacy and safety of basal insulin peglispro (BIL) with those of insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (T2D).

Methods

In this phase III, multicentre, double‐blind, 26‐week study, we randomized patients with T2D [glycated haemoglobin (HbA1c) ≥7 and <12%, on ≥1 insulin injections daily) to BIL (n = 691) or glargine (n = 678), in combination with lispro.

Results

At week 26, the primary objective of non‐inferiority of BIL versus glargine for HbA1c reduction was achieved (least squares mean difference −0.21%; 95% confidence interval −0.31 to −0.11%), with statistical superiority of BIL with multiplicity adjustment (p < 0.001). HbA1c at baseline was 8.4% versus 8.5% for BIL versus glargine and at 26 weeks it was 6.8% versus 7.0%. At 26 weeks, more patients reached HbA1c <7% with BIL than with glargine (63.3% vs 53.3%; p < 0.001), the nocturnal hypoglycaemia rate (≤3.9 mmol/l) was lower with BIL (0.51 vs 0.92 events/30 days; p < 0.001), but the daytime hypoglycaemia rate was higher with BIL (5.47 vs 4.53 events/30 days; p < 0.001). The total hypoglycaemia relative rate was 1.10 (p = 0.053). At 26 weeks, patients in the BIL group had lower fasting serum glucose levels, higher basal insulin dosing, with no statistically significant difference in prandial or total insulin dosing, reduced glucose variability and less weight gain (1.3 kg vs 2.2 kg) compared with the glargine group. The BIL group had higher mean triglyceride and aminotransferase levels.

Conclusions

In patients with T2D, BIL with insulin lispro provided greater improvement in glycaemic control with less nocturnal hypoglycaemia, lower glucose variability and less weight gain compared with glargine. The daytime hypoglycaemia rate and mean triglyceride and aminotransferase levels were higher with BIL.