bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct inflammatory phenotypes of microglia and monocyte‐derived macrophages in Alzheimer's disease models: effects of aging and amyloid pathology
Authors: Martin Elodie , Boucher Céline , Fontaine Bertrand , Delarasse Cécile
Published: October 2016

Alzheimer's disease (AD) is a neurodegenerative disease characterized by formation of amyloid‐β (Aβ) plaques, activated microglia, and neuronal cell death leading to progressive dementia. Recent data indicate that microglia and monocyte‐derived macrophages (MDM) are key players in the initiation and progression of AD, yet their respective roles remain to be clarified. As AD occurs mostly in the elderly and aging impairs myeloid functions, we addressed the inflammatory profile of microglia and MDM during aging in TgAPP/PS1 and TgAPP/PS1dE9, two transgenic AD mouse models, compared to WT littermates. We only found MDM infiltration in very aged mice. We determined that MDM highly expressed activation markers at basal state. In contrast, microglia exhibited an activated phenotype only with normal aging and Aβ pathology. Our study showed that CD14 and CD36, two receptors involved in phagocytosis, were upregulated during Aβ pathogenesis. Moreover, we observed, at the protein levels in AD models, higher production of pro‐inflammatory mediators: IL‐1β, p40, iNOS, CCL‐3, CCL‐4, and CXCL‐1. Taken together, our data indicate that microglia and MDM display distinct phenotypes in AD models and highlight the specific effects of normal aging vs Aβ peptides on inflammatory processes that occur during the disease progression. These precise phenotypes of different subpopulations of myeloid cells in normal and pathologic conditions may allow the design of pertinent therapeutic strategy for AD.
Cocaine‐induced synaptic structural modification is differentially regulated by dopamine D1 and D3 receptors‐mediated signaling pathways
Authors: Zhang Lei , Huang Lu , Lu Kangrong , Liu Yutong , Tu Genghong , Zhu Mengjuan , Ying Li , Zhao Jinlan , Liu N. , Guo Fukun , Zhang Lin , Zhang Lu
Published: October 2016

Synaptic plasticity plays a critical role in cocaine addiction. The dopamine D1 and D3 receptors differentially regulate the cocaine‐induced gene expression, structural remodeling and behavioral response. However, how these two receptors coordinately mediate the ultra‐structural changes of synapses after cocaine exposure and whether these changes are behaviorally relevant are still not clear. Here, using quantitative electron microscopy, we show that D1 and D3 receptors have distinct roles in regulating cocaine‐induced ultra‐structural changes of synapses in the nucleus accumbens and caudoputamen. Pre‐treatment of cocaine‐treated mice with D3 receptor antagonist NGB2904 resulted in an increase in the ratio of total and asymmetric synapse to neuron and in the length of postsynaptic densities, compared with cocaine treatment alone. In contrast, pre‐treatment of cocaine‐treated mice with D1 receptor antagonist SCH23390 caused a reduction in synapse‐to‐neuron ratio and in postsynaptic densities length. Similarly, NGB2904 and SCH23390 showed opposite/differential effects on cocaine‐induced structural plasticity, conditioned place preference and locomotor activity and signaling activation, including the activation of ERK, CREB and NR1 and the expression of c‐fos and Cdk5. Therefore, we provide direct electron microscopy evidence that dopamine D1 and D3 receptors reciprocally regulate the ultra‐structural changes of synapses following chronic exposure to cocaine. In addition, our data suggest that D1 and D3 receptors may regulate cocaine‐induced ultra‐structural changes and behavior responses by impact on structural plasticity and signaling transduction.
Survival and life expectancy of the treeProtea roupelliaesubsp.roupelliaein a montane grassland savanna: Effects of fire regime and plant structure
Authors: Smith Francois Richard , Granger James Edmund
Published: October 2016

Survival and life expectancy are key demographic determinants of population dynamics. Using data collected in a field experiment monitored over 14 years in montane grassland of the Ukhahlamba‐Drakensberg Park, South Africa, we determined the effects of components of fire regime and plant structure on the survival and life expectancy of the treeProtea roupelliaesubsp.roupelliae(Proteaceae). The field experiment comprised six plots (0.2–0.5 ha in area) from which the survival and life expectancies of 1567 juveniles (non‐reproductives) and 329 adults (reproductives) were estimated in response to differences in fire frequency, biennial seasonal fire, flame height, juvenile height, adult height, basal area and canopy vigour. Juvenile survival and life expectancies were highest when fires were excluded for 8 years. However, a fire after 12 years of fire exclusion and another fire 2 years later eliminated all juveniles. Over the same 14‐year period of biennial fires, juvenile survival was 5%. Juvenile survival and life expectancy were higher after biennial, winter fires than after annual, winter fires. Flame height had no effect on juvenile survival and life expectancy. Both survival and life expectancy of juveniles increased as plants got older and grew taller. Adult survival was unaffected by fire frequency, flame height or tree size, but the survival of adults in response to fire seasonality was inconclusive. Adults with low canopy vigour (<25%) were negatively affected by fire. Juvenile survival and life expectancy are critical bottlenecks in the demography ofP. roupelliae. This species is neither a reseeder nor a resprouter. It avoids lethal fire damage by being restricted to rocky habitats with low fire intensities. Biennial winter fires least threaten the survival and life expectancy ofP. roupelliaeand impact least on its role in the summer feeding and breeding of Gurney's sugarbird.
High‐flow humidified nasal oxygenation vs. standard face mask oxygenation
Authors: Pillai A. , Daga V. , Lewis J. , Mahmoud M. , Mushambi M. , Bogod D.
Published: October 2016

Ten healthy volunteers received oxygen for 1 min, 2 min and 3 min at 10 l.min−1 via a face mask, or humidified oxygen at 60 l.min−1 via nasal prongs (OptiflowTM) with the mouth closed and with the mouth open. The mean (SD) end‐tidal oxygen partial pressure after 3 min face mask and Optiflow oxygenation, with mouth closed and open, were: 88.5 (6.2) kPa; 85.6 (6.4) kPa and 48.7 (26.4) kPa, respectively, p = 0.001. The equivalent mean (SD) transcutaneous oxygen partial pressures were: 34.6 (5.4) kPa; 36.4 (6.5) kPa and 25.5 (15.7) kPa, respectively, p = 0.03. High‐flow humidified nasal oxygenation for 3 min with the mouth closed was as effective as 3 min face mask oxygenation.
An observational study of critical care physicians' assessment and decision‐making practices in response to patient referrals
Authors: Charlesworth M. , Mort M. , Smith A. F.
Published: October 2016

Previous studies of critical care admissions have largely compared patients that have been granted or declined admission. To better understand the decision process itself, our ethnographic approach combined observation of and interviews with critical care physicians in a large English hospital. We observed 30 critical care doctors managing 71 referrals and conducted ten interviews with senior decision‐makers to explore the themes raised by our observations. We analysed data using the constant comparative method. We found that the decision to move a patient to critical care was just one way in which the trajectory of critical illness could be modified. When patients were admitted to critical care, it was not always for invasive monitoring or advanced organ support, with some admitted for more general medical and/or nursing care. When patients were declined admission, they were not simply forgotten or left behind; they nevertheless underwent careful assessment and follow‐up. Thus, depicting admission or refusal as a binary event is misleading. We suggest that prescriptive admission algorithms are problematic for clinicians, in that they may not take into account the complexity of clinical practice.
Sovereign Power, Biopower, and the Reach of the West in an Age of Diaspora‐Centred Development
Authors: Boyle Mark , Ho Elaine Lynn‐Ee
Published: October 2016

Why at this particular historical moment has there emerged a rousing interest in the potential contribution of diasporas to the development of migrant sending states and why is this diaspora turn so pervasive throughout the global South? The central premise of this paper is that the rapid ascent of diaspora‐centred development cannot be understood apart from historical developments in the West's approach to governing international spaces. Once predicated upon sovereign power, rule over distant others is increasingly coming to depend upon biopolitical projects which conspire to discipline and normalize the conduct of others at a distance so as to create self‐reliant and resilient market actors. We argue that an age of diaspora‐centred development has emerged as a consequence of this shift and is partly constitutive of it. We develop our argument with reference to Giorgio Agamben's “Homo Sacer” project and in particular the theological genealogy of Western political constructs he presents in his book The Kingdom and the Glory (2011). We provide for illustration profiles of three projects which have played a significant role in birthing and conditioning the current diaspora option: the World Bank's Knowledge for Development Programme (K4D); the US‐based International Diaspora Engagement Alliance (IdEA); and the EU/UN Joint Migration and Development Initiative Migration4Development project (JMDI‐M4D). Drawing upon economic theology, we make a case for construing these projects as elements of the West's emerging Oikonomia after the age of empire.
Towards an Energy Politics In‐Against‐and‐Beyond the State: Berlin's Struggle for Energy Democracy
Authors: Angel James
Published: October 2016

Social movements in struggle around energy are currently developing an imaginary of “energy democracy” to signify the emancipatory energy transitions they desire. Deploying a scholar‐activist perspective, this paper contributes to debates around the concretisation of the energy democracy imaginary by exploring the relationship of energy democracy movements to the state. To do so, I focus on the experiences of the Berliner Energietisch campaign, which in 2013 forced (and lost) a referendum aiming to extend—and democratise—the local state's role in Berlin's energy governance. Drawing on relational theories of the state, I argue that it is productive to read Berliner Energietisch as enacting an energy politics in‐against‐and‐beyond the state. In making this argument, I draw out implications for theoretical and strategic debates around the commons and the state.
Parents reported reduced symptoms and improved satisfaction after fundoplication and their perceptions were an important outcome measure
Authors: Heinrich Martina , Kain Alexandra , Bergmann Florian , von Schweinitz Dietrich
Published: October 2016

Aim

Fundoplication is required for children with chronic recurrent gastro‐oesophageal reflux disease (GERD). The aim of this study was to report parental perceptions of symptoms and overall satisfaction with the long‐term course following fundoplication with special reference to patients with GERD risk factors.

Methods

We studied 34 patients, with a median age of 6.5 ± 4.9 years, who received fundoplication between 2001 and 2005. Clinical information and surgical complications were recorded. Parents were interviewed to evaluate post‐operative symptoms, mode of nutrition and satisfaction.

Results

The median follow‐up time was 7.3 years. Comorbidities were neurological impairment in 15 patients, other gastrointestinal disorders in seven patients and isolated GERD in 12 patients. The parents reported that fundoplication effectively treated initial reflux symptoms in 60% and improved symptoms in 37%. Vomiting and reflux‐associated pain were treated most effectively. Pulmonary symptoms often remained unchanged in neurologically impaired children. Redo fundoplication was necessary in seven patients. Only two parents regretted consenting to surgery.

Conclusion

A high percentage of parents reported improved gastrointestinal reflux‐related symptoms and a high level of satisfaction following fundoplication. Parental perceptions of GERD symptoms should be an important outcome measure when assessing the efficacy of antireflux surgery in children in routine clinical follow‐up.
Comparison on the physico‐chemical and nutritional qualities of normal and abnormal colored fresh chicken liver
Authors: Xiong Guoyuan , Gao Xueqin , Zheng Haibo , Li Xin , Xu Xinglian , Zhou Guanghong
Published: October 2016

This study evaluated the differences of physico‐chemical and nutritional qualities between abnormal colored chicken livers (ANCCLs) and normal colored chicken livers (NCCLs) and the safety of the both livers. Compared with NCCLs, ANCCLs were lower in protein, water contents (P < 0.01), pH and pigment contents (P < 0.05). NCCLs contained higher polyunsaturated fatty acid (PUFA) and saturated fatty acids (SFA) (P < 0.05). The PUFA/SFA ratio of NCCLs was 0.453, higher (P < 0.05) than that of ANCCLs. The contents of alanine, valine, tyrosine, lysine and histidine in NCCLs were higher (P < 0.05) than in ANCCLs. The contents of K, Na, P, Cu, Fe and Se of NCCLs were higher (P < 0.05), but the Ca content was lower (P < 0.05). The content of the heavy metals (As, Hg, Pb and Cd) of the two types of livers complied with food safety requirements. Although NCCLs had higher nutritional value than ANCCLs, both livers were acceptable for human consumption.
Permanence of proliferating cells in developing, juvenile and adult knee epiphyses of lizards in relation to bone growth and regeneration
Authors: Alibardi Lorenzo
Published: October 2016

The distribution of long‐labelling‐retaining cells, putative progenitor or stem cells, in the developing knees of embryo, juvenile and adult lizards has been analysed using H3‐thymidine autoradiography and 5BrdU immunohistochemistry. Proliferating cells are present in developing cartilaginous femur and tibia, especially in the epiphyses where a higher cell multiplication likely determines their typical enlarged shape in comparison with the diaphyses where chondroblast proliferation is low to absent. Sparse 5BrdU‐labelled cells remain in the articular and growth plate cartilages of the epiphyses in older stages of development and are still detected in developing epiphyses 13 days after injection of 5BrdU. This indicates they are slow‐cycling cells, a typical characteristic for progenitor or stem cells. Long retaining 5BrdU‐labelled cells remain in the articular surface also during adult life where they likely sustain the growth of long bones. Adult epiphyses show secondary ossification centres where the articular cartilage is partially or largely replaced by bone trabeculae. The damage in the epiphysis of lizards stimulates the proliferation of progenitor cells for the regeneration of new cartilaginous epiphyses. The localization of cells capable of proliferation in the epiphyses of adult femur and tibia pre‐adapts these lizards to cartilage regeneration in case of injury.
The protective effect of the natural compound hesperetin against fulminant hepatitis in vivo and in vitro
Authors: Bai Xueting , Yang Peixuan , Zhou Qiaoling , Cai Bozhi , Buist‐Homan Manon , Cheng He , Jiang Jiyang , Shen Daifei , Li Lijun , Luo Xiajiong , Faber Klaas Nico , Moshage Han , Shi Ganggang
Published: October 2016

Background and Purpose

Liver diseases are mostly accompanied by inflammation and hepatocyte death. Therapeutic approaches targeting both hepatocyte injury and inflammation are not available. Natural compounds are considered as potential treatment for inflammatory liver diseases. Hesperetin, a flavonoid component of citrus fruits, has been reported to have anti‐inflammatory properties. The aim of this study was to evaluate the cytoprotective and anti‐inflammatory properties of hesperetin both in vitro and in models of fulminant hepatitis.

Experimental Approach

Apoptotic cell death and inflammation were induced in primary cultures of rat hepatocytes by bile acids and cytokine mixture respectively. Apoptosis was quantified by caspase‐3 activity and necrosis by LDH release. The concanavalin A (ConA) and D‐galactosamine/LPS (D‐GalN/LPS) were used as models of fulminant hepatitis. Liver injury was assessed by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver histology and TUNEL assay and inflammation by inducible NOS (iNOS) expression.

Key Results

Hesperetin blocked bile acid‐induced apoptosis and cytokine‐induced inflammation in rat hepatocytes. Moreover, hesperetin improved liver histology and protected against hepatocyte injury in ConA‐ and D‐GalN/LPS‐induced fulminant hepatitis, as assessed by TUNEL assay and serum AST and ALT levels. Hesperetin also reduced expression of the inflammatory marker iNOS and the expression and serum levels of TNFα and IFN‐γ, the main mediators of cell toxicity in fulminant hepatitis.

Conclusion and Implications

Hesperetin has anti‐inflammatory and cytoprotective actions in models of acute liver toxicity. Hesperetin therefore has therapeutic potential for the treatment of inflammatory liver diseases accompanied by extensive hepatocyte injury, such as fulminant hepatitis.
Impact of volcanism on the sedimentary record of the Neuquén rift basin, Argentina: towards a cause and effect model
Authors: D'Elia Leandro , Martí Joan , Muravchik Martín , Bilmes Andrés , Franzese Juan R.
Published: October 2016

The analysis of volcano‐sedimentary infill in sedimentary basins constitutes a challenge for basin analysis and hydrocarbon exploration worldwide. In order to understand the contribution of volcanism to the sedimentary record in rift basins, we study the Jurassic effusive‐explosive volcanic infill of an inverted extensional depocentre at the Neuquén Basin, Argentina. A cause and effect model that evaluates the relationship between volcanism and sedimentation was devised to develop a conceptual model for the tectono‐stratigraphic evolution of this volcanic rift basin. We show how the variations in the volcanism, coupled with the activity of extensional faults, determined the types of volcanic edifices (i.e., composite volcanoes, graben‐calderas, and lava fields). Volcanic edifices controlled the stacking patterns of the volcanic units as well as sedimentary systems. The landform of the volcanic edifices, as well as the styles and scales of the eruptions governed the sedimentary input to the basin, setting the main variables of the sedimentary systems, such as provenance, grain size, transport and deposition and geometry. As a result, the contrasting volcaniclastic input, from higher volcaniclastic input to lower volcaniclastic input, associated with different subsidence patterns, determined the high‐resolution syn‐rift infill patterns of the extensional depocentre. The cause and effect model presented in this study isolates the variables of the volcanic environments that control the sedimentary scenarios. We suggest that, by adjusting the first order input parameters of the model, these cause and effect scenarios could be adapted to similar rift basins, in order to establish predictive facies models with stratigraphic controls, and the impact of volcanism on their stratigraphic records.
Potential capacity of endoscopic screening for gastric cancer in Japan
Authors: Hamashima Chisato , Goto Rei
Published: October 2016

In 2016, the Japanese government decided to introduce endoscopic screening for gastric cancer as a national program. To provide endoscopic screening nationwide, we estimated the proportion of increase in the number of endoscopic examinations with the introduction of endoscopic screening, based on a national survey. The total number of endoscopic examinations has increased, particularly in clinics. Based on the national survey, the total number of participants in gastric cancer screening was 3 784 967. If 30% of the participants are switched from radiographic screening to endoscopic screening, approximately 1 million additional endoscopic examinations are needed. In Japan, the participation rates in gastric cancer screening and the number of hospitals and clinics offering upper gastrointestinal endoscopy vary among the 47 prefectures. If the participation rates are high and the numbers of hospitals and clinics are small, the proportion of increase becomes larger. Based on the same assumption, 50% of big cities can provide endoscopic screening with a 5% increase in the total number of endoscopic examinations. However, 16.7% of the medical districts are available for endoscopic screening within a 5% increase in the total number of endoscopic examinations. Despite the Japanese government's decision to introduce endoscopic screening for gastric cancer nationwide, its immediate introduction remains difficult because of insufficient medical resources in rural areas. This implies that endoscopic screening will be initially introduced to big cities. To promote endoscopic screening for gastric cancer nationwide, the disparity of medical resources must first be resolved.
Development of a screening tool enabling identification of infants and toddlers at risk of family abuse and neglect: a feasibility study from three South European countries
Authors: Ezpeleta L. , Pérez‐Robles R. , Fanti K. A. , Karveli V. , Katsimicha E. , Nikolaidis G. , Hadjicharalambous M. Z. , Hatzinikolaou K.
Published: October 2016

Background

Child abuse is a health and social problem, and few screening instruments are available for the detection of risk in primary health care. The aim was to develop a screening instrument to be used by professionals in the public health care sector, thus enabling the detection of infants and toddlers at risk of emotional and physical abuse and neglect, and to provide evidence for the feasibility of the instrument in Cyprus, Greece and Spain.

Method

A total of 50 health professionals from paediatric public health‐care centres in the three countries were involved in a three‐step process for guiding the development of the screening tool and its application.

Results

A nine‐item screening tool, consisting of items assessing relational emotional abuse, physical abuse and other risk factors, was developed. The screening tool was applied on a total of 219 families with 0 to 3‐year‐old children attending public health centres in the three countries. Clinicians reported that they agreed on the inclusion of the questions (86.4–100%) and that they found the questions to be useful for the clinical evaluation of the family (63.2–100%).

Conclusion

The screening tool shows considerable face validity and was reported feasible by an international set of clinicians.
Strengthening Causal Inference in Developmental Research
Authors: Miller Portia , Henry Daphne , Votruba‐Drzal Elizabeth
Published: October 2016

Demonstrating causal effects in developmental studies is important if results are to guide programs and policies that improve the lives of children and families. Yet, human development is complex and dynamic, and researchers are often limited to correlational data to answer their questions, which challenges the establishment of causal relations. In this article, we summarize potential threats to internal validity researchers encounter when analyzing correlational data and present several methods to strengthen internal validity. We suggest that developmental scientists consider using these methods in their studies to strengthen causal inferences and enhance the impact of their research.
Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels
Authors: Nguyen T , Johnston S , Clarke L , Smith P , Staines D , Marshall-Gradisnik S
Published: October 2016

Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dimCD16+NK cells and CD56brightCD16dim/– NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2-aminoethoxydiphenyl borate (2APB) and ionomycin. Unstimulated CD56brightCD16dim/– NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS-stimulated CD56brightCD16dim/–NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dimCD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux. Furthermore, TG-stimulated CD56dimCD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.
Cultural Ecosystem Services in Protected Areas: Understanding Bundles, Trade‐Offs, and Synergies
Authors: Ament Judith M. , Moore Christine A. , Herbst Marna , Cumming Graeme S.
Published: October 2016

The concept of ecosystem services (ES) provides a potentially useful tool for decision‐making in natural area management. Provisioning and regulating ES often occur in “bundles” that are cohesive because of coprovisioning or codependence. We asked whether individual preferences for cultural benefits also define service bundles. Data from a large survey of visitor preferences (n = 3,131 respondents) from all 19 South African National Parks indicated five bundles of cultural ecosystem services: (1) “natural history,” (2) “recreation,” (3) “sense of place,” (4) “safari experiences,” and (5) “outdoor lifestyle.” Trade‐offs and synergies between bundles of services depended on the ecosystem providing them and on alignment between demand for services and the supply of particular service bundles in specific ecosystems. Our results show that identifying demand for multiple services can both help us to understand why people visit and value protected areas, and better inform the management choices that influence service provision.
‘Hints’ in the horn: diagnostic clues in the stratum corneum
Authors: Cardoso José Carlos , Veraitch Ophelia , Gianotti Raffaele , Ferrara Gerardo , Tomasini Carlo F. , Singh Manuraj , Zalaudek Iris , Stefanato Catherine M.
Published: October 2016

The stratum corneum or horny layer is the uppermost layer of the epidermis, and is mainly responsible for the skin's barrier function. In spite of its complexity at the ultrastructural and molecular level, the features accessible to visualization on conventional histology are relatively limited. Nevertheless, knowledge of subtle clues that one may observe in the stratum corneum can prove useful in a wide range of situations in dermatopathology.

We herein review a selection of common and rare entities in which the horny layer may reveal significantly important hints for the diagnosis. These clues include parakeratosis and its different patterns (focal, confluent, alternating, associated with spongiosis, epidermal hyperplasia or lichenoid changes), subcorneal acantholysis, infectious organisms in the stratum corneum (including fungal, bacterial and parasitic), thickening or thinning of the stratum corneum and the presence of different kinds of pigment. Even when normal, the horny layer may prove to be useful when seen in association with severe epidermal damage, a combination of features testifying to the acute nature of the underlying pathological process.
A randomized clinical trial of basal insulin peglispro vs NPH in insulin‐naïve patients with type 2 diabetes: the IMAGINE 6 trial
Authors: Grunberger G. , Chen L. , Rodriguez A. , Tinahones F. J. , Jacober S. J. , Bue‐Valleskey J. ,   on behalf of the IMAGINE 6 Investigators
Published: October 2016

Aims

Basal insulin peglispro (BIL) has a longer duration of action than conventional insulin analogues and a hepato‐preferential mechanism of action. This study assessed whether BIL was non‐inferior to isophane insulin (NPH) in reducing HbA1c in insulin‐naïve patients with type 2 diabetes, when added to pre‐study oral anti‐hyperglycaemic medications.

Materials and methods

This was a Phase 3, open‐label, treat‐to‐target (TTT), randomized trial with a 2‐week lead‐in, 26‐week treatment and a 4‐week safety follow‐up period. Patients were randomized to bedtime (pm) NPH, morning (am) BIL or pm BIL in a 1:1:1 ratio.

Results

Six hundred and forty‐one patients [NPH, n = 213; BIL, n = 428 (am, n = 213; pm, n = 215)] received study drug. BIL was non‐inferior to NPH for HbA1c change from baseline at Week 26 with a between‐treatment difference (95% confidence interval) of −0.37% (−0.50, −0.23%). HbA1c at baseline was 8.5%, and was lower in BIL‐ vs NPH‐treated patients after 26 weeks of treatment (6.8% vs 7.1%; P < .001). More BIL‐treated patients achieved HbA1c <7.0% and HbA1c <7.0% without nocturnal hypoglycaemia. Fasting serum glucose levels and nocturnal hypoglycaemia rates were lower in BIL‐treated patients; total hypoglycaemia rates were similar. Treatment‐emergent adverse events were similar between groups. Fasting triglycerides decreased from baseline in both groups and to a greater extent with NPH, but were not significantly different between groups at Week 26. Mean alanine aminotransferase (ALT) increased with BIL treatment, but there was no evidence of acute severe hepatotoxicity.

Conclusions

In this TTT study, BIL treatment showed clinically relevant improvements in glycaemic control and a significant reduction in nocturnal hypoglycaemia compared to NPH.
Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes
Authors: Cusi K. , Sanyal A. J. , Zhang S. , Hoogwerf B. J. , Chang A. M. , Jacober S. J. , Bue‐Valleskey J. M. , Higdon A. N. , Bastyr E. J. , Haupt A. , Hartman M. L.
Published: October 2016

Aims

To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D).

Materials and Methods

Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin‐naïve T2D patients and 163 T2D patients previously treated with basal insulin.

Results

Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine‐treated patients at 4‐78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin‐naїve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL. In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01).

Conclusions

Compared to glargine, patients treated with BIL had higher ALT and LFC at 52‐78 weeks. No severe drug‐induced liver injury was apparent with BIL treatment for up to 78 weeks.
Reduced peripheral activity leading to hepato‐preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes
Authors: Mudaliar S. , Henry R. R. , Ciaraldi T. P. , Armstrong D. A. , Burke P. M. , Pettus J. H. , Garhyan P. , Choi S. L. , Knadler M. P. , Lam E. C. Q. , Prince M. J. , Bose N. , Porksen N. K. , Sinha V. P. , Linnebjerg H. , Jacober S. J.
Published: October 2016

Aims

Basal insulin peglispro (BIL), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine (GL) on endogenous glucose production (EGP), glucose disposal rate (GDR) and lipolysis in patients with type 1 diabetes.

Materials and Methods

This was a randomized, open‐label, four‐period, crossover study. Patients received intravenous infusions of BIL and GL, each at two dose levels selected for partial and maximal suppression of EGP, during an 8 to 10 h euglycemic clamp procedure with d‐[3‐3H] glucose.

Results

Following correction for equivalent human insulin concentrations (EHIC), low‐dose GL infusion resulted in similar EGP at the end of the clamp compared to low‐dose BIL infusion (GL/BIL ratio of 1.03) but a higher GDR (GL/BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL. Consistent with this, the EHIC‐corrected GDR/EGP at the end of the clamp was 1.72‐fold greater for GL than BIL following low‐dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp.

Conclusions

Compared with GL, BIL restored the hepato‐peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.
A meta‐analysis comparing clinical effects of short‐ or long‐acting GLP‐1 receptor agonists versus insulin treatment from head‐to‐head studies in type 2 diabetic patients
Authors: Abd El Aziz Mirna S. , Kahle Melanie , Meier Juris J. , Nauck Michael A.
Published: October 2016

Aims

To study differences in clinical outcomes between initiating glucagon‐like peptide‐1 receptor agonist (GLP‐1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose‐lowering medications (OGLM).

Methods

Prospective, randomized trials comparing GLP‐1 RA and insulin treatment head‐to‐head as add‐on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared.

Results

Of 712 publications identified, 23 describing 19 clinical trials were included in the meta‐analysis. Compared to insulin, GLP‐1 RAs reduced HbA1c more effectively (Δ −.12%,
P
< .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ −1.8 mmol/L,
P
< .0001). GLP‐1 RAs reduced bodyweight more effectively (Δ −3.71 kg;
P
< .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP‐1 RAs (
P
< .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP‐1 RAs (
P
< .0001). Triglycerides and LDL cholesterol were significantly lower with GLP‐1 RAs. Long‐acting GLP‐1 RAs were better than short‐acting GLP‐1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight.

Conclusions

Slightly better glycaemic control can be achieved by adding GLP‐1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP‐1 RAs.
From Schism to Synthesis: The Off‐Centre Radical‐Reformist Role of Development Management
Authors: Ramizo Godofredo
Published: October 2016

In a wide range of issues such as aid effectiveness, poverty reduction and planning, development management has witnessed a schism between reformists and radicals. This article traces the ‘schism’ between reformist and radical views, critiques their unnecessary dichotomization and proposes an epistemologically‐grounded metaphor for managing divergent ideas. Moving beyond the schism, the article examines current conceptions from Gulrajani that the synthesis should be at the ‘centre’ of the spectrum between radical and reformist frames. The article then proposes an ‘off‐centre’ radical‐reformist synthesis with a less apologetic acceptance of reformist or ‘managerialist’ approaches.
Who Contributes to the Provision of Public Goods at the Community Level? The Case of Potable Water in Ghana
Authors: Useche Pilar
Published: October 2016

This article offers an analytical framework to explain participation in the provision of drinking water in communities in Ghana along with empirical evidence of the individual factors that influence this provision. Framed in the context of the debate about the devolution of responsibilities from the government to the users of public goods to increase management efficiency and sustainability, the study analyzes how individuals respond to potable water participation activities. Distinguishing activities by the type of participation incentives they offer, the study finds that social exclusion is more likely in activities that lack effort complementarities and which have larger impacts on output allocation. Appropriation of social benefits is found to determine participation more strongly than the appropriation of the natural resource itself.
Observational research rigour alone does not justify causal inference
Authors: Ejima Keisuke , Li Peng , Smith Daniel L. , Nagy Tim R. , Kadish Inga , van Groen Thomas , Dawson John A. , Yang Yongbin , Patki Amit , Allison David B.
Published: October 2016

Background

Differing opinions exist on whether associations obtained in observational studies can be reliable indicators of a causal effect if the observational study is sufficiently well controlled and executed.

Materials and methods

To test this, we conducted two animal observational studies that were rigorously controlled and executed beyond what is achieved in studies of humans. In study 1, we randomized 332 genetically identical C57BL/6J mice into three diet groups with differing food energy allotments and recorded individual self‐selected daily energy intake and lifespan. In study 2, 60 male mice (CD1) were paired and divided into two groups for a 2‐week feeding regimen. We evaluated the association between weight gain and food consumption. Within each pair, one animal was randomly assigned to an S group in which the animals had free access to food. The second paired animal (R group) was provided exactly the same diet that their S partner ate the day before.

Results

In study 1, across all three groups, we found a significant negative effect of energy intake on lifespan. However, we found a positive association between food intake and lifespan among the ad libitum feeding group: 29·99 (95% CI: 8·2–51·7) days per daily kcal. In study 2, we found a significant (P = 0·003) group (randomized vs. self‐selected)‐by‐food consumption interaction effect on weight gain.

Conclusion

At least in nutrition research, associations derived from observational studies may not be reliable indicators of causal effects, even with the most rigorous study designs achievable.
First‐episode psychosis: Ongoing mental health service utilization during the stable period for adolescents
Authors: Gearing Robin E. , Brewer Kathryne B. , Mian Irfan , Moore Kiara , Fisher Prudence , Hamilton Jane , Mandiberg James
Published: October 2016

Aim

The timely identification and treatment of psychosis are increasingly the focus of early interventions, with research targeting the initial high‐risk period in the months following first‐episode hospitalization. Ongoing treatment after stabilization is also essential in the years following a first‐episode psychosis (FEP), but has received less research attention. In this study, variables that could impact continued psychiatric service utilization by adolescents following their FEP and temporal patterns in service utilization are examined.

Methods

Families of 52 adolescents (aged 14.4 ± 2.5 years) discharged following a hospitalization for FEP were contacted two or more years following the adolescents’ discharge. A chart review (Time 1) of hospital records provided clinical data on each adolescent's psychiatric diagnosis, symptoms, illness course, medications and family history. Follow‐up (Time 2) data were collected from parents/caregivers using a questionnaire enquiring about post‐discharge treatment history and service utilization.

Results

Bivariate analyses were conducted to identify Time 1 variables associated with psychiatric service utilization at Time 2. Significant variables were included in a logistic regression model and three variables were independently associated with continued service utilization: having a primary diagnosis of schizophrenia (odds ratio (OR) = 24.0; P = 0.02), not having a first‐degree relative with depression (OR = 0.12; P = 0.05) and fewer months since the last inpatient discharge (OR = 0.92; P = 0.02).

Conclusions

Findings suggest: (1) the importance of early diagnosis, (2) that a relative with depression may negatively influence the adolescent's ongoing service utilization, and (3) that 18 months post‐discharge may be a critical time to review treatment strategies and collaborate with youth and families to ensure appropriateness of services.
Predictors of functioning in people suffering from first‐episode psychosis 1 year into entering early intervention service in Hong Kong
Authors: Chong Catherine Shiu‐yin , Siu Man‐Wah , Kwan Condy Hoi‐shuen , Chang Wing‐Chung , Lee Edwin Ho‐ming , Chan Sherry Kit‐wa , Hui Christy Lai‐ming , Tam Fiona Yee‐ki , Chen Eric Yu‐hai , Lo William Tak‐lam
Published: October 2016

Aim

To explore the changes of functioning in people suffering from first‐episode psychosis throughout their first year into an early intervention service, and the baseline predictors of their functioning levels at baseline, 6 and 12 months

Method

Consecutive subjects presenting to an early intervention service were recruited from 1 February 2013 to 31 May 2015. Information on their socio‐demographic status was collected. Structured instruments were used to assess their premorbid functioning, duration of untreated psychosis, psychopathology and insight at baseline. Psychosocial functioning was assessed by Social Occupational Functioning Assessment Scale (SOFAS) and Role Functioning Scale at baseline, 6 and 12 months.

Results

A total of 269 subjects were recruited. The mean baseline scores for SOFAS were 53.1 (standard deviation = 13.6) and 21.5 (standard deviation = 4.0), respectively. Positive and negative psychopathology, insight and mode of onset were significant factors associated with baseline functioning. Functioning by both instruments showed significant improvement after 6 months, and the gains were maintained at 12 months. For SOFAS, baseline insight (P = 0.008), education attainment (P = 0.016) and its own baseline score (P = 0.024) were predictive at 6 months, while for 12 months, only education attainment was predictive (P = 0.008). For Role Functioning Scale, its baseline score (P = 0.034) was predictive at 6 months, while at 12 months, only female gender predicted better role functioning.

Conclusion

Factors predictive of functioning levels at the three time points were different. Phase‐specific intervention should be offered to enhance functional recovery of people with first‐episode psychosis.
Complex Education Systems: from steering change to governance
Authors: Michel Alain
Published: October 2016

The theories and approaches of steering/monitoring a process of change within education systems have evolved over the last 20 years or so as a result of many factors such as globalisation and decentralisation, a faster pace of change, increasing expectations and demands from various stakeholders (parents, employers, teacher unions, etc.) and the growing influence of OECD and of the EU in the field of education because of some more or less explicit standards and policy recommendations. All these evolutions contributed to increase the complexity of the education systems and of the instruments and procedures required to establish some coherence between the initiatives of a large number of more autonomous stakeholders. Our main objective here is to describe how the previous notions and concepts used in analysing the conditions for steering education systems have been gradually integrated within a larger paradigm: the ‘governance of multi‐level complex education systems’.
Encoding of global visual motion in the nidopallium caudolaterale of behaving crows
Authors: Wagener Lysann , Nieder Andreas
Published: October 2016

Songbirds possess acute vision. How higher brain centres represent basic and parameterised visual stimuli to process sensory signals according to their behavioural importance has not been studied in a systematic way. We therefore examined how carrion crows (Corvus corone) and their nidopallial visual neurons process global visual motion information in dynamic random‐dot displays during a delayed match‐to‐sample (DMS) task. The behavioural data show that moderately fast motion speeds (16° of visual angle/s) result in superior direction discrimination performance. To characterise how neurons encode and maintain task‐relevant visual motion information, we recorded the single‐unit activity in the telencephalic association area ‘nidopallium caudolaterale’ (NCL) of behaving crows. The NCL is considered to be the avian analogue of the mammalian prefrontal cortex. Almost a third (28%) of randomly selected NCL neurons responded selectively to the motion direction of the sample stimulus, mostly to downward motions. Only few NCL neurons (7.5%) responded consistently to specific motion directions during the delay period. In error trials, when the crows chose the wrong motion direction, the encoding of motion direction was significantly reduced. This indicates that sensory representations of NCL neurons are relevant to the birds’ behaviour. These data suggest that the corvid NCL, even though operating at the apex of the telencephalic processing hierarchy, constitutes a telencephalic site for global motion integration.
If Reason is ‘in the World’, Where Exactly is it Located?
Authors: Redding Paul
Published: October 2016

In his recent book James Kreines argues that for Hegel reason is “in the world”, but how we are to understand the idea of reason's being so located? One answer, suggested by more traditional theocentric readings of Hegel, would be to appeal to the idea of a divine thought, coursing through the world. Another answer, more congenial to modern sensibilities, might locate reason within the rational activities of inter‐subjectively connected human beings, as suggested by Terry Pinkard's idea of the “sociality of reason”. Kreines seems to want to avoid suggestions of the former, but in distancing himself from approaches like the latter, he also seems to refuse the more metaphysically modest alternative. In retracing the contours of Kreines's nuanced attempt to reinflate Hegel's metaphysics as a “metaphysics of reason”, I pose the question as to whether he can avoid reintroducing a more extravagantly metaphysical Hegel than he wishes.