bluuebunny/crossref_metadata_2025 huggingface dataset:
Extreme prescribed fire during drought reduces survival and density of woody resprouters
Authors: Twidwell Dirac , Rogers William E. , Wonkka Carissa L. , Taylor Charles A. , Kreuter Urs P.
Published: April 2016

Management intervention in ecosystems with degraded environmental services requires innovative resource management strategies that go beyond conventional restoration and conservation practices. We established a unique study that experimentally targeted extreme fire conditions during drought in humid subtropical and semi‐arid ecoregions.

In the southern Great Plains of North America, conventional restoration and conservation practices have been either historically ineffective or economically cost‐prohibitive at restoring grass‐dominated ecosystems following conversion to resprouting shrublands. Our aim was to assess the potential for extreme fire during drought to force the system along an alternate ecological trajectory from its current progression towards closed‐canopy resprouting shrubland, something that conventional fire prescriptions have been unable to accomplish.

We first tested the potential for high‐intensity fires exhibiting extreme behaviour to disrupt the progression from grassland to shrubland. In both ecoregions, significant levels of mortality were observed for mature woody resprouters. As a result, densities were either maintained or reduced 3 years following extreme fire treatments, whereas resprouter densities continued to increase in areas that were not burned.

A second interventionist approach involving extreme fire and herbicide treatment combinations was not supported. Interactions between prescribed extreme fire and herbicide did not significantly reduce resprouter densities more than using herbicide alone at either site.

Synthesis and applications. Extreme fires during drought resulted in exceptionally high levels of mortality across all sizes of woody resprouters and limited recruitment, resulting in 35–55% lower densities of resprouters than in areas not burned. These findings counter prevailing scientific and management expectations, which are based largely on studies that impose tight controls over prescribed fire conditions and avoid extreme fire behaviour. Future interventions for controlling woody resprouters with fire may require rethinking the present ideology that extreme fire behaviour has no place in modern social–ecological landscapes.
Lack of functional redundancy in the relationship between microbial diversity and ecosystem functioning
Authors: Delgado‐Baquerizo Manuel , Giaramida Luca , Reich Peter B. , Khachane Amit N. , Hamonts Kelly , Edwards Christine , Lawton Linda A. , Singh Brajesh K.
Published: April 2016

Biodiversity is declining world‐wide with detrimental effects on ecosystems. However, we lack a quantitative understanding of the shape of the relationship between microbial biodiversity and ecosystem function (BEF). This limits our understanding of how microbial diversity depletion can impact key functions for human well‐being, including pollutant detoxification.

Three independent microcosm experiments were conducted to evaluate the direction (i.e. positive, negative or null) and the shape of the relationships between bacterial diversity and both broad (i.e. microbial respiration) and specialized (i.e. toxin degradation) functions in five Australian and two UK freshwater ecosystems using next‐generation sequencing platforms.

Reduced bacterial diversity, even after accounting for biomass, caused a decrease in broad (i.e. cumulative microbial respiration) and specialized (biodegradation of two important toxins) functions in all cases. Unlike the positive but decelerating BEF relationship observed most frequently in plants and animals, most evaluated functional measurements were related to bacterial diversity in a non‐redundant fashion (e.g. exponentially and/or linearly).

Synthesis. Our results suggest that there is a lack of functional redundancy in the relationship between bacterial diversity and ecosystem functioning; thus, the consequences of declining microbial diversity on ecosystem functioning and human welfare have likely been considerably underestimated.
Early colonization of functional groups of microbes in the infant gut
Authors: Pham Van T. , Lacroix Christophe , Braegger Christian P. , Chassard Christophe
Published: April 2016

The colonization of the infant gut is crucial for early life development. Although the composition and diversity of the infant gut microbiota (GM) has been well described at a taxonomic level, functional aspects of this ecosystem remain unexplored. In the infant gut, lactate is produced by a number of bacteria and plays an important role in the trophic chain of the fermentation process. However, little is known about the lactate‐utilizing bacteria (LUB) community in infants and their impact on gut health. By combining culture‐based and molecular methods, we intensively studied LUB in fecal samples of 40 healthy infants on both taxonomic and functional levels. We demonstrated metabolic cross‐feeding of lactate and identified keystone species specified for lactate utilization. The interactions of such species and their metabolic outcome could have direct impacts on infant health, either beneficial (production of short chain fatty acids) or detrimental (accumulation of hydrogen or hydrogen sulfide). We identified mode of delivery as a strong determinant for lactate‐producing and ‐utilizing bacteria levels. These findings present the early establishment of GM with a novel perspective and emphasize the importance of lactate utilization in infancy.
The human gut microbiome in health: establishment and resilience of microbiota over a lifetime
Authors: Greenhalgh Kacy , Meyer Kristen M. , Aagaard Kjersti M. , Wilmes Paul
Published: April 2016

With technological advances in culture‐independent molecular methods, we are uncovering a new facet of our natural history by accounting for the vast diversity of microbial life which colonizes the human body. The human microbiome contributes functional genes and metabolites which affect human physiology and are, therefore, considered an important factor for maintaining health. Much has been described in the past decade based primarily on 16S rRNA gene amplicon sequencing regarding the diversity, structure, stability and dynamics of human microbiota in their various body habitats, most notably within the gastrointestinal tract (GIT). Relatively high levels of variation have been described across different stages of life and geographical locations for the GIT microbiome. These observations may prove helpful for the future contextualization of patterns in other body habitats especially in relation to identifying generalizable trends over human lifetime. Given the large degree of complexity and variability, a key challenge will be how to define baseline healthy microbiomes and how to identify features which reflect deviations therefrom in the future. In this context, metagenomics and functional omics will likely play a central role as they will allow resolution of microbiome‐conferred functionalities associated with health. Such information will be vital for formulating therapeutic interventions aimed at managing microbiota‐mediated health particularly in the GIT over the course of a human lifetime.
Therapist implementation and parent experiences of the three phases of Functional Family Therapy
Authors: Hartnett Dan , Carr Alan , Hamilton Elena , Sexton Thomas L.
Published: April 2016

Despite the widespread adoption of manualized model‐driven approaches to family therapy, little is known about how therapists implement and families experience the specific guiding practices involved in individual models. The aim of the present study was to use a qualitative methodology to describe therapist implementation and family experiences of the three phases of Functional Family Therapy (FFT). Five FFT therapists and four parents of families who had been treated by those therapists were interviewed and thematic analysis performed to analyse the data. Results suggest that both common factor and model‐specific treatment elements, flexibility within model delivery, and strategies which aim to improve parental self‐efficacy and communication are key elements of successful therapy when practised within a manualized model‐driven framework. Limitations such as the retrospective nature of the study, and avenues for future research, such as the inclusion of the entire client family, are discussed.

Practitioner points

Early in FFT, combine basic therapeutic skills such as empathy, warmth and unconditional positive regard with model specific skills such as reframing

In the middle sessions of FFT, match the development of specific behaviour change skills (e.g. communication, conflict management, and emotional regulation) to families’ particular goals

In later sessions of FFT, support the generalization of gains made within therapy to other contexts and future situations to prevent relapse
A Case of Lethal Idiopathic Plasmacytic Lymphadenopathy with Polyclonal Hypergammaglobulinemia: A Medical Challenge for the Forensic Pathologist
Authors: Tattoli Lucia , Solarino Biagio , Schiraldi Oronzo , Di Vella Giancarlo
Published: April 2016

A rare case of lethal idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hyperimmunoglobulinemia with chronic renal failure is described. A 40‐year‐old woman who had suffered from upper airways disease was admitted to the Emergency Room with acute renal failure and hypergammaglobulinemia. She developed pericardial effusion, a pruritic rash, splenomegaly and fell into a coma after 6 days. Multiple myeloma, infection, collagenopathy, and coagulopathy were ruled out. Finally, a form of malignant hypergammapathy was suspected. At autopsy, lymph nodes were infiltrated by polyclonal plasma cells and lymphocytes, with erythrophagocytosis features; immunohistochemistry confirmed the plasma cells (CD138+), with a prevalence of kappa‐positive cells, B (CD20+) and T (CD3+) cells. Kidneys showed advanced glomerulosclerosis containing similar infiltrates. The cause of death was IPL with polyclonal hypergammaglobulinemia and advanced renal failure. Similar cases are unusual, and possible medical liability associated with failure to diagnose and treat idiopathic plasmacytic lymphadenopathy deserves discussion and further studies.
Phenotypic plasticity in Drosophila cactophilic species: the effect of competition, density, and breeding sites
Authors: Fanara Juan Jose , Werenkraut Victoria
Published: April 2016

Changes in the environmental conditions experienced by naturally occurring populations are frequently accompanied by changes in adaptive traits allowing the organism to cope with environmental unpredictability. Phenotypic plasticity is a major aspect of adaptation and it has been involved in population dynamics of interacting species. In this study, phenotypic plasticity (i.e., environmental sensitivity) of morphological adaptive traits were analyzed in the cactophilic species Drosophila buzzatii and Drosophila koepferae (Diptera: Drosophilidae) considering the effect of crowding conditions (low and high density), type of competition (intraspecific and interspecific competition) and cacti hosts (Opuntia and Columnar cacti). All traits (wing length, wing width, thorax length, wing loading and wing aspect) showed significant variation for each environmental factor considered in both Drosophila species. The phenotypic plasticity pattern observed for each trait was different within and between these cactophilic Drosophila species depending on the environmental factor analyzed suggesting that body size‐related traits respond almost independently to environmental heterogeneity. The effects of ecological factors analyzed in this study are discussed in order to elucidate the causal factors investigated (type of competition, crowding conditions and alternative host) affecting the election of the breeding site and/or the range of distribution of these cactophilic species.
Beyond habitat structure: Landscape heterogeneity explains the monito del monte (Dromiciops gliroides) occurrence and behavior at habitats dominated by exotic trees
Authors: SALAZAR Daniela A. , FONTÚRBEL Francisco E.
Published: April 2016

Habitat structure determines species occurrence and behavior. However, human activities are altering natural habitat structure, potentially hampering native species due to the loss of nesting cavities, shelter or movement pathways. The South American temperate rainforest is experiencing an accelerated loss and degradation, compromising the persistence of many native species, and particularly of the monito del monte (Dromiciops gliroides Thomas, 1894), an arboreal marsupial that plays a key role as seed disperser. Aiming to compare 2 contrasting habitats (a native forest and a transformed habitat composed of abandoned Eucalyptus plantations and native understory vegetation), we assessed D. gliroides' occurrence using camera traps and measured several structural features (e.g. shrub and bamboo cover, deadwood presence, moss abundance) at 100 camera locations. Complementarily, we used radio telemetry to assess its spatial ecology, aiming to depict a more complete scenario. Moss abundance was the only significant variable explaining D. gliroides occurrence between habitats, and no structural variable explained its occurrence at the transformed habitat. There were no differences in home range, core area or inter‐individual overlapping. In the transformed habitats, tracked individuals used native and Eucalyptus‐associated vegetation types according to their abundance. Diurnal locations (and, hence, nesting sites) were located exclusively in native vegetation. The landscape heterogeneity resulting from the vicinity of native and Eucalyptus‐associated vegetation likely explains D. gliroides occurrence better than the habitat structure itself, as it may be use Eucalyptus‐associated vegetation for feeding purposes but depend on native vegetation for nesting.
Tolerance Testing for Cooked Porridge made from a Sorghum Based Fortified Blended Food
Authors: Chanadang Sirichat , Chambers Edgar IV , Alavi Sajid
Published: April 2016

Products that will be prepared by consumers must be tolerant to various cooking procedures that those consumers may use. Fortified blended foods (FBFs) are used as a source of nutrition for disaster or famine relief in developing countries. Many FBFs are served as porridge and may have a wide of solids content, cooking times and variations in added ingredients. Sorghum is being examined as a potential alternative to wheat and corn based FBF products. This study was intended to evaluate the tolerance to preparation variations for porridge made as a FBF intended for food aid. Whole Sorghum Soy Blend (WSSB), a fortified, extruded, ground cooked cereal was selected as the FBF for this study. Descriptive sensory analysis and Bostwick flow rate measurements were performed to evaluate the tolerance of porridge products made from variations in ingredients and cooking procedures. The results showed that most sensory properties were only marginally affected although some expected large differences in a few sensory properties were found when solids content varied (that is, thickness, adhesiveness) or fruit (banana flavor) was added. Moreover, Bostwick flow rate was a reasonable indicator of thickness characteristics of porridges in some cases, but not in others. Tolerance testing showed that the sensory properties of WSSB had high tolerance to variations in cooking procedures, which means that the product can be modified during preparation by consumers without having a major impact on most sensory properties other than ones they intended to change such as thickness, sweetness, or fruit flavor.
Rapid Detection of Melamine in Tap Water and Milk Using Conjugated “One‐Step” Molecularly Imprinted Polymers‐Surface Enhanced Raman Spectroscopic Sensor
Authors: Hu Yaxi , Lu Xiaonan
Published: April 2016

An innovative “one‐step” sensor conjugating molecularly imprinted polymers and surface enhanced Raman spectroscopic‐active substrate (MIPs‐SERS) was investigated for simultaneous extraction and determination of melamine in tap water and milk. This sensor was fabricated by integrating silver nanoparticles (AgNPs) with MIPs synthesized by bulk polymerization of melamine (template), methacrylic acid (functional monomer), ethylene glycol dimethacrylate (cross‐linking agent), and 2,2’‐azobisisobutyronitrile (initiator). Static and kinetic adsorption tests validated the specific affinity of MIPs‐AgNPs to melamine and the rapid adsorption equilibration rate. Principal component analysis segregated SERS spectral features of tap water and milk samples with different melamine concentrations. Partial least squares regression models correlated melamine concentrations in tap water and skim milk with SERS spectral features. The limit of detection (LOD) and limit of quantification (LOQ) of melamine in tap water were determined as 0.0019 and 0.0064 mmol/L, while the LOD and LOQ were 0.0165 and 0.055 mmol/L for the determination of melamine in skim milk. However, this sensor is not ideal to quantify melamine in tap water and skim milk. By conjugating MIPs with SERS‐active substrate (that is, AgNPs), reproducibility of SERS spectral features was increased, resulting in more accurate detection. The time required to determine melamine in tap water and milk were 6 and 25 min, respectively. The low LOD, LOQ, and rapid detection confirm the potential of applying this sensor for accurate and high‐throughput detection of melamine in tap water and milk.
The diagnostic utility of combined diffusion‐weighted imaging and conventional magnetic resonance imaging for detection and localization of non palpable undescended testes
Authors: Emad‐Eldin Sally , Abo‐Elnagaa Nashwa , Hanna Sameh AZ , Abdel‐Satar Ayman H
Published: April 2016

Introduction

We aimed to evaluate the diagnostic performance of combined diffusion weighted imaging (DWI) and conventional magnetic resonance imaging (MRI), including fat‐suppression T2WI for identification and localization of non palpable undescended testes (UDTs).

Methods

This prospective study included 40 consecutive patients, with 47 non‐palpable undescended testes (unilateral in 33 cases and bilateral in seven cases). Their age ranged from 5 months to 18 years, mean = 7.5 ± 5.9 years. MRI examinations included T1WI, T2WI, fat‐suppression T2WI and DWI at b value of 50, 400 and 800 s/mm2. All patients underwent laparoscopic exploration.

Results

According to the laparoscopy findings, the final diagnoses of the location of UDTs were: intra‐canalicular (n = 18, 38%), low intra‐abdominal (n = 6, 13%), high intra‐abdominal (n = 5, 11%). Absent or vanishing testes were detected in 18 cases (38%). The diagnostic accuracy, sensitivity, specificity of combined DWI and conventional MRI were 95.7%, 93.5% and 100% respectively.

Conclusion

Combined DWI and MRI showed a greater performance compared to conventional MRI alone for identification of non‐palpable UDTs. Based on our findings, we can obviate the need for diagnostic laparoscopy in patients who had preoperative detection of inguinal testes or nubbins. However, laparoscopy is still needed to confirm an absent rather than undetected non‐viable abdominal testes.
The ecologist's field guide to sequence‐based identification of biodiversity
Authors: Creer Simon , Deiner Kristy , Frey Serita , Porazinska Dorota , Taberlet Pierre , Thomas W. Kelley , Potter Caitlin , Bik Holly M.
Published: April 2016

The past 100 years of ecological research has seen substantial progress in understanding the natural world and likely effects of change, whether natural or anthropogenic. Traditional ecological approaches underpin such advances, but would additionally benefit from recent developments in the sequence‐based quantification of biodiversity from the fields of molecular ecology and genomics. By building on a long and rich history of molecular taxonomy and taking advantage of the new generation of DNA sequencing technologies, we are gaining previously impossible insights into alpha and beta diversity from all domains of life, irrespective of body size. While a number of complementary reviews are available in specialist journals, our aim here is to succinctly describe the different technologies available within the omics toolbox and showcase the opportunities available to contemporary ecologists to advance our understanding of biodiversity and its potential roles in ecosystems.

Starting in the field, we walk the reader through sampling and preservation of genomic material, including typical taxonomy marker genes used for species identification. Moving on to the laboratory, we cover nucleic acid extraction approaches and highlight the principal features of using marker gene assessment, metagenomics, metatranscriptomics, single‐cell genomics and targeted genome sequencing as complementary approaches to assess the taxonomic and functional characteristics of biodiversity. We additionally provide clear guidance on the forms of DNA found in the environmental samples (e.g. environmental vs. ancient DNA) and highlight a selection of case studies, including the investigation of trophic relationships/food webs. Given the maturity of sequence‐based identification of prokaryotes and microbial eukaryotes, more exposure is given to macrobial communities. We additionally illustrate current approaches to genomic data analysis and highlight the exciting prospects of the publicly available data underpinning published sequence‐based studies.

Given that ecology ‘has to count’, we identify the impact that molecular genetic analyses have had on stakeholders and end‐users and predict future developments for the fields of biomonitoring. Furthermore, we conclude by highlighting future opportunities in the field of systems ecology afforded by effective engagement between the fields of traditional and molecular ecology.
Rice mountain: assessment of the Thai rice pledging program
Authors: Permani Risti , Vanzetti David
Published: April 2016

The Thai Government introduced a generous price support program for paddy rice in 2011. The policy terminated in mid 2014 with the dismissal of the democratically elected Prime Minister, Ms Yingluck Shinawatra. There is an interest in understanding the welfare effects of the policy given the ongoing civil suit put against the former Prime Minister and the large stocks that remain. This study therefore analyses the welfare effects of various Thai rice policy options using a 10‐region, dynamic, stochastic, partial equilibrium model of world rice trade. It finds that while the Thai policy was effective in supporting the incomes of rice producers in the short run, the burden imposed on taxpayers and consumers seems difficult to justify.
Quadrate lobe: a reliable landmark for bile duct anatomy during laparoscopic cholecystectomy
Authors: Rajkomar Kheman , Bowman Matthew , Rodgers Michael , Koea Jonathan B.
Published: April 2016

Background

This investigation was undertaken to determine whether the shape of the inferior surface quadrate lobe (segment IV) can assist in defining a safe starting point for dissection during laparoscopic cholecystectomy.

Methods

Patients undergoing laparoscopic cholecystectomy were prospectively audited. Intraoperative cholangiograms and photographs of the quadrate lobe were reviewed measuring the angle between the cystic duct and common bile duct and its relationship to quadrate shape.

Results

The results of 56 patients were included. The shape of the inferior surface of the quadrate lobe was rectangular in 35, pyramidal in 13 and square in eight patients. The median cystic/bile duct angle was 43°, 37° and 26° for square, rectangular and pyramidal quadrate shapes, respectively. The angle for pyramidal‐shaped lobes was narrower than that for rectangular or square lobes (P < 0.05). Regression analysis showed an inverse relationship between the shape ratio and the cystic/bile duct angle (P = 0.015).

Conclusion

This investigation confirms a relationship between the shape of the inferior surface of the quadrate lobe and the cystic/bile duct angle and suggests that the anatomy of the inferior surface of the quadrate lobe can be used to define an optimal starting point for dissection of the biliary cystic triangle.
Cell death pattern in lens epithelium of cataract patients
Authors: Osnes‐Ringen Øyvind , Berg Kristiane Haug , Moe Morten C. , Zetterström Charlotta , Røger Magnus , Nicolaissen Bjørn
Published: April 2016

Purpose

Apoptosis, a type of programmed cell death, is observed in various types of cataract and in cultured lens epithelium subjected to oxidative damage. We have recently described oxidative DNA base damage in epithelium in age‐related cataract and cultured cells, and we here aimed to examine such epithelium for markers for proliferation, initiation of apoptosis and morphological patterns of cell damage.

Methods

Samples (n = 75) were analysed by light microscopy/electron microscopy (LM/EM); immunohistochemistry (IHC) for PCNA and Ki67 (DNA synthesis/proliferation); TUNEL assay (DNA fragmentation/apoptosis); and protein/gene expression of Caspase‐3 (apoptotic effector molecule) and BAX/Bcl2 (pro‐/anti‐apoptotic marker) in fresh/cultured epithelium by IHC and qRT‐PCR.

Results

In fresh samples, the majority of cells were Ki67−/PCNA+. BAX/BCL−2‐ratio was approximately 1, and Caspase‐3 levels were low. TUNEL stained scattered nuclei/nuclear fragments (9/6302 cells). Main morphological signs of cell damage included rupture of cell membranes and hydration of cytoplasm and nuclei. Cultivation increased levels of BAX and Bcl2 by IHC and qRT‐PCR (approximately 10‐fold upregulation). Caspase‐3 levels remained low by IHC with similar expression in fresh and cultured samples by qRT‐PCR.

Conclusion

Genomic stress and DNA repair may explain the contrasting expression of Ki67/PCNA in fresh epithelium. Despite low levels of Caspase‐3 and similar expression of BAX/Bcl‐2, a low incidence of apoptosis may be detected in epithelium in age‐related corticonuclear cataract. Epithelium may be transferred to culture without an increase in expression of Caspase‐3, one of the central mediators of apoptosis.
Functional characterization of eight rare missense CYP1B1 variants involved in congenital glaucoma and their association with null genotypes
Authors: Medina‐Trillo Cristina , Ferre‐Fernández Jesús‐José , Aroca‐Aguilar José‐Daniel , Bonet‐Fernández Juan‐Manuel , Escribano Julio
Published: April 2016

Purpose

To evaluate the function of eight missense CYP1B1 single nucleotide variants (SNVs) previously identified in patients with primary congenital glaucoma (PCG).

Methods

The eight variants were obtained by site‐directed mutagenesis and transiently expressed in human embryonic kidney 293‐T (HEK‐293T) cells. The catalytic activity, protein stability and subcellular localization of the different recombinant CYP1B1 variants were assessed in this cell line.

Results

Six of the mutant CYP1B1 proteins (p.L89P, p.A106D, p.R390S, p.P437L, p.C470Y and S485F) showed catalytic activity values ranging from 0% to 4% of those of the wild‐type protein and were considered null variants. The activity values of the two remaining variants (p.F123L and p.A237E) were close to 20% of that of the wild‐type enzyme and were classified as hypomorphic variants. Reduced protein stability contributed partially to the decreased catalytic activity of two of the mutant enzymes (p.L89P and p.A106D). None of the CYP1B1 variants showed intracellular aggregation and they all displayed a normal subcellular localization in the endoplasmic reticulum, suggesting that they had folded into a wild‐type‐like structure. The enzymatic activity associated with the different genotypes in which these CYP1B1 variants were present was estimated to range from 0% to 10% of that of the wild‐type genotype.

Conclusion

These results confirm the pathogenicity of the analysed missense CYP1B1 variants and further support the concept that either absent or very low CYP1B1 activity levels are the primary molecular defect involved in PCG pathogenesis.
The macrophage activation marker sCD163 combined with markers of the Enhanced Liver Fibrosis (ELF) score predicts clinically significant portal hypertension in patients with cirrhosis
Authors: Sandahl T. D. , McGrail R. , Møller H. J. , Reverter E. , Møller S. , Turon F. , Hernández‐Gea V. , Bendtsen F. , Vilstrup H. , Garcia‐Pagan J. C. , Grønbæk H.
Published: April 2016

Background

Noninvasive identification of significant portal hypertension in patients with cirrhosis is needed in hepatology practice.

Aim

To investigate whether the combination of sCD163 as a hepatic inflammation marker and the fibrosis markers of the Enhanced Liver Fibrosis score (ELF) can predict portal hypertension in patients with cirrhosis.

Methods

We measured sCD163 and the ELF components (hyaluronic acid, tissue inhibitor of metalloproteinase‐1 and procollagen‐III aminopeptide) in two separate cohorts of cirrhosis patients that underwent hepatic vein catheterisation. To test the predictive accuracy we developed a CD163‐fibrosis portal hypertension score in an estimation cohort (n = 80) and validated the score in an independent cohort (n = 80). A HVPG ≥10 mmHg was considered clinically significant.

Results

Both sCD163 and the ELF components increased in a stepwise manner with the patients' Child–Pugh score (P < 0.001, all), and also with increasing HVPG (P < 0.001). receiver operator characteristics (ROC) analyses showed that each one of the individual components predicted a HVPG >10 mmHg with AUROC′s of approximately 0.80. The combined score optimised by logistic regression analyses improved the AUROC to 0.91 in the estimation cohort and 0.90 in the validation cohort. Furthermore, a high value of the combined score was associated with a high short‐term mortality.

Conclusions

The combination of the macrophage activation marker sCD163 and the fibrosis markers predicted significant portal hypertension in patients with cirrhosis. This score may prove useful for screening purposes and highlights the importance of both the inflammatory and the fibrotic components of cirrhotic portal hypertension.
The therapeutic potential of mTOR inhibitors in breast cancer
Authors: Steelman Linda S. , Martelli Alberto M. , Cocco Lucio , Libra Massimo , Nicoletti Ferdinando , Abrams Stephen L. , McCubrey James A.
Published: April 2016

Rapamycin and modified rapamycins (rapalogs) have been used to prevent allograft rejection after organ transplant for over 15 years. The mechanistic target of rapamycin (mTOR) has been determined to be a key component of the mTORC1 complex which consists of the serine/threonine kinase TOR and at least five other proteins which are involved in regulating its activity. Some of the best characterized substrates of mTORC1 are proteins which are key kinases involved in the regulation of cell growth (e.g., p70S6K) and protein translation (e.g., 4E‐BP1). These proteins may in some cases serve as indicators to sensitivity to rapamycin‐related therapies. Dysregulation of mTORC1 activity frequently occurs due to mutations at, or amplifications of, upstream growth factor receptors (e.g., human epidermal growth factor receptor‐2, HER2) as well as kinases (e.g., PI3K) and phosphatases (e.g., PTEN) critical in the regulation of cell growth. More recently, it has been shown that certain rapalogs may enhance the effectiveness of hormonal‐based therapies for breast cancer patients who have become resistant to endocrine therapy. The combined treatment of certain rapalogs (e.g., everolimus) and aromatase inhibitors (e.g., exemestane) has been approved by the United States Food and Drug Administration (US FDA) and other drug regulatory agencies to treat estrogen receptor positive (ER+) breast cancer patients who have become resistant to hormonal‐based therapies and have progressed. This review will summarize recent basic and clinical research in the area and evaluate potential novel therapeutic approaches.
Injection site reactions after subcutaneous oligonucleotide therapy
Authors: van Meer Leonie , Moerland Matthijs , Gallagher Jolie , van Doorn Martijn B. A. , Prens Errol P. , Cohen Adam F. , Rissmann Robert , Burggraaf Jacobus
Published: April 2016

Oligonucleotides (ONs) are short fragments of nucleic acids, currently being investigated as therapeutic agents. When administered subcutaneously (sc), ONs cause a specific local reaction originating around the injection site, such as erythema, itching, discomfort and pain, including more severe manifestations such as ulceration or necrosis. These injection site reactions (ISRs) are common, but rather poorly described in the literature. With this review, we aim to provide an overview on the extent of the problem of ISRs, based on reported incidence. A structured literature search was performed to identify reported incidence and clinical features of ISRs which yielded 70 manuscripts that contained information regarding ISRs. The data from literature was combined with data on file available at our institution. All sc administered ONs described in the literature lead to the occurrence of ISRs. The percentage of trial subjects that developed ISRs ranged from 22 to 100% depending on ON. The majority of ONs caused ISRs in more than 70% of the trial subjects. The severity of the observed reactions varied between different ONs. Occurrence rate as well as severity of ISRs increases with higher doses. For chemistry and target of the compounds, no clear association regarding ISR incidence or severity was identified. All ONs developed to date are associated with ISRs. Overcoming the problem of ISRs might add greatly to the potential success of sc‐administered ONs. Knowledge of these skin reactions and their specific immunostimulatory properties should be increased in order to obtain ONs that are more suitable for long‐term use and clinically applicable in a broader patient population.
Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with hepatic or renal impairment
Authors: Kaufmann Priska , Cruz Hans G. , Krause Andreas , Ulč Ivan , Halabi Atef , Dingemanse Jasper
Published: April 2016

Aim

The aim of the present study was to explore the effect of hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.

Methods

Two prospective, open‐label studies evaluated the PK of selexipag and its active metabolite ACT‐333679 in healthy subjects and in subjects with mild, moderate and severe hepatic impairment or severe renal function impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration–time profiles.

Results

Exposure increased with the severity of hepatic impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration–time curve from time zero to infinity (AUC0–∞) for selexipag and ACT‐333679 increased 2.1‐fold (1.7–2.6) and 1.2‐fold (0.9–1.6) in subjects with mild hepatic impairment, and 4.5‐fold (3.4–5.8) and 2.2‐fold (1.7–2.8) in subjects with moderate hepatic impairment when compared with healthy subjects. The two subjects with severe hepatic impairment showed similar dose‐normalized exposure to that of subjects with moderate hepatic impairment. A 1.7‐fold increase in the AUC0–∞ of selexipag and ACT‐333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT‐333679 was higher in subjects with mild or moderate hepatic impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.

Conclusions

Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with mild or moderate hepatic impairment or SRFI. However, doses should be up‐titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe hepatic impairment.
Oracle Estimation of Parametric Models Under Boundary Constraints
Authors: Wong Kin Yau , Goldberg Yair , Fine Jason P.
Published: April 2016

In many classical estimation problems, the parameter space has a boundary. In most cases, the standard asymptotic properties of the estimator do not hold when some of the underlying true parameters lie on the boundary. However, without knowledge of the true parameter values, confidence intervals constructed assuming that the parameters lie in the interior are generally over-conservative. A penalized estimation method is proposed in this article to address this issue. An adaptive lasso procedure is employed to shrink the parameters to the boundary, yielding oracle inference which adapt to whether or not the true parameters are on the boundary. When the true parameters are on the boundary, the inference is equivalent to that which would be achieved with a priori knowledge of the boundary, while if the converse is true, the inference is equivalent to that which is obtained in the interior of the parameter space. The method is demonstrated under two practical scenarios, namely the frailty survival model and linear regression with order-restricted parameters. Simulation studies and real data analyses show that the method performs well with realistic sample sizes and exhibits certain advantages over standard methods.
Moment Reconstruction and Moment-Adjusted Imputation When Exposure Is Generated by a Complex, Nonlinear Random Effects Modeling Process
Authors: Potgieter Cornelis J. , Wei Rubin , Kipnis Victor , Freedman Laurence S. , Carroll Raymond J.
Published: April 2016

For the classical, homoscedastic measurement error model, moment reconstruction (Freedman et al., 2004, 2008) and moment-adjusted imputation (Thomas et al., 2011) are appealing, computationally simple imputation-like methods for general model fitting. Like classical regression calibration, the idea is to replace the unobserved variable subject to measurement error with a proxy that can be used in a variety of analyses. Moment reconstruction and moment-adjusted imputation differ from regression calibration in that they attempt to match multiple features of the latent variable, and also to match some of the latent variable's relationships with the response and additional covariates. In this note, we consider a problem where true exposure is generated by a complex, nonlinear random effects modeling process, and develop analogues of moment reconstruction and moment-adjusted imputation for this case. This general model includes classical measurement errors, Berkson measurement errors, mixtures of Berkson and classical errors and problems that are not measurement error problems, but also cases where the data-generating process for true exposure is a complex, nonlinear random effects modeling process. The methods are illustrated using the National Institutes of Health–AARP Diet and Health Study where the latent variable is a dietary pattern score called the Healthy Eating Index-2005. We also show how our general model includes methods used in radiation epidemiology as a special case. Simulations are used to illustrate the methods.
Pregnancy loss and risk of ischaemic stroke and myocardial infarction
Authors: Maino Alberto , Siegerink Bob , Algra Ale , Martinelli Ida , Peyvandi Flora , Rosendaal Frits R.
Published: April 2016

We investigated whether pregnancy loss increases the risk of arterial thrombosis in young women. Women (age 18–50 years) with ischaemic stroke (IS) or myocardial infarction (MI) and at least one pregnancy were compared for pregnancy loss in a control group. Odds ratios (OR) with 95% confidence intervals (CI), adjusted for matching variables, cardiovascular risk factors, cardiovascular family history and the presence of antiphospholipid antibodies, were calculated for the number of pregnancy losses as well as the type of unsuccessful pregnancy (early miscarriage, late miscarriage and stillbirth). 165 IS cases, 218 MI cases and 743 controls were included. Women with multiple (≥3) pregnancy loss had a doubled risk of arterial thrombosis (OR 2·37, 95%CI 0·99–5·70) compared with women without pregnancy loss, similarly to women who experienced stillbirth (OR 1·68, 95%CI 0·79–3·55). Both relative risks were higher for IS (OR 3·51, 95%CI 1·08–11·35 and 2·06, 95%CI 0·81–5·23, respectively) than for MI (OR 2·04, 95%CI 0·71–5·86 and 1·04, 95%CI 0·39–2·79). Adjustment for antiphospholipid antibodies did not affect the estimates. Multiple pregnancy loss and stillbirth increases the risk of IS and, to a lesser extent, of MI, even when other cardiovascular risk factors and antiphospholipid antibodies are accounted for.
Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001–12
Authors: Srour Samer A. , Devesa Susan S. , Morton Lindsay M. , Check David P. , Curtis Rochelle E. , Linet Martha S. , Dores Graça M.
Published: April 2016

Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population‐based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population‐based data, we comprehensively assessed subtype‐specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001–12). IRs were highest for polycythaemia vera (PV) (IR = 10·9) and essential thrombocythaemia (ET) (IR = 9·6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs = 1·4–2·3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non‐Hispanic whites (NHWs), with the exception of BCR‐ABL1‐positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN‐unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five‐year RS was more favourable for younger (<60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (>90%) for younger PV and ET patients and lowest (<20%) for older chronic myelomonocytic leukaemia and atypical BCR‐ABL1‐negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals.
Combining an epithelial repair factor and anti‐fibrotic with a corticosteroid offers optimal treatment for allergic airways disease
Authors: Patel K P , Giraud A S , Samuel C S , Royce S G
Published: April 2016

Background and Purpose

We evaluated the extent to which individual versus combination treatments that specifically target airway epithelial damage [trefoil factor‐2 (TFF2)], airway fibrosis [serelaxin (RLX)] or airway inflammation [dexamethasone (DEX)] reversed the pathogenesis of chronic allergic airways disease (AAD).

Experimental Approach

Following induction of ovalbumin (OVA)‐induced chronic AAD in 6–8 week female Balb/c mice, animals were i.p. administered naphthalene (NA) on day 64 to induce epithelial damage, then received daily intranasal administration of RLX (0.8 mg·mL−1), TFF2 (0.5 mg·mL−1), DEX (0.5 mg·mL−1), RLX + TFF2 or RLX + TFF2 + DEX from days 67–74. On day 75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. The control group was treated with saline + corn oil (vehicle for NA).

Key Results

OVA + NA‐injured mice demonstrated significantly increased airway inflammation, airway remodelling (AWR) (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix accumulation and fibronectin deposition; total lung collagen concentration), and significantly reduced airway dynamic compliance (cDyn). RLX + TFF2 markedly reversed several measures of OVA + NA‐induced AWR and normalized the reduction in cDyn. The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial extracellular matrix accumulation/fibronectin deposition and total lung collagen concentration (by 50–90%) and also normalized the reduction of cDyn.

Conclusions and Implications

Combining an epithelial repair factor and anti‐fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma and may act as an effective adjunct therapy to anti‐inflammatory corticosteroids.
An improved approach for geocoding Canadian postal code–based data in health‐related studies
Authors: Rosu Andrei , Chen Dongmei
Published: April 2016

Key Messages

An enhanced postal code geocoding approach improves positional accuracy compared to the traditional approach.

The improved geocoded postal codes were in closer proximity to residential areas by approximately 25 m at the urban level and 300 m at the rural level for Ontario.

The improvement in positional accuracy can potentially reduce bias and false conclusions in public health and other population‐based studies.
A pilot randomized controlled trial comparing computer‐assisted cognitive rehabilitation, stimulant medication, and an active control in the treatment of ADHD
Authors: Azami Saeed , Moghadas Alireza , Sohrabi‐Esmrood Faramarz , Nazifi Morteza , Mirmohamad Mahdieh , Hemmati Fatemeh , Ahmadi Ameneh , Hamzeh‐poor Pariya , Khari Saeedeh , Lakes Kimberley
Published: April 2016

Background

This research aimed to compare computer‐assisted cognitive rehabilitation (CACR) psychostimulants (MED) and placebo CACR (PCACR) in the treatment of ADHD using a multiarm parallel design.

Methods

Thirty‐four boys with ADHD, aged 7–12, were randomly assigned to either CACR (n = 12), MED (n = 11), or PCACR (n = 11). However, the study was not blinded and medication doses might be suboptimal given the lack of titration. Continuous performance test, Tower‐of‐London, forward/backward digit span, span board, Raven's progressive matrices, and SNAP‐IV were completed at baseline, posttest, and follow‐up.

Results

Computer‐assisted cognitive rehabilitation outperformed both MED and PCACR on backward digit span at posttest and PCACR at follow‐up. CACR outperformed PCACR and MED on forward digit span at posttest and PCACR at follow‐up. CACR outperformed MED on span board at posttest. CACR outperformed PCACR and MED on Raven's matrices at posttest. CACR and PCACR scored lower than MED on ADHD‐PHI at posttest. CACR scored lower than MED on ADHD‐C at posttest.

Conclusions

Immediately after interventions, CACR improved certain simple executive functions (EFs) as much as active stimulant medication. On complex EFs, CACR was superior to active stimulant medication and PCACR. CACR reduced behavioral symptoms of ADHD more than active stimulant medication. However, at 3‐month follow‐up, maintenance of the CACR gains was weak.
Early Life Stress: What Is the Human Chapter of the Mammalian Story?
Authors: Gunnar Megan R.
Published: April 2016

About the time I started kindergarten, a researcher in a laboratory far away picked up a baby rat, handled it briefly, and returned it to the nest. The rat grew up to be resilient to stress, as did its brothers and sisters who were also handled. The effect was traced to changes in the brain's regulation of the body's stress and emotion systems. Thus was born the field of early experiences and stress. Years later, as a research assistant, I pondered why babies cried when uncontrollable toys made loud noises and stumbled into the same field of early experiences and stress. I have spent more than 35 years trying to use our vast knowledge of the neurobiology of stress and development in animals to understand how adverse care during early human development affects physical and mental health. This essay traces my own development as I have sought to understand the human chapter in this mammalian story.