bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of procyanidin supplementation on the immune responses of broilers challenged with lipopolysaccharide
Authors: Wu Qiu Jue , Wang Yu Qin , Qi Yan Xia
Published: November 2016

In the present study, the effect of dietary procyanidin (PCA, from pine needles) supplementation on the innate immunity of broilers were investigated. The experiment was designed as a 2 × 4 factorial arrangement (eight cages / treatment; six birds (one‐day‐old) / cage) with dietary PCA concentrations (0, 0.05, 0.075 and 0.1%) and two immune treatments (injection of lipopolysaccharide (LPS) (0.5 mg/kg body weight) or saline). LPS was dissolved in sterile 9 g/L (w/v) NaCl solution at 16, 18, 20 days of age to mimic immune stress. The remaining birds were injected with saline as a placebo. The results indicated that, prior to LPS challenge, the PCA diet had no significant effect on bird growth performance. The injection of LPS was also not associated with any significant changes in poultry performance. LPS injection increased the activity of nitrogen oxides (NOx) and the concentrations of inflammatory cytokines (interferon‐γ (IFN‐γ), interleukin‐1β (IL‐1β), IL‐2, IL‐4, IL‐6 and IL‐10) in serum; dietary PCA decreased these concentrations (P < 0.05) in the PCA 0.1% group, further illustrating the immune effect of PCA. In conclusion, PCA supplementation has a beneficial effect on LPS challenge, which may be associated with the inhibition of the secretion of cytokines and decrease in the proinflammatory marker NOx.
Evaluation of a cow‐side milk progesterone assay and assessment of the positive predictive value of oestrus diagnosis by dairy farmers in New South Wales
Authors: Ingenhoff L , Hall E , House JK
Published: November 2016

Objectives

The three objectives of this study were to determine the positive predictive value (PPV) of oestrus diagnosis (heat detection accuracy) by dairy farmers, calculate the diagnostic sensitivity and specificity of the P4 Rapid milk progesterone assay for detecting a corpus luteum and evaluate the economics of using a cow‐side milk progesterone assay designed to aid oestrus diagnosis.

Methods

Milk samples were collected from 752 cows diagnosed in oestrus by farm personnel on 14 dairy farms. Samples were tested using the P4 Rapid milk progesterone assay to estimate the PPV of oestrus diagnosis at each farm and a crude pooled mean of PPV of oestrus diagnosis across all farms. A further 156 milk samples were collected from cows with luteal tissue status determined by transrectal ultrasound and tested by the P4 Rapid assay to enable calculation of the sensitivity and specificity of the P4 Rapid assay.

Results

For pooled farm samples, the PPV was 97.0%, with a range between farms of 88.9–100%. Sensitivity of the P4 Rapid milk progesterone assay for detecting a corpus luteum was 90.1% and specificity was 98.7%. Misclassification of oestrus in cows previously identified as pregnant was the most common cause of false‐positive oestrus diagnoses by farm personnel.

Conclusion

Routine testing of milk progesterone in all cows diagnosed in oestrus is not economically justified and may even slightly reduce submission rates; conversely, strategic use of cow‐side milk progesterone assays can improve herd reproductive performance by facilitating decisions on whether to rebreed cows previously diagnosed as pregnant.
Assessment of pharmacokinetic interaction between rilotumumab and epirubicin, cisplatin and capecitabine (ECX) in a Phase 3 study in gastric cancer
Authors: Zhang Yilong , Kuchimanchi Mita , Zhu Min , Doshi Sameer , Hoang Tien , Kasichayanula Sreeneeranj
Published: November 2016

Aims

Rilotumumab is a fully human monoclonal antibody investigated for the treatment of MET‐positive gastric cancer. The aim of this study was to evaluate the potential pharmacokinetic (PK)‐based drug–drug interaction (DDI) between rilotumumab and epirubicin (E), cisplatin(C) and capecitabine (X).

Methods

This was a Phase 3 double‐blind, placebo‐controlled study, in which rilotumumab, epirubicin and cisplatin were administered intravenously at 15 mg kg−1, 50 mg m−2, and 60 mg m−2 Q3W, respectively, while capecitabine was given orally at 625 mg m−2 twice daily. Rilotumumab PK samples were taken at pre‐dose and at the end‐of‐infusion from all patients in cycles 1, 3, 5 and 7. ECX PK samples were taken in cycle 3 from patients who participated in the intensive PK assessment. ECX PK was assessed by non‐compartmental (NCA) analyses and PK parameters were compared between two arms. Rilotumumab PK was assessed by comparing the observed rilotumumab serum concentrations with model‐predicted concentrations using a population PK model developed from previous Phase 1 and Phase 2 studies.

Results

The study enrolled 609 patients. ECX plasma concentrations in the presence and absence of rilotumumab were similar, as demonstrated by the geometric mean ratios for Cmax and AUC, which were close to 1.0, suggesting ECX PK was not affected by co‐administration of rilotumumab. The observed rilotumumab serum concentrations were similar to the values predicted by population PK modelling on the basis of a prediction‐corrected visual predictive check, indicating rilotumumab exposure was not affected by co‐administration of ECX.

Conclusions

The results suggest lack of PK‐based DDI between rilotumumab and ECX.
Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections
Authors: Kamaruzzaman Nor Fadhilah , Kendall Sharon , Good Liam
Published: November 2016

Infectious diseases continue to threaten human and animal health and welfare globally, impacting millions of lives and causing substantial economic loss. The use of antibacterials has been only partially successful in reducing disease impact. Bacterial cells are inherently resilient, and the therapy challenge is increased by the development of antibacterial resistance, the formation of biofilms and the ability of certain clinically important pathogens to invade and localize within host cells. Invasion into host cells provides protection from both antibacterials and the host immune system. Poor delivery of antibacterials into host cells causes inadequate bacterial clearance, resulting in chronic and unresolved infections. In this review, we discuss the challenges associated with existing antibacterial therapies with a focus on intracellular pathogens. We consider the requirements for successful treatment of intracellular infections and novel platforms currently under development. Finally, we discuss novel strategies to improve drug penetration into host cells. As an example, we discuss our recent demonstration that the cell penetrating cationic polymer polyhexamethylene biguanide has antibacterial activity against intracellular Staphylococcus aureus.

Linked Articles

This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro‐organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc
Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets
Authors: Akoumianakis Ioannis , Tarun Akansha , Antoniades Charalambos
Published: November 2016

Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H2S, glucagon‐like peptide 1 or pro‐inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT.

Linked Articles

This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue – Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc
Personal income tax progressivity and output volatility: Evidence from OECD countries
Authors: Rieth Malte , Checherita‐Westphal Cristina , Attinasi Maria‐Grazia
Published: November 2016

This paper investigates empirically the effect of personal income tax progressivity on output volatility using macro data from a sample of OECD countries over the period 1982–2009. Our measure of progressivity is based on the difference between the marginal and the average personal income tax rate for the average production worker. We find supportive empirical evidence for the hypothesis that higher personal income tax progressivity leads to lower output volatility. This effect comes in addition to the stabilizing impact of government size and it is equally important in economic terms. All other factors constant, countries with more progressive personal income tax systems seem to benefit from stronger automatic stabilizers.
Price dispersion in a directed search model
Authors: Huang Ce
Published: November 2016

This paper investigates a directed search model in which some buyers are uninformed about prices. We find that sellers' strategies are given by discrete distributions in any symmetric pricing equilibrium. When the proportion of uninformed buyers is sufficiently high, the unique symmetric pricing equilibrium involves a countably infinite number of atoms.
Affect recognition among adolescents in therapeutic schools: relationships with posttraumatic stress disorder and conduct disorder symptoms
Authors: Javdani Shabnam , Sadeh Naomi , Donenberg Geri R. , Emerson Erin M. , Houck Christopher , Brown Larry K.
Published: November 2016

Background

Posttraumatic stress disorder (PTSD) and conduct disorder (CD) symptoms often co‐occur in adolescence, but little is known about whether they show common or distinct emotional processing deficits.

Method

We examined the effects of PTSD and CD symptoms on facial affect processing in youth with emotional and behavior problems. Teens enrolled in therapeutic day schools (N = 371; ages 13–19) completed a structured diagnostic assessment and the Diagnostic Analysis of Nonverbal Accuracy‐2 facial affect recognition task.

Results

Posttraumatic stress disorder symptoms were associated with deficits in the recognition of angry facial expressions, specifically the false identification of angry faces as fearful. CD symptoms were associated with greater difficulty correctly identifying sadness.

Conclusions

Findings suggest specificity in the relationships of PTSD and CD symptoms with emotional processing.
Neural Reactivity to Emotional Faces May Mediate the Relationship Between Childhood Empathy and Adolescent Prosocial Behavior
Authors: Flournoy John C. , Pfeifer Jennifer H. , Moore William E. , Tackman Allison M. , Masten Carrie L. , Mazziotta John C. , Iacoboni Marco , Dapretto Mirella
Published: November 2016

Reactivity to others’ emotions not only can result in empathic concern (EC), an important motivator of prosocial behavior, but can also result in personal distress (PD), which may hinder prosocial behavior. Examining neural substrates of emotional reactivity may elucidate how EC and PD differentially influence prosocial behavior. Participants (N = 57) provided measures of EC, PD, prosocial behavior, and neural responses to emotional expressions at ages 10 and 13. Initial EC predicted subsequent prosocial behavior. Initial EC and PD predicted subsequent reactivity to emotions in the inferior frontal gyrus (IFG) and inferior parietal lobule, respectively. Activity in the IFG, a region linked to mirror neuron processes, as well as cognitive control and language, mediated the relation between initial EC and subsequent prosocial behavior.
What You Want Versus What's Good for You: Paternalistic Motivation in Children's Helping Behavior
Authors: Martin Alia , Lin Kelsey , Olson Kristina R.
Published: November 2016

Children help others to complete their goals. Yet adults are sometimes motivated to help others in a “paternalistic” way, overriding a recipient's desires if they conflict with the recipient's best interests. Experiments investigated whether 5‐year‐olds (n = 100) consider a recipient's desire, and the consequences of fulfilling this desire, when helping. Children overrode a request for chocolate in favor of giving fruit snacks, if chocolate would make the recipient sick. Children did not override a request for chocolate in favor of carrots, even if chocolate would make the recipient sick, but they gave carrots if the recipient requested them. By age 5, children balance different motivations when helping, considering the recipient's desires, consequences of fulfilling them, and alternative forms of helping available.
Defective expression of apoptosis-related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation
Authors: de Oliveira G L V , Ferreira A F , Gasparotto E P L , Kashima S , Covas D T , Guerreiro C T , Brum D G , Barreira A A , Voltarelli J C , Simões B P , Oliveira M C , de Castro F A , Malmegrim K C R
Published: November 2016

Defective apoptosis might be involved in the pathogenesis of multiple sclerosis (MS). We evaluated apoptosis-related molecules in MS patients before and after autologous haematopoietic stem cell transplantation (AHSCT) using BCNU, Etoposide, AraC and Melphalan (BEAM) or cyclophosphamide (CY)-based conditioning regimens. Patients were followed for clinical and immunological parameters for 2 years after AHSCT. At baseline, MS patients had decreased proapoptotic BAD, BAX and FASL and increased A1 gene expression when compared with healthy counterparts. In the BEAM group, BAK, BIK, BIMEL, FAS, FASL, A1, BCL2, BCLXL, CFLIPL and CIAP2 genes were up-regulated after AHSCT. With the exception of BIK, BIMEL and A1, all genes reached levels similar to controls at day + 720 post-transplantation. Furthermore, in these patients, we observed increased CD8+ Fas+ T cell frequencies after AHSCT when compared to baseline. In the CY group, we observed increased BAX, BCLW, CFLIPL and CIAP1 and decreased BIK and BID gene expressions after transplantation. At day + 720 post-AHSCT, the expression of BAX, FAS, FASL, BCL2, BCLXL and CIAP1 was similar to that of controls. Protein analyses showed increased Bcl-2 expression before transplantation. At 1 year post-AHSCT, expression of Bak, Bim, Bcl-2, Bcl-xL and cFlip-L was decreased when compared to baseline values. In summary, our findings suggest that normalization of apoptosis-related molecules is associated with the early therapeutic effects of AHSCT in MS patients. These mechanisms may be involved in the re-establishment of immune tolerance during the first 2 years post-transplantation.
Hypoxia inducible factor-1α-induced interleukin-33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease
Authors: Sun M , He C , Wu W , Zhou G , Liu F , Cong Y , Liu Z
Published: November 2016

Intestinal epithelial cells (IECs), an important barrier to gut microbiota, are subject to low oxygen tension, particularly during intestinal inflammation. Hypoxia inducible factor-1α (HIF-1α) is expressed highly in the inflamed mucosa of inflammatory bowel disease (IBD) and functions as a key regulator in maintenance of intestinal homeostasis. However, how IEC-derived HIF-1α regulates intestinal immune responses in IBD is still not understood completely. We report here that the expression of HIF-1α and IL-33 was increased significantly in the inflamed mucosa of IBD patients as well as mice with colitis induced by dextran sulphate sodium (DSS). The levels of interleukin (IL)−33 were correlated positively with that of HIF-1α. A HIF-1α-interacting element was identified in the promoter region of IL-33, indicating that HIF-1α activity regulates IL-33 expression. Furthermore, tumour necrosis factor (TNF) facilitated the HIF-1α-dependent IL-33 expression in IEC. Our data thus demonstrate that HIF-1α-dependent IL-33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.
Diagnostic accuracy of Thyroid Imaging Reporting and Data System in the prediction of malignancy in nodules with atypia and follicular lesion of undetermined significance cytologies
Authors: Baser Husniye , Cakir Bekir , Topaloglu Oya , Alkan Afra , Polat Sefika Burcak , Dogan Hayriye Tatli , Yazicioğlu Mustafa Omer , Aydin Cevdet , Ersoy Reyhan
Published: November 2016

Objective

Thyroid Imaging Reporting and Data System (TIRADS) is a simple and reliable reporting system for the prediction of malignancy. We aimed to determine the role of TIRADS in the prediction of malignancy in subcategories of Bethesda Category III, atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS).

Design & patients

A total of 461 nodules with AUS cytology in 450 patients and 179 nodules with FLUS cytology in 168 patients were included. Ultrasonography (US) features and postoperative histopathology results were documented. Every suspicious US feature was scored as 1 and 0 according to the presence or not, respectively. TIRADS category of each nodule was determined.

Results

In AUS subcategory, histopathologically malignant nodules had significantly different TIRADS categories compared to benign nodules (P = 0·001), but this was not the case in FLUS subcategory (P = 0·121). In AUS group, malignant nodules had significantly higher prevalance of microcalcification, hypoechogenicity and anteroposterior/transverse ratio than benign ones (P < 0·001, P < 0·001 and P = 0·003, respectively) and TIRADS categories of 4c and 5 were more frequent in malignant nodules (P < 0·05). Microcalcification, hypoechogenicity and TIRADS were found to be associated with malignancy in multivariate logistic regression analysis in this subcategory. TIRADS category ≥4c was associated with malignancy (AUC ± SE: 0·584 ± 0·028). In FLUS subcategory, there was no significant difference between histopathologically malignant and benign nodules with respect to suspicious US features (P > 0·05, all).

Conclusion

TIRADS seems to be useful in predicting malignancy and planning further management in the AUS subcategory, but not quite so in the FLUS subcategory.
Assessment of early atherosclerosis and left ventricular dysfunction in children with 21‐hydroxylase deficiency
Authors: Özdemir Rahmi , Korkmaz Hüseyin Anil , Küçük Mehmet , Karadeniz Cem , Meşe Timur , Özkan Behzat
Published: November 2016

Aim

We analysed 25 children with 21‐hydroxylase deficiency who received glucocorticoid and/or mineralocorticoid treatment for at least 12 months to determine the effects of the disease and its treatment on vascular structures and ventricular function.

Methods

Twenty‐five patients with 21‐hydroxylase‐deficient congenital adrenal hyperplasia (CAH) and 25 control subjects were enrolled into this observational, cross‐sectional study. The patients were investigated in terms of fasting blood glucose and insulin; fasting serum lipid profile; serum 17‐hydroxyprogesterone; dehydroepiandrosterone sulphate; androstenedione; and adrenocorticotropic hormone. M‐mode tracings of the wall motion of major arteries were obtained to measure carotid intima‐media thickness (cIMT), as well as elasticity and distensibility of the aorta and carotid artery. Conventional and relatively new tissue Doppler imaging techniques were employed to assess ventricular systolic and diastolic functions.

Results

The median age and weight of patients were 9·4 years (1·5–16·75) and 35·5 kg (7·5–76·3), respectively. The median duration of treatment was 52·2 months. Tissue Doppler imaging measurements revealed left ventricular diastolic impairment in the patient group compared to the controls. Carotid intima‐media thickness, stiffness index, elastic modulus of the aorta and carotid artery were significantly higher; meanwhile, aortic distensibility and carotid distensibility were lower in the patient group, all of which indicates the presence of subclinical atherosclerosis. BMI was found to be an independent variable for cIMT (ß: 0·5, P = 0·01) and aortic stiffness index (ß: 0·52, P < 0·001).

Conclusion

Cardiovascular function and the elastic properties of major arteries are disturbed in children and adolescents with 21‐hydroxylase‐deficient CAH.
Sufficiency and Suitability of Global Biodiversity Indicators for Monitoring Progress to 2020 Targets
Authors: Mcowen Chris J. , Ivory Sarah , Dixon Matthew J. R. , Regan Eugenie C. , Obrecht Andreas , Tittensor Derek P. , Teller Anne , Chenery Anna M.
Published: November 2016

Biodiversity indicators are widely used tools to help determine rates of biodiversity change and the success or failure of efforts to conserve it. However, their sufficiency and suitability in providing information for decision‐makers is unclear. Here, we review the indicators brought together under the Biodiversity Indicator Partnership to monitor progress towards the Aichi Targets to determine where there are gaps. Of the 20 Aichi Biodiversity Targets, Targets 2, 3, and 15 are missing indicators entirely. Scoring the indicators in relation to their alignment, temporal relevance and spatial scale shows additional gaps under Targets 1, 13, and 16–20. Predominately, gaps were found to be socio‐economic in nature (i.e., benefits, pressures, and responses) rather than status‐related (i.e., states), principally due to a poor alignment between the indicator and the text of the Aichi Target. Hence, it is critical that existing indicators are properly resourced and maintained and new indicators developed to be able to effectively monitor biodiversity and its influencing factors to 2020 and beyond.
Congenital infantile fibrosarcoma mimicking a cutaneous vascular lesion: a case report and review of the literature
Authors: Enos Tyler , Hosler Gregory A. , Uddin Naseem , Mir Adnan
Published: November 2016

Congenital infantile fibrosarcoma (CIFS) is a rare neoplasm of infancy that occurs most frequently in the extremities, and when presenting in the skin, may sometimes resemble infantile hemangiomas or other vascular lesions. Clinically, these tumors differ from hemangiomas in the time of onset, morphology, and growth pattern and must be evaluated histologically for definitive diagnosis. We describe an infant with a neoplasm involving the distal left forearm initially presumed to be a vascular lesion after evaluation by two separate ultrasound studies. He presented at seven weeks of life with a multinodular lesion that had enlarged significantly since birth, and the skin biopsy revealed a fibrosarcoma. This case highlights an unusual cutaneous presentation of CIFS, which varies in appearance from the previous 12 cases reported in the literature. We review the clinical manifestations of these congenital masses and emphasize early diagnosis for conservative therapy and improved prognosis.
Frequency‐dependent selection for rare genotypes promotes genetic diversity of a tropical palm
Authors: Browne Luke , Karubian Jordan
Published: November 2016

Negative frequency‐dependent selection among species is a key driver of community diversity in natural systems, but the degree to which negative frequency‐dependent selection shapes patterns of survival and genetic diversity within species is poorly understood. In a 5‐year field experiment, we show that seedlings of a tropical palm with rare genotypes had a pronounced survival advantage over seedlings with common genotypes, with effect sizes comparable to that of light availability. This ‘rare genotype advantage’ led to an increase in population‐wide genetic diversity among seedlings compared to null expectations, as predicted by negative frequency‐dependent selection, and increased reproductive success in adult trees with rare genotypes. These results suggest that within‐species negative frequency‐dependent selection of genotypes can shape genetic variation on ecologically relevant timescales in natural systems and may be a key, overlooked source of non‐random mortality for tropical plants.
No association between Borrelia burgdorferi antibodies and amyotrophic lateral sclerosis in a case–control study
Authors: Visser A. E. , Verduyn Lunel F. M. , Veldink J. H. , van den Berg L. H.
Published: November 2016

Background and purpose

Previous studies, mostly case reports and uncontrolled studies, provide a low level of evidence for the hypothesized link between Lyme disease and amyotrophic lateral sclerosis (ALS). In order to make evidence‐based recommendations regarding testing for Borrelia burgdorferi antibodies in the diagnostic work‐up for ALS, the objective of this study was to explore the evidence for an association between these antibodies and ALS in a case–control design including age‐, gender‐ and residency‐matched controls.

Methods

A total of 491 patients with ALS were matched to 982 controls. IgG titers against B. burgdorferi were determined by an enzyme‐linked immunosorbent assay and, in the case of positivity or borderline results, a western blot was performed. Conditional logistic regression and Fisher's exact tests were used to compare the antibody titers or positivity between patients and controls.

Results

No difference in seroprevalence of Borrelia was found between patients (4.1%) and controls (5.9%). Clinical characteristics and survival were similar between seropositive and seronegative patients. Moreover, patients with a spinal onset were not more frequently seropositive compared with patients with a bulbar onset (P = 0.47), and neither were patients with a short diagnostic delay of <6 months compared with controls (P = 0.69). None of the 20 patients with a diagnostic delay of <3 months tested positive for IgM antibodies, suggestive of a recent infection.

Conclusion

This large case–control study provides evidence for a lack of association between B. burgdorferi antibodies and ALS, and therefore does not support the inclusion of routine testing for these antibodies in the diagnostic work‐up in patients with classical ALS.
Metabolic injury in a variable rat model of post–status epilepticus
Authors: Pearce Patrice S. , Wu Yijen , Rapuano Amedeo , Kelly Kevin M. , de Lanerolle Nihal , Pan Jullie W.
Published: November 2016

Objective

In vivo studies of epilepsy typically use prolonged status epilepticus to generate recurrent seizures. However, reports on variable status duration have found discrete differences in injury after 40–50 min of seizures, suggesting a pathophysiologic sensitivity to seizure duration. In this report we take a multivariate cluster analysis to study a short duration status epilepticus model using in vivo 7T magnetic resonance spectroscopy (MRS) and histologic evaluation.

Methods

The Hellier Dudek model was applied with 45 min of status epilepticus after which the animals were imaged twice, at 3 days and 3 weeks post–status epilepticus. Single voxel point resolved spectroscopy (PRESS) MRS was used to acquire data from the dentate gyrus and CA3 region of the hippocampus, assessing metabolite ratios to total creatine (tCr). In a subset of animals after the second imaging study, brains were analyzed histologically by Nissl staining.

Results

A hierarchical cluster analysis performed on the 3‐day data from 21 kainate‐treated animals (dentate gyrus voxel) segregated into two clusters, denoted by KM (more injured, n = 6) and KL (less injured, n = 15). Although there was no difference in kainate dosing or seizure count between them, the metabolic pattern of injury was different. The KM group displayed the largest significant changes in neuronal and glial parameters; the KL group displayed milder but significant changes. At 3 weeks, the KL group returned to normal compared to controls, whereas the KM group persisted with depressed N‐acetyl aspartate (NAA)/tCr, glutamate/tCr, and increased inositol/tCr and glutamine/tCr. The classification was also consistent with subsequent histologic patterns at 3 weeks.

Significance

Although a short status period might be expected to generate a continuous distribution of metabolic injury, these data show that the short Hellier Dudek model appears to generate two levels of injury. The changes seen in segregated groups persisted into 3 weeks, and can be interpreted according to neuronal and glial biomarkers consistent with histology results.
Dihydroartemisinin counteracts fibrotic portal hypertension via farnesoid X receptor‐dependent inhibition of hepatic stellate cell contraction
Authors: Xu Wenxuan , Lu Chunfeng , Zhang Feng , Shao Jiangjuan , Yao Shunyu , Zheng Shizhong
Published: November 2016

Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis‐related portal hypertension still requires clarification. In this study, gain‐ and loss‐of‐function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl4‐caused hepatic fibrosis and portal hypertension. Immunofluorescence staining visually showed a decrease in FXR expression in CCl4‐administrated rat HSC but an increase in that in DHA‐treated rat HSC. Serum diagnostics and morphological analyses consistently indicated that DHA exhibited hepatoprotective effects on CCl4‐induced liver injury. DHA also reduced CCl4‐caused inflammatory mediator expression and inflammatory cell infiltration. These improvements were further enhanced by INT‐747 but weakened by Z‐guggulsterone. Noteworthily, DHA, analogous to INT‐747, significantly lowered portal vein pressure and suppressed fibrogenesis. Experiments on mice using FXR shRNA lentivirus consolidated the results above. Mechanistically, inhibition of HSC activation and contraction was found as a cellular basis for DHA to relieve portal hypertension. These findings demonstrated that DHA attenuated portal hypertension in fibrotic rodents possibly by targeting HSC contraction via a FXR activation‐dependent mechanism. FXR could be a target molecule for reducing portal hypertension during hepatic fibrosis.
Nutrients associated with terrestrial dissolved organic matter drive changes in zooplankton:phytoplankton biomass ratios in an alpine lake
Authors: Kissman Carrie E. H. , Williamson Craig E. , Rose Kevin C. , Saros Jasmine E.
Published: November 2016

Dissolved organic matter (DOM) is increasing in many lakes due to climate change and other environmental forcing. A 21‐day microcosm experiment that manipulated terrestrial DOM was used to determine the effect of DOM on zooplankton:phytoplankton biomass ratios (z:p). We predicted that if DOM additions increase the amount of fixed carbon available for higher trophic levels through stimulation of the microbial loop and hence zooplankton, the z:p will increase. However, if DOM additions increase other nutrients besides fixed carbon, we predict stable or decreasing z:p due to nutrient stimulation of phytoplankton that subsequently enhances zooplankton.

The effects of experimental additions of terrestrially derived DOM on zooplankton, phytoplankton, z:p and zooplankton net grazing were assessed in microcosms (sealed bags) incubated in the epilimnion (shallow; 1.5 m) and hypolimnion (deep; 8.0 m) strata of an alpine lake.

DOM addition treatments (DOM+) had a 6.0‐ to 7.5‐fold increase in phytoplankton biomass relative to controls, but only a 1.3‐ to 1.5‐fold increase in zooplankton biomass, on day 21 of the experiment. The z:p was, thus, lower in the DOM+ treatments (ratios: 2.3 deep and 4.4 shallow) than in the control treatments (ratios: 13.4 deep and 17.5 shallow), providing evidence that DOM additions provide nutrient subsidies besides fixed carbon that stimulate phytoplankton biomass accumulation.

The increase in zooplankton biomass during the experiment was similar in magnitude to the total amount of dissolved organic carbon (DOC) in the DOM added in the sealed bags at the beginning of the experiment, which suggests zooplankton biomass stimulation due to increased phytoplankton biomass, and not from DOM through the microbial loop, which would have greater trophic transfer losses. The consumer net grazing effect in the DOM+ treatments was reduced by 2.8‐fold in the shallow stratum and by 2.9‐fold in the deep stratum relative to the control treatments, indicating that zooplankton were unable to exert strong top–down control on the primary producers.

The role of nutrients needs to be considered when examining the response of pelagic ecosystems to inputs of terrestrial DOM, especially in lakes with lower DOC concentrations.
Effects of mixing on the pelagic food web in shallow lakes
Authors: Blottière Lydie , Jaffar‐Bandjee Mourad , Jacquet Stéphan , Millot Alexis , Hulot Florence D.
Published: November 2016

We examined the effects of wind‐induced mixing and particle resuspension on the pelagic food web in eutrophic shallow lakes. These processes are known to have a major impact on a variety of biological, physical or chemical parameters such as the underwater light climate, the nutrient availability in the water column and the abundance and composition of the phytoplankton community. However, little is known about the effects of these processes on other compartments of the freshwater food web.

We conducted a 9‐week experiment comprising a manipulation of mixing intensity in 15 m3 mesocosms equipped with wavemakers in order to explore the impact of two mixing regimes on water chemistry as well as viral, bacterial, phytoplankton and zooplankton communities.

The turbidity level in mixed mesocosms (compared to calm conditions) was higher on average, especially at the bottom, indicating a successful resuspension of the sediment bed. Mixing increased chlorophyll a concentration without any clear increase in algal abundance, measured as cell counts by flow cytometry, which pointed to a change in species composition or a physiological adaptation to mixing. pH increased strongly in mixed mesocosms, suggesting enhanced primary productivity in perturbed conditions. Zooplankton responses to mixing were neutral for cladocerans and negative for copepods, which potentially mediated top–down controls on the rotifer population.

Bacterial and viral abundances were not significantly changed by the mixing regimes; however, peaks of viral lysis of heterotrophic bacteria were seen in each mixed mesocosm, while none were observed in calm mesocosms. These results suggest that viral lysis is enhanced by the water column mixing.

Our experiment demonstrates that mixing is likely to influence shallow lake functioning through a complex combination of direct and indirect effects on the underwater light climate and water chemistry, phytoplankton physiology and productivity, zooplankton growth and possibly virus–host interactions. These complex effects could play a major role in structuring pelagic and benthic communities in shallow lakes.
Identifying the microbial taxa that consistently respond to soil warming across time and space
Authors: Oliverio Angela M. , Bradford Mark A. , Fierer Noah
Published: November 2016

Soil microbial communities are the key drivers of many terrestrial biogeochemical processes. However, we currently lack a generalizable understanding of how these soil communities will change in response to predicted increases in global temperatures and which microbial lineages will be most impacted. Here, using high‐throughput marker gene sequencing of soils collected from 18 sites throughout North America included in a 100‐day laboratory incubation experiment, we identified a core group of abundant and nearly ubiquitous soil microbes that shift in relative abundance with elevated soil temperatures. We then validated and narrowed our list of temperature‐sensitive microbes by comparing the results from this laboratory experiment with data compiled from 210 soils representing multiple, independent global field studies sampled across spatial gradients with a wide range in mean annual temperatures. Our results reveal predictable and consistent responses to temperature for a core group of 189 ubiquitous soil bacterial and archaeal taxa, with these taxa exhibiting similar temperature responses across a broad range of soil types. These microbial ‘bioindicators’ are useful for understanding how soil microbial communities respond to warming and to discriminate between the direct and indirect effects of soil warming on microbial communities. Those taxa that were found to be sensitive to temperature represented a wide range of lineages and the direction of the temperature responses were not predictable from phylogeny alone, indicating that temperature responses are difficult to predict from simply describing soil microbial communities at broad taxonomic or phylogenetic levels of resolution. Together, these results lay the foundation for a more predictive understanding of how soil microbial communities respond to soil warming and how warming may ultimately lead to changes in soil biogeochemical processes.
Breast conservation in ductal carcinoma in situ (DCIS): what defines optimal margins?
Authors: Toss Michael S , Pinder Sarah E , Green Andrew R , Thomas Jeremy , Morgan David A L , Robertson John F R , Ellis Ian O , Rakha Emad A
Published: November 2016

The introduction of mammographic screening has resulted in a rise in the detection rate of ductal carcinoma in situ (DCIS), currently accounting for one‐fifth of screen‐detected breast cancers. Although 60–70% of DCIS are treated with breast‐conserving surgery (BCS) with or without radiotherapy, the frequency of subsequent surgery to re‐excise positive margins in order to reduce the probability of recurrences remains high. DCIS recurrence is associated not only with financial, health and psychological implications; approximately half these recurrences are invasive disease. An appropriate margin width for patients undergoing BCS for invasive breast cancer has been largely agreed. Although there is a perception that such recommendations may be applicable to DCIS, major differences exist which may affect this application. Importantly, DCIS patients often do not receive systemic adjuvant (endocrine) therapy and not all receive radiotherapy in routine practice. There is evidence that wide margins (i.e. >10 mm) confer better protection against recurrence than positive (i.e. 0 mm) margins; however, there remains a debate concerning the optimum margin width between 0 and 10 mm. Previous studies have demonstrated that radiation therapy may not compensate for lack of re‐excision in those patients with positive or close margins, while wide margins will inevitably compromise cosmesis and patients’ body image perception. This review aims to address the clinical question of the minimal margin width in DCIS treated with BCS that is associated with the lowest recurrence rate and when, therefore, further surgical intervention for re‐excision can be safely avoided. A range of clinical circumstances that might affect this are considered.
PD‐1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis’
Authors: Gonzalez Raul S , Salaria Safia N , Bohannon Caitlin D , Huber Aaron R , Feely Michael M , Shi Chanjuan
Published: November 2016

Aims

PD‐1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune‐type side effects, including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied.

Methods and results

We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD‐1 or PD‐L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra‐epithelial neutrophils and increased crypt/gland apoptosis, although intra‐epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow‐up endoscopies were not performed.

Conclusions

PD‐1/PD‐L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA‐4 inhibitors and PI3Kδ inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra‐epithelial lymphocytes and crypt rupture may help to distinguish PD‐1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft‐versus‐host disease, cytomegalovirus infection and autoimmune enteropathy.
A highly resistant structure between cuticle and cortex of human hair
Authors: Takahashi T. , Yoshida S.
Published: November 2016

Objective

To clarify the presence and properties of a unique structure which is located between the cuticle and cortex of human hair.

Methods

Whole hair fibre and longitudinally split hair were used. Treated with a mixture of urea, reductant and alkaline, hair was split at the interface between cuticle and cortex. The residues in the solution were observed by microscope, and the distribution of lipids and protein was determined.

Results

From the treated longitudinally split hair, a membrane‐like structure which was located at the interface between cuticle and cortex was obtained. This structure showed especially high resistance against chemical treatment and was thought to be the region into which the proximal roots of the cuticle cells are embedded. It was supposed that some steryl glucoside‐like lipid, of which the presence in the cuticle and cortex interface was previously reported, is located in this structure.

Conclusion

This study proposed the presence of a membrane‐like structure, which is highly resistant against chemical treatment, at the region between cuticle and cortex of human hair. This may protect cortex from external stimuli more firmly than the surface part of cuticle.
Nonisothermal sintering of Cr2AlC powder
Authors: Rajkumar Yembadi , Rahul Bapurao M. , Ananth Akash Puppala , Panigrahi Bharat B.
Published: November 2016

This work studies the sintering behavior of ultrafine powder of Cr2AlC compound during nonisothermal heating using a dilatometer. Sample exhibits relatively slower densification under pressureless condition where relative density increased from about 61% (green compact) to about 73% during heating up to 1350°C. Axial shrinkage data were analyzed through the volume diffusion and grain boundary diffusion‐based sintering models. Estimated activation energy of sintering (352kJ/mol) for volume diffusion mechanism, was found to be closely matching with the reported activation energy of chromium diffusivity, indicating volume diffusion as a controlling mechanism and chromium as a major diffuser in Cr2AlC.
Flow cytometry analysis of DNA ploidy levels and protein profiles distinguish between populations of Lumbriculus (Annelida: Clitellata)
Authors: Tweeten Kay A. , Morris Samantha J.
Published: November 2016

Variations in DNA ploidy have been observed in Lumbriculus, a freshwater annelid, as well as in other clitellates. Interpretation and application of experimental results using these animals may be impacted as ploidy levels affect the protein expression, reproductive behavior, and response to stressors. Ploidy is typically determined by chromosome spreads, a time‐consuming and inefficient method. We adapted flow cytometry protocols used on vertebrates and plants to determine the ploidy levels in different populations of Lumbriculus, including a laboratory strain (Environmental Protection Agency), a commercial strain (Aquatic Foods), and worms collected from natural habitats. To isolate nuclei, worms were homogenized, filtered to remove cell debris, and centrifuged through Optiprep™ density gradients. Nuclei were recovered, treated with RNAse, and stained with propidium iodide. Flow cytometry of the labeled nuclei showed that Lumbriculus from natural habitats in Minnesota and Iowa were diploid, with an estimated genome size of 2.7 pg. Populations from natural habitats in California and Oregon were highly polyploid, as were the laboratory and commercial strains. Chromosome spreads verified the high ploidy levels indicated by flow cytometry results, but also suggested that flow cytometry may be underestimating the DNA content levels. Staining of nuclei with diamidino‐2‐phenylindole indicated that this may be due to high levels of heterochromatin in nuclei from polyploid forms of Lumbriculus. To further compare the populations, proteins in worm homogenates were subjected to isoelectrofocusing gel electrophoresis. Distinct protein profiles were seen; one was shared in common by the diploid worms, the other was characteristic of polyploid populations. Diploid worms could also be distinguished from polyploid worms based on differences in hemoglobin linker proteins. The results further support taxonomic classification of the diploid and polyploid forms of Lumbriculus as distinct species.
Re‐entrant relaxor behavior in BaTiO3‐Bi(Zn2/3Nb1/3)O3 ceramics
Authors: Wu Longwen , Wang Xiaohui , Shen Zhengbo , Luo Bingcheng , Li Longtu
Published: November 2016

The (1−x)BaTiO3−xBi(Zn2/3Nb1/3)O3 (x=0.10‐0.25) ceramics were fabricated via solid‐state reactions. Temperature‐dependent polarization measurement reveals that with the temperature lowering, the remnant polarization increases till a maximum value before it decreases, showing a reentrant phenomenon. Absence of apparent switching current peaks in the current density as a function of electric field should indicate the lack of a ferroelectric transition, which is further verified by the consistent macroscopic phase structure from the Raman spectra. An anomalous peak in the full width at half maximum of a deconvoluted mode at ~515 cm−1 suggests the entering of a more disordered state of dipolar dynamics, which may be originated from the competition between the freezing of polar nanoregions and the random interacting fields.
Fracture mechanics of sharp scratch strength of polycrystalline alumina
Authors: Cook Robert F.
Published: November 2016

The strength of a polycrystalline alumina containing controlled scratches introduced by translated sharp contacts is investigated and described by a multiscale fracture mechanics model. Inert strength measurements of samples containing quasi‐static and translated Vickers indentation contacts showed that scratches degraded the strength at normal contact loads an order of magnitude less than those for quasi‐static indentation. The fracture mechanics model developed to describe strength degradation by scratches over the full range of contact loads included toughening effects by crack‐wake bridging at the microscale and lateral crack‐based residual stress relaxation effects at the mesoscale. A critical element of the model is the nonlinear scaling of the residual stress field of a scratch with the normal contact load acting during scratch formation. The similarities and differences in the scratch model in comparison with prior indentation‐strength fracture mechanics models are highlighted by parallel development of both. Central to the scratch model is the use of easily controlled normal contact load as the scratch‐strength measurement variable. Scratch length and orientation are shown to have significant effects on strength. The distributions of scratch widths controlling the intrinsic strengths of as‐received samples are determined and agreement with the observed scratch dimensions is demonstrated.